STANDAR 7
PENELITIAN, PELAYANAN/PENGABDIAN KEPADA MASYARAKAT, DAN KERJASAMA
7.1 Agenda, judul, dan jaringan penelitian dosen di RS Pendidikan
Tuliskan agenda dan judul penelitian dosen di RS Pendidikan mengikuti format tabel berikut.
Agenda
No. Nama Dosen
Penelitian
(1) (2) (3)
Prof. dr. A Jayalangkara
1 2020
Tanra, Ph.D, Sp.KJ (K)
Prof. dr. A Jayalangkara
2 2020
Tanra, Ph.D, Sp.KJ (K)
Prof. dr. A Jayalangkara
3 2020
Tanra, Ph.D, Sp.KJ (K)
Prof. dr. A Jayalangkara
4 2020
Tanra, Ph.D, Sp.KJ (K)
Prof. dr. A Jayalangkara
5 2020
Tanra, Ph.D, Sp.KJ (K)
Prof. dr. A Jayalangkara
6 2020
Tanra, Ph.D, Sp.KJ (K)
Prof. dr. A Jayalangkara
7 2019
Tanra, Ph.D, Sp.KJ (K)
Prof. dr. A Jayalangkara
8 2019
Tanra, Ph.D, Sp.KJ (K)
Keterlibatan dengan
Judul Penelitian
Jaringan Penelitian*
(4) (5)
Department of Psychiatry,
Inje University Haeundae
QT interval prolongation noted in Paik Hospital, Busan,
one percent of 2553 Asian patients Republic of Korea
with schizophrenia: Findings from
the REAP‐AP survey
Relationship Between Body Mass Department of Psychiatry,
Index And Extrapyramidal Inje University Haeundae
Symptoms in Asian Patients With Paik Hospital, Busan,
Republic of Korea
Schizophrenia : The Research on
Asian Psychotropic Prescription
Patterns For Antyipsychotics
(REAP-AD)
Network analysis of the depressive Department of Psychiatry,
symptom profiles in Asian patients Inje University Haeundae
with depressive disorders: Findings Paik Hospital, Busan,
Republic of Korea
from the Research on Asian
Psychotropic Prescription Patterns
for Antidepressants (REAP-AD)
Patterns of long acting injectable Institute of Mental Health,
antipsychotic use and associated Buangkok Green Medical
clinical factors in schizophrenia
Park, Singapore
among 15 Asian countries and
region
Dyskinesia is most centrally situated
in an estimated network of Department of Psychiatry,
extrapyramidal syndrome in Asian Inje University Haeundae
patients with schizophrenia: findings Paik Hospital, Busan,
Republic of Korea
from research on Asian psychotropic
prescription patterns for
Antipsychotic
s
Coprescription of mood stabilizers Institute of Mental Health,
in schizophrenia, dosing, and Buangkok Green Medical
Park, Singapore
clinical correlates: An international
study
The Side Effect of Haloperidol in Halal Center, Hasanuddin
Schizophrenic Patients: Analysis of University, Indonesia
Red Blood Cell Distribution Width Public Health, Mandala
Waluya College, Indonesia
(RDW) and Mean Platelet Volume
(MPV) Values
Electroconvulsive shock restores
the decreased coverage of brain
blood vessels by astrocytic endfeet Department of Psychiatry,
and ameliorates depressive-like Shimane University
behavior
 Concurrent antipsychotic use in
Prof. dr. A Jayalangkara older adults treated with
9 2019 antidepressants in Asia
Tanra, Ph.D, Sp.KJ (K)
Cannabis use correlates with
Prof. dr. A Jayalangkara aggressive behavior and long-acting
10 2019
Tanra, Ph.D, Sp.KJ (K) injectable antipsychotic treatment in
Asian patients with schizophrenia
Establishing the cut-off scores for
Prof. dr. A Jayalangkara
the severity ranges of schizophrenia
11 2019
Tanra, Ph.D, Sp.KJ (K) on the BPRS-6 scale: findings from
the REAP-AP
Predicting Symptomatic and
Prof. dr. A Jayalangkara Functional Improvements over 1
12 2019 Year in Patients with First-Episode
Tanra, Ph.D, Sp.KJ (K)
Psychosis Using Resting-State
Electroencephalography
The Side Effect of Haloperidol in
Schizophrenic Patients: Analysis of
Dr. dr. Sonny Teddy Lisal, Red Blood Cell Distribution Width
13 2019
Sp.KJ (RDW) and Mean Platelet Volume
(MPV) Values
The Side Effect of Haloperidol in
Schizophrenic Patients: Analysis of
Dr. dr. Saidah Syamsuddin, Red Blood Cell Distribution Width
14 2019 (RDW) and Mean Platelet Volume
Sp.KJ
(MPV) Values
Electroconvulsive shock restores
the decreased coverage of brain
dr. Erlyn Limoa, Ph.D,
15 2019 blood vessels by astrocytic endfeet
Sp.KJ
and ameliorates depressive-like
behavior
The Side Effect of Haloperidol in
Schizophrenic Patients: Analysis of
16 dr. Hawaidah, Sp.KJ (K) 2019 Red Blood Cell Distribution Width
(RDW) and Mean Platelet Volume
(MPV) Values
Predicting Symptomatic and
dr.Rinvil Renaldi, Sp.KJ Functional Improvements over 1
17 2019 Year in Patients with First-Episode
(K) A&R
Psychosis Using Resting-State
Electroencephalography
Physical comorbidities in older
Prof. dr. A. Jayalangkara adults receiving antidepressants in
18 2018
Tanra, Ph.D, Sp.KJ Asia
Psychotropic drug-prescribing
Prof. dr. A. Jayalangkara correlates of disorganized speech in
19 2018 Asians with schizophrenia: The
Tanra, Ph.D, Sp.KJ
REAP-AP study
Unit of Psychiatry, Faculty
of Health Sciences,
University of Macau,
Macao SAR
Department of Psychiatry,
Inje University Haeundae
Paik Hospital, Busan,
Republic of Korea
Department of Psychiatry,
Hanyang University Guri
Hospital, Gyeongchunro,
Guri, Gyeonggi, Republic
of Korea
Department of
Neuropsychiatry, Seoul
National University
Hospital, Seoul, Republic
of Korea
Halal Center, Hasanuddin
University, Indonesia
Public Health, Mandala
Waluya College, Indonesia
Halal Center, Hasanuddin
University, Indonesia
Public Health, Mandala
Waluya College, Indonesia
Department of Psychiatry,
Shimane University
Halal Center, Hasanuddin
University, Indonesia
Public Health, Mandala
Waluya College, Indonesia
Department of
Neuropsychiatry, Seoul
National University
Hospital, Seoul, Republic
of Korea
Department of Neurology,
The Affiliated Brain
Hospital of Guangzhou
Medical University
(Guangzhou Hui Hospital),
Guangzhou,
Department of Psychiatry,
Inje University College of
Medicine and Haeundae
Paik Hospital
 Gunn rats with glial activation in
the hippocampus show prolonged -Department of Psychiatry,
dr. Erlyn Limoa, Ph.D, immobility time in the forced Shimane University,
20 2018
Sp.KJ swimming test and tail suspension Izumo, Japan
test

Gunn rats with glial activation in

the hippocampus show prolonged -Department of Psychiatry,
dr. Kristian Liaury, immobility time in the forced Shimane University,
21 2018
Ph.D,Sp.KJ swimming test and tail suspension Izumo, Japan
test

• Contoh penelitian dengan jaringan internasional: penelitian bidang dalam bentuk multi national study. Contoh
penelitian dengan jaringan nasional: penelitian yang bekerjasama dengan lembaga penelitian nasional (LIPI, BPPT,
Litbangkes dll)

1.1. Penelitian Dosen di RS Pendidikan yang Bidang Keahliannya Sesuai dengan PS

No Nama Dosen Bidang Agenda Judul Penelitian Sesuai/ Tidak

Keahlian Penelitian sesuai Bidang
keahlian
1. 2. 3. 5.
1. QT interval prolongation noted
in one percent of 2553 Asian Sesuai
2020
patients with schizophrenia:
Findings from the REAP‐AP
survey
2. Relationship between body
2020 Sesuai
mass index and extrapyramidal
symptomps in ASIAN Patients
with schizophrenia : the
research on ASIAN
Psychotropic prescription
Prof. dr. A Jayalangkara Psikiatri patterns for antipsychotics
1
Tanra, Ph.D, Sp.KJ (K) Biologi (REAP-AP)
2020 3. Network analysis of the Sesuai

depressive symptom profiles in

Asian patients with depressive
disorders: Findings from the
Research on Asian Psychotropic
Prescription Patterns for
Antidepressants (REAP-AD)
Sesuai
2020 4. Patterns of long acting
injectable antipsychotic use and
associated clinical factors in
schizophrenia
 among 15 Asian countries and
2020 region Sesuai

5. Dyskinesia is most centrally

situated in an estimated network
of extrapyramidal syndrome in
Asian patients with
schizophrenia: findings from
research on Asian psychotropic
prescription patterns for

2020 antipsychotics
Sesuai
6. Coprescription of mood
stabilizers in schizophrenia,
dosing, and clinical correlates:
An international study
Concurrent antipsychotic use in
older adults treated with
2019 antidepressants in Asia
7. Socio-economic-demographic Ssesuai

determinants of depression in
Indonesia: A hospital-based
2019 study
8. Cannabis use correlates with
Sesuai
aggressive behavior and long-
acting injectable antipsychotic
treatment in Asian patients with
schizophrenia
2019
9. Establishing the cut-off scores
Sesuai
for the severity ranges of
schizophrenia on the BPRS-6
scale: findings from the REAP-
AP

1. Nutrition, Mental Status and Sesuai

Level of 8-hydroxy2-
2018 deoxyguanosine (OHdG) Urine
dr. Erlyn Limoa, Ph.D,
2. as Predictors of Premenstrual
Sp.KJ
Syndrome (PMS) in Adolescent
Girls

1. Socio-economic-demographic Sesuai
dr. Kristian Liaury, Ph.D, determinants of depression in
3 2020
Sp.KJ Indonesia: A hospital-based
study
 7.2.1 Tuliskan judul artikel ilmiah/karya ilmiah/buku yang dipublikasikan selama tiga tahun terakhir oleh dosen di RS Pendidikan
PS dengan mengikuti format tabel berikut.
Tahun Tingkat*
Dihasilkan/ Penyajia
Interna-
No. Judul Nama-nama Dosen Dipublikasi n/ Nasio
Lokal sional
kan pada Publikas Nal
i
(1) (2) (3) (4) (5) (6) (7) (8)
QT interval prolongation noted
in one percent of 2553 Asian
Prof. dr. A
1. patients with schizophrenia: Jayalangkara Tanra, 2020
√
Findings from the REAP‐AP Ph.D, Sp.KJ (K)
survey
Relationship between body
mass index and extrapyramidal
symptomps in ASIAN Patients
with the Prof. dr. A
schizophrenia :
2 Jayalangkara Tanra, 2020
research on ASIAN √
Ph.D, Sp.KJ (K)
Psychotropic prescription
patterns for antipsychotics
(REAP-AP)
Network analysis of the
depressive symptom profiles in
Asian patients with depressive
disorders: Findings from the Prof. dr. A
3 Jayalangkara Tanra, 2020
Research on Asian √
Ph.D, Sp.KJ (K)
Psychotropic Prescription
Patterns for Antidepressants
(REAP-AD)
Patterns of long acting
injectable antipsychotic use
Prof. dr. A
4 and associated clinical factors Jayalangkara Tanra, 2020
√
in schizophrenia among 15 Ph.D, Sp.KJ (K)
Asian countries and region
Dyskinesia is most centrally
situated in an estimated
network of extrapyramidal
syndrome in Asian patients Prof. dr. A
5 Jayalangkara Tanra, 2020
with schizophrenia: findings √
Ph.D, Sp.KJ (K)
from research on Asian
psychotropic prescription
patterns for antipsychotics
Coprescription of mood Prof. dr. A
6 Jayalangkara Tanra, 2020
stabilizers in schizophrenia, √
Ph.D, Sp.KJ (K)
 dosing, and clinical correlates:
An international study
Effect of Non-Computerized
Cognitive Remediation and Dr. dr. Saidah
Syamsuddin, Sp.KJ
7 Risperidone to Improve 2020
√
Disability Function in Dr. dr. Sonny T
Lisal, Sp.KJ
Schizophrenia
The Effect of Olanzapine on
Dr. dr. Saidah
the Improvement of the Syamsuddin, Sp.KJ
8 2020 √
Clinical Symptom of
Dr. dr. Sonny T
Schizophrenia Lisal, Sp.KJ
Comparison Between
Combination Of Risperidone
dr. Erlyn Limoa,
And Haloperidol Therapy With Sp.KJ, Ph.D
Combination Of Risperidone
9 Dr. dr. Saidah 2020 √
And Chlorpromazine Therapy Syamsuddin, Sp.KJ
On Clinical Symptom
Dr. dr. Sonny T
Improvement Of Lisal, Sp.KJ
Schizophrenia
Pengaruh allopurinol sebagai
adjuvan terhadap perbaikan
Prof. dr. A
10 gejala klinis pasien skizofrenia Jayalangkara Tanra, 2020 √
yang mendapatkan antipsikotik Ph.D, Sp.KJ (K)
atipikal
Pengaruh adjuvan vitamin d3
pada fungsi kognitif pasien
Dr. dr. Sonny T
11 2020 √
skizofrenia yang mendapat Lisal, Sp.KJ
terapi antipsikotik atipikal
Pengaruh Adjuvan Vitamin C
pada Gejala Klinis Pasien
12 Dr. dr. H. M Faisal 2020 √
Skizofrenia yang Mendapat Idrus, Sp.KJ (K)
Terapi Antipsikotik Tipikal
Perbaikan fungsi kognitif pada
pasien skizofrenia yang
13 mendapat terapi antipsikotik Dr. dr. Saidah 2020 √
Syamsuddin, Sp.KJ
atipikal dengan ajuvan omega-
3
Pengaruh Pemberian Probiotik
Sebagai Terapi Adjuvan
14 dr. Hawaidah, 2020 √
Terhadap Perbaikan Gejala Sp.KJ(K)
Klinis Depresi
 Pengaruh Pemberian Kapsul
Curcumin Sebagai Terapi
Adjuvan Terhadap Perbaikan
15 dr. Erlyn Limoa, 2020 √
Gejala Pada Pasien Depresi Sp.KJ, Ph.D
yang Mendapat Terapi
Antidepresan SSRI
N-Acetylcycsteine as Adjuvant Dr. dr. Saidah 2019
Therapy In The Improvement Syamsuddin, Sp.KJ
16 √
of Depressive Symptoms

Comparison of Clonazepam Dr. dr. Sonny T 2019

and Trihexyphenidil As The Lisal, Sp.KJ
17 Treatment For Extrapyramidal √
Symptoms Induced by
Haloperidol
N--Acetylcycsteine as Dr. dr. Saidah 2019
Adjuvant Therapy In The Syamsuddin, Sp.KJ
18 √
Improvement Of
Schizophrenia
The Efficacy of Vitamin D3 Dr. dr. Sonny T 2019
As Adjuvant Therapy In The Lisal, Sp.KJ
19 √
Improvement of Depressive
Symptoms
The Effect of Benzodiazepine dr. Erlyn 2019
Limoa,Ph.D,Sp.KJ
in Combination of Haloperidol
20 √
to Schizophrenic Patient with
Agitation
Risperidone and Olanzapine Dr. dr. H. M Faisal 2019
Idrus, Sp.KJ (K)
Comparison on Cognitive

21 Function and Aggresivity √

Improvement of Schizophrenic
Patients
Sistemic Lupus Eritematosus Dr. dr. Sonny T 2019
Comorbid Suspect Neuroleptic Lisal, Sp.KJ
22 √
Malignant Syndrome

Amitriptilyne and FLuoxetine dr. A. Suheyra 2019

Comparison on Peripheral Syauki, M.Kes,
23 Total Blood CHolesterol Sp.KJ
√
Levels of Major Depressive
Disorder Patients
Abnormalities in Glucose Dr.dr.H.M.Faisal 2019
Blood Level During Idrus,Sp.KJ (K)
Antipsychotic Treatment in
Schizophrenia Patients dr.Theodorus
Singara, Sp.KJ (K)
24
Dr.dr.Saidah √
Syamsuddin1, Sp.KJ,

Dr.dr.Sonny T. Lisal,
Sp.KJ
Salivary Alpha Amylase Prof.dr.Andi 2019
25 Jayalangkara
Enzyme and Salivary Cortisol √
 Level in Depression after Tanra,Ph.D,Sp.KJ
Treatment with Fluoxetine (K)

Dr.Hawaidah,Sp.KJ
(K)

Dr.dr.Saidah
Syamsuddin,Sp.KJ

Dr.dr.Sonny Teddy
Lisal, Sp.KJ
Potential Link between T102C Dr.dr.H.M.Faisal
Polymorphism in the Serotonin Idrus,Sp.KJ (K)
Receptors (5-HT2A) Gene and
Dr.dr.Saidah
26 Treatment Response of Syamsuddin.Sp.KJ, 2019 √

Risperidone on Schizophrenia
Dr.dr.Sonny T. Lisal,
Sp.KJ
Differentiation in Neurological dr.Wempy
Thioritz,Sp.KJ (K),
Soft Sign Scores on
Schizophrenic Patients With dr. Erlyn Limoa,
Antipsychotic Treatment Ph.D,Sp.KJ,
27 2019 √
Dr.dr.Saidah
Syamsuddin,Sp.KJ,

Dr.dr.Sonny Teddy
Lisal, Sp.KJ
Comparison Of BDNF Dr.dr.Sonny Teddy
Lisal,Sp.KJ.
(BRAIN-DERIVED
NEUROTROPHIC FACTOR) Prof.dr.Nur Aeni.
M.A.
28 Level In Depressed Patients 2019 √
Fattah,Sp.KJ(K),
Given Fluoxetine And
Sertraline
Dr.dr.Saidah
Syamsuddin, Sp.KJ.
Pengaruh Cognitive Dr.dr.Sonny Teddy
Behavioral Therapy (CBT) Lisal, Sp.KJ,
Terhadap Tingkat Gejala
29 2019 √
Depresi dan Risiko Bunuh Diri
pada Pasien skizofrenia Rawat
Jalan
Pengaruh Terapi RealitasDr.dr.Saidah
Terhadap Perbaikan Stigma Syamsuddin,Sp.KJ,
31 2019 √
Diri Dan Risiko Bunuh Diri
Pada Pasien AIDS
Perbandingan Kadar Dr.dr.H.M.Faisal
Kolesterol Total Mahasiswa Idrus,Sp.KJ (K),
32 2019 √
Fakultas Kedokteran Yang
 Mengalami Depresi Dan Ide
Bunuh Diri
Pengaruh Cognitive
dr.A. Suheyra
Behavioral Therapy (CBT) Syauki,
M.Kes.Sp.KJ
Terhadap Tingkat Derajat

33 Depresi dan Risiko Bunuh Diri 2019 √

pada Pasien Tuberculosis
Multi Drug Resistant (TB-
MDR)
Pengaruh Terapi Realitas
Dr.dr.Saidah
Terhadap Perbaikan Tingkat Syamsuddin,Sp.KJ,
Gejala Depresi Pada
34 2019 √
Masyarakat Daerah Bencana
Paska Longsor Di Kabupaten
Gowa Tahun 2019
Hubungan HDRS Dengan Dr.dr.Sonny Teddy
Adiksi Smartphone Pada Lisal, Sp.KJ,

35 Mahasiswa Program 2019 √

Pendidikan Dokter (MPPD)
RS.Wahidin Sudirohusodo
Efektivitas Cognitive Behavior
dr. Erlyn Limoa, 2019
Therapy (CBT) Pada Pasien Ph.D,Sp.KJ
36 √
Depresi Dengan Risiko Bunuh
Diri
Gangguan Afektif Bipolar
Prof.dr.Andi 2019
Jayalangkara
Komorbid Dengan Gangguan
Tanra,Ph.D,Sp.KJ
Kepribadian Ambang (K)

37 (Borderline Personality √
dr.Rinvil
Disorder) Fokus Pada Renaldi,M.Kes.,Sp.
Tatalaksana: Self Harm Dan KJ (K) A&R
Gangguan Impuls Seksual
Profil Sosiodemografik Dr. dr. Saidah 2019
Mahasiswa Program Profesi Syamsuddin, Sp.KJ
Dokter Spesialis Fakultas
38 √
Kedokteran Unhas Terhadap
Burnout Syndrome Dan
Distress Psikologis
Efikasi Terapi Holtikultura
dr.A. Suheyra 2019
Terhadap Perbaikan Gejala Syauki,
39 M.Kes.Sp.KJ √
Klinis Dan Kualtias Hidup
Pasien Skizofrenia
 The Effectiveness of the Dr. dr. H. M Faisal 2019
Idrus, Sp.KJ(K)
Combination Therapy of
Risperidone, Group dr. Erlyn Limoa,
Sp.KJ, Ph.D
Psychotherapy and
40 √
Occupational Therapy
on Dr. dr. Saidah
Syamsuddin, Sp.KJ
Cognitive Functions and the
Quality of Life of Dr. dr. Sonny T
Schizophrenia Patients Lisal, Sp.KJ

The Side Effect of Haloperidol Prof. dr. A. 2019

in Schizophrenic Patients: Jayalangkara Tanra
Analysis of Red Blood Cell Ph.D, Sp.KJ (K)
Distribution Width (RDW) and
Mean Platelet Volume (MPV) dr. Hawaidah, Sp.KJ
Values (K)
41 √
Dr. dr. Saidah
Syamsuddin, Sp.KJ

Dr. dr. Sonny T

Lisal, Sp.KJ
Predicting Symptomatic and Dr. dr. Rinvil 2019
Functional Improvements over Renaldi, M.Kes,
Sp.KJ (K) A&R,
1 Year in Patients with First-
42 √
Episode Psychosis Using Prof. dr. A.
Resting-State Jayalangkara Tanra
Ph.D, Sp.KJ (K),
Electroencephalography
Electroconvulsive shock dr. Erlyn Limoa, 2019
restores the decreased Ph.D, Sp.KJ, Prof.
coverage of brain blood vessels dr. A. Jayalangkara
43 by astrocytic endfeet and √
ameliorates depressive-like Tanra, Ph.D, Sp.KJ
behavior (K),

Concurrent antipsychotic use Prof. dr. A. 2019

Jayalangkara Tanra,
44 in older adults treated with √
Ph.D, Sp.KJ (K)
antidepressants in Asia
Cannabis use correlates with Prof. dr. A. 2019
Jayalangkara Tanra,
aggressive behavior and long- Ph.D, Sp.KJ (K)
45 acting injectable antipsychotic √
treatment in Asian patients
with schizophrenia
The Polymorphisms of DRD2 Dr. dr. Saidah 2019
Syamsuddin, Sp.KJ
141-C Ins/Del Receptor

46 Influenced the
Treatment Prof. dr. A. √
Jayalangkara Tanra,
Responses of Schizophrenia
Ph.D, Sp.KJ (K)
Patients.
Polymorphisms of Dopamine Dr. dr. Saidah 2019
Syamsuddin, Sp.KJ
47 D2 Receptor (DRD2) and √
Dopamine Transporterr (DAT)
 Geneon Response Therapy of dr. Erlyn Limoa,
Ph.D,Sp.KJ
Schizophrenia Patients
Dr. dr. Sonny T.
Lisal, Sp.KJ

Prof. dr. A.
Jayalangkara Tanra,
Ph.D, Sp.KJ (K)

Establishing the cut-off scores

Prof. dr. A. 2019
Jayalangkara Tanra,
for the severity ranges of
Ph.D, Sp.KJ (K)
48 schizophrenia on the BPRS-6 √
scale: findings from the REAP-
AP
The Efectivity Of Giving Folic dr. Erlyn 2018
On Improvement of Limoa,Ph.D,Sp.KJ
Depression Symstoms In

49 Epilepsy Patients For √

International Conference On
Neuroscience, Neurology and
Psychiatry
The Efficacy vitamin B12 anddr. A. Suheyra 2018
Folate acid as Adjuvant Syauki, M.Kes,
Sp.KJ
therapyto improvingnegative

50 symtoms of skizofrenia √
patients for International
Conference On Neuroscience,
Neurology and Psychiatry
Hubungan Lokasi dan Luas Dr. dr. H. M Faisal 2018
Infark dengan Fungsi Kognitif Idrus, Sp.KJ (K)

51 dan Keadaan Depresi pada √

Penderita Neurolgy
Hemorragic syndrome (NHS)
Pengaruh Kortikosteroid Dr. dr. Sonny T 2018
Terhadap Derajat Depresi Pada Lisal, Sp.KJ
52 √
Pasien Rheumatoid Arthritis
Hubungan intensitas nyeri Dr. dr. Sonny T 2018
kepala tipe tegang dengan Lisal, Sp.KJ
53 √
derajat depresi
Perbandingan Frekuensi Dr.dr.Saidah 2018
Kejang Pada Pasien Psikotik Syamsuddin,Sp.K,
54 Epilepsi yang Mendapat Terapi √
Haloperidol Dengan
Risperidone
Penggunaan Monitor Nadi Dr.dr.Saidah 2018
Sebagai Alternatif Modalitas Syamsuddin,Sp.K,
55 √
Biofeedback Pada Terapi
Relaksasi Terhadap Perbaikan
 Gejala Klinis Gangguan
Cemas
Perbandingan Perubahan berat Prof dr. A. 2018
badan paien Skizofrenia Jayalangkara Tanra
56 √
dengan pemberian antipsikotik Ph.D, Sp.KJ(K)
tipikal dan atipikal
Changes of Body Weight and Dr. dr. Saidah 2018
Triglyceride Level in Syamsuddin,Sp.KJ
Schizophrenia Patients Treated
with Atypical Antipsychotics dr. Hawaidah,
57 Sp.KJ (K), √

Dr. dr. Sonny T

Lisal, Sp.KJ
Comparison of Sleep Quality Dr. dr. H. M Faisal 2018
Using Pittsburgh Sleep Quality Idrus, Sp.KJ (K)
Index (PSQI) on Patient with
58 Anxiety Disorders Treated Dr. dr. Sonny T √
Using Long-Term and Short- Lisal, Sp.KJ
Term Benzodiazepine
Therapydr
Effect of Non-Computerized Dr. dr. Sonny T 2018
Cognitive Remediation on the Lisal, Sp.KJ
59 Cognitive Function of the √
Schizophrenic Patients Treated Dr.dr.Saidah
with Typical Antipsychotic Syamsuddin,Sp.KJ,
Comparison between Dr. dr. Sonny T 2018
Carbamazepine and Lisal, Sp.KJ
Divalproate on the
60 Improvement of Clinical Dr.dr.Saidah √
Symptoms of Bipolar Mania Syamsuddin,Sp.KJ,
with Psychotic Feature
Gunn rats with glial activation dr. Erlyn 2018
in the hippocampus show Limoa,Ph.D,Sp.KJ,
61 prolonged immobility time in √
the forced swimming test and dr. Kristian Liaury,
tail suspension test
Ph.D, Sp.KJ,
Physical comorbidities in older Prof. dr. A. 2018
62 adults receiving Jayalangkara Tanra, √
antidepressants in Asia Ph.D, Sp.KJ (K)
Psychotropic drug-prescribing Prof. dr. A. 2018
correlates of disorganized Jayalangkara Tanra,
63 speech in Asians with Ph.D, Sp.KJ (K) √
schizophrenia: The REAP-AP
study
Nutrition, Mental Status and
Level of 8-hydroxy2-
deoxyguanosine (OHdG)
dr. Erlyn Limoa,
64 Urine as Predictors of 2018
Ph.D, Sp.KJ √
Premenstrual Syndrome
(PMS) in Adolescent Girls

Jumlah nc= 1 nb= 22 na= 41

Catatan: * = tuliskan banyaknya dosen di RS Pendidikan program studi yang terlibat

7.2.2 Tuliskan dosen yang melakukan penelitian dengan melibatkan peserta didik untuk penelitian karya ilmiahnya, pada tahun
akademik terakhir (TS).

No. Nama Dosen
(1) (2)
Dr. dr. Saidah Syamsuddin, Sp.KJ
1.
Dr. dr. Sonny T Lisal, Sp.KJ
Dr. dr. Saidah Syamsuddin, Sp.KJ
2 Improvement of the Clinical Symptom of
Dr. dr. Sonny T Lisal, Sp.KJ
Dr. dr. Saidah Syamsuddin, Sp.KJ
3 With Combination Of Risperidone And
Dr. dr. Sonny T Lisal, Sp.KJ
dr. Erlyn Limoa, Sp.KJ, Ph.D
4 depression symptoms, cognition function
Prof. dr. A. Jayalangkara Tanra,
5 skizofrenia yang mendapatkan antipsikotik
Ph.D, Sp.KJ (K)
6 Dr. dr. Sonny T Lisal, Sp.KJ
7 Dr. dr. H. M Faisal Idrus, Sp.KJ (K)
8 Dr. dr. Saidah Syamsuddin, Sp.KJ
9 dr. Hawaidah, Sp.KJ(K)
10 dr. Erlyn Limoa, Sp.KJ, Ph.D
11 Dr. dr. Saidah Syamsuddin, Sp.KJ
Dr. dr. Sonny T Lisal, Sp.KJ
12
13 Dr. dr. Saidah Syamsuddin, Sp.KJ
Jumlah Peserta didik
Topik Penelitian
yang Terlibat
(3) (4)
dr. Anisa
Effect of Non-Computerized Cognitive Dr. dr. Saidah Syamsuddin,
Remediation and Risperidone to Improve Sp.KJ
Disability Function in Schizophrenia Dr. dr. Sonny T Lisal,
Sp.KJ
dr. Balgis
The Effect of Olanzapine on the Dr. dr. Saidah Syamsuddin,
Sp.KJ
Schizophrenia Dr. dr. Sonny T Lisal,
Sp.KJ
dr. Ismariani Mandan
Comparison Between Combination Of dr. Erlyn Limoa, Sp.KJ,
Risperidone And Haloperidol Therapy Ph.D
Dr. dr. Saidah Syamsuddin,
Sp.KJ
Chlorpromazine Therapy On Clinical
Symptom Improvement Of Schizophrenia Dr. dr. Sonny T Lisal,
Sp.KJ
The influence of fluoxetine therapy
combination of rational emotive behaviour
therapy againts the improvement of dr. Veraferial Muchtar
dr. Erlyn Limoa, Sp.KJ,
and improvement of brain-derived Ph.D
neurotrophic factors serum levels in
patients with depressive
Pengaruh allopurinol sebagai adjuvan
dr. Otto Parandangi
terhadap perbaikan gejala klinis pasien
Prof. dr. A. Jayalangkara
atipikal Tanra, Ph.D, Sp.KJ (K)
Pengaruh adjuvan vitamin d3 pada fungsi dr. Tri Anny Rakhmawati
kognitif pasien skizofrenia yang mendapat Dr. dr. Sonny T Lisal,
terapi antipsikotik atipikal Sp.KJ
Pengaruh Adjuvan Vitamin C pada Gejala dr. Yuliastuty
Klinis Pasien Skizofrenia yang Mendapat Dr. dr. H. M Faisal Idrus,
Terapi Antipsikotik Tipikal Sp.KJ (K)
Perbaikan fungsi kognitif pada pasien
dr. Herwina
skizofrenia yang mendapat terapi
antipsikotik atipikal dengan ajuvan omega- Dr. dr. Saidah Syamsuddin,
3 Sp.KJ
Pengaruh Pemberian Probiotik Sebagai
dr. Mirna M Zain
Terapi Adjuvan Terhadap Perbaikan
Gejala Klinis Depresi dr. Hawaidah, Sp.KJ(K)
Pengaruh Pemberian Kapsul Curcumin
dr. Lilik Haryani
Sebagai Terapi Adjuvan Terhadap
Perbaikan Gejala Pada Pasien Depresi dr. Erlyn Limoa, Sp.KJ,
yang Mendapat Terapi Antidepresan SSRI Ph.D
N-ACETYLCYSTEIN AS ADJUVANT dr Tenri Padad
THERAPY IN THE IMPROVEMENT OF Dr. dr. Saidah Syamsuddin,
DEPRESSIVE SYMPTOMS Sp.KJ
COMPARISON OF CLONAZEPAM dr. Erwiani Sutono
AND TRIHEXYPHENIDIL AS THE Dr. dr. Sonny T Lisal,
TREATMENT FOR Sp.KJ
EXTRAPYRAMIDAL SYMPTOMS
INDUCED BY HALOPERIDOL
N-ACETYLCYCSTEINE AS dr. Wahyu Eka Putra Gani
ADJUVANT THERAPY FOR CLINICAL Dr. dr. Saidah Syamsuddin,
IMPROVEMENT OF SCHIZOPHRENIA Sp.KJ
 THE EFFICACY OF VITAMIN D3 AS dr. Ekachaeryanti Zain
ADJUVANT THERAPY Dr. dr. Sonny T Lisal,
Dr. dr. Sonny T Lisal, Sp.KJ IN THE IMPROVEMENT OF Sp.KJ
14
DEPRESSIVE SYMPTOMS

THE EFFECT OF BENZODIAZEPINE IN dr. Veraferial Muchtar

dr. Erlyn Limoa,Ph.D,Sp.KJ COMBINATION OF HALOPERIDOL dr. Erlyn
15
TO SCHIZOPHRENIC PATIENT WITH Limoa,Ph.D,Sp.KJ
AGITATION
RISPERIDONE AND OLANZAPINE dr. Lusiana Indah Winata
COMPARISON ON COGNITIVE Dr. dr. H. M Faisal Idrus,
16 Dr. dr. H. M Faisal Idrus, Sp.KJ (K) FUNCTION AND AGGRESIVITY Sp.KJ (K)
IMPROVEMENT OF SCHIZOPHRENIC
PATIENTS
Sistemic Lupus Eritematosus Comorbid dr. Santiwati Anda
Dr. dr. Sonny T Lisal, Sp.KJ Suspect Neuroleptic Malignant Syndrome Dr. dr. Sonny T Lisal,
17
Sp.KJ

AMITRIPTYLINE AND FLUOXETINE dr Ahyani Muslimin

COMPARISON ON PERIPHERAL dr. A. Suheyra Syauki,
18 dr. A. Suheyra Syauki, M.Kes, Sp.KJ TOTAL BLOOD CHOLESTEROL M.Kes, Sp.KJ
LEVELS OF MAJOR DEPRESSIVE
DISORDER PATIENTS
Abnormalities in Glucose Blood Level dr.Dwiwahyu Ningsih
During Antipsychotic Treatment in Dr.dr.H.M.Faisal
Dr.dr.H.M.Faisal Idrus,Sp.KJ (K) Schizophrenia Patients Idrus,Sp.KJ (K)
dr.Theodorus Singara, Sp.KJ (K) dr.Theodorus Singara,
19 Dr.dr.Saidah Syamsuddin1, Sp.KJ, Sp.KJ (K)
Dr.dr.Sonny T. Lisal, Sp.KJ Dr.dr.Saidah Syamsuddin,
Sp.KJ, Dr.dr.Sonny T.
Lisal, Sp.KJ
Salivary Alpha Amylase Enzyme and dr.Mayamariska Sanusi,
Salivary Cortisol Level in Depression after Prof.dr.Andi Jayalangkara
Prof.dr.Andi Jayalangkara Treatment with Fluoxetine Tanra,Ph.D,Sp.KJ (K)
Tanra,Ph.D,Sp.KJ (K) Dr.Hawaidah,Sp.KJ (K),
20 Dr.Hawaidah,Sp.KJ (K), Dr.dr.Saidah
Dr.dr.Saidah Syamsuddin,Sp.KJ, Syamsuddin,Sp.KJ,
Dr.dr.Sonny Teddy Lisal, Sp.KJ Dr.dr.Sonny Teddy Lisal,
Sp.KJ

Potential Link between T102C dr.Andi Fatimah

Polymorphism in the Serotonin Receptors Dr.dr.H.M.Faisal
Dr.dr.H.M.Faisal Idrus,Sp.KJ (K) (5-HT2A) Gene and Treatment Response
Dr.dr.Saidah Syamsuddin1, Sp.KJ, Idrus,Sp.KJ (K)
21 of Risperidone on Schizophrenia
Dr.dr.Sonny T. Lisal, Sp.KJ Dr.dr.Saidah Syamsuddin1,
Sp.KJ, Dr.dr.Sonny T.
Lisal, Sp.KJ
Differentiation in Neurological Soft Sign dr.Hutomo JC
Scores on Schizophrenic Patients With dr.Wempy Thioritz,Sp.KJ
dr.Wempy Thioritz,Sp.KJ (K), Antipsychotic Treatment (K),
dr. Erlyn Limoa, Ph.D,Sp.KJ, dr. Erlyn Limoa,
22
Dr.dr.Saidah Syamsuddin,Sp.KJ, Ph.D,Sp.KJ, Dr.dr.Saidah
Dr.dr.Sonny Teddy Lisal, Sp.KJ Syamsuddin,Sp.KJ,
Dr.dr.Sonny Teddy Lisal,
Sp.KJ
Comparison Of BDNF (BRAIN- dr. Rahmawati Nur Indah
DERIVED NEUROTROPHIC FACTOR) Dr.dr.Sonny Teddy
Dr.dr.Sonny Teddy Lisal,Sp.KJ. Level In Depressed Patients Given Lisal,Sp.KJ. Prof.dr.Nur
Prof.dr.Nur Aeni. M.A. Fluoxetine And Sertraline
23 Aeni. M.A.
Fattah,Sp.KJ(K),
Fattah,Sp.KJ(K),
Dr.dr.Saidah Syamsuddin1, Sp.KJ.
Dr.dr.Saidah Syamsuddin1,
Sp.KJ.
Pengaruh Cognitive Behavioral Therapy dr. Santiwanti Anda
24 Dr.dr.Sonny Teddy Lisal, Sp.KJ, (CBT) Terhadap Tingkat Gejala Depresi Dr.dr.Sonny Teddy Lisal,
Sp.KJ,

25 Dr.dr.Saidah Syamsuddin,Sp.KJ,
26 Dr.dr.H.M.Faisal Idrus,Sp.KJ (K),
27 dr.A. Suheyra Syauki, M.Kes.Sp.KJ
28 Dr.dr.Saidah Syamsuddin,Sp.KJ,
29 Dr.dr.Sonny Teddy Lisal, Sp.KJ,
30 dr. Erlyn Limoa, Ph.D,Sp.KJ
Prof.dr.Andi Jayalangkara
Tanra,Ph.D,Sp.KJ (K),
31
dr.Rinvil Renaldi,M.Kes.,Sp.KJ (K)
A&R
32 Dr. dr. Saidah Syamsuddin, Sp.KJ
33 dr.A. Suheyra Syauki, M.Kes.Sp.KJ
Dr. dr. H. M Faisal Idrus, Sp.KJ(K)
dr. Erlyn Limoa, Sp.KJ, Ph.D
34 Dr. dr. Saidah Syamsuddin, Sp.KJ
Dr. dr. Sonny T Lisal, Sp.KJ
Prof. dr. A. Jayalangkara Tanra
Ph.D, Sp.KJ (K)
35 dr. Hawaidah, Sp.KJ (K)
Dr. dr. Saidah Syamsuddin, Sp.KJ
Dr. dr. Sonny T Lisal, Sp.KJ
dr. Erlyn Limoa, Ph.D, Sp.KJ, Prof.
36 dr. A. Jayalangkara Tanra, Ph.D,
Sp.KJ (K),
dan Risiko Bunuh Diri pada Pasien
skizofrenia Rawat Jalan
Pengaruh Terapi Realitas Terhadap dr.Ahyani Muslimin
Perbaikan Stigma Diri Dan Risiko Bunuh Dr.dr.Saidah
Diri Pada Pasien AIDS Syamsuddin,Sp.KJ,
Perbandingan Kadar Kolesterol Total dr.Otto Parandangi
Mahasiswa Fakultas Kedokteran Yang Dr.dr.H.M.Faisal
Mengalami Depresi Dan Ide Bunuh Diri Idrus,Sp.KJ (K),
Pengaruh Cognitive Behavioral Therapy dr.Tri Anny Rakhmawati
(CBT) Terhadap Tingkat Derajat Depresi dr.A. Suheyra Syauki,
dan Risiko Bunuh Diri pada Pasien M.Kes.Sp.KJ
Tuberculosis Multi Drug Resistant (TB-
MDR)
Pengaruh Terapi Realitas Terhadap dr.Yuliastuty
Perbaikan Tingkat Gejala Depresi Pada Dr.dr.Saidah
Masyarakat Daerah Bencana Paska Syamsuddin,Sp.KJ,
Longsor Di Kabupaten Gowa Tahun 2019
Hubungan HDRS Dengan Adiksi dr.Herwina
Smartphone Pada Mahasiswa Program Dr.dr.Sonny Teddy Lisal,
Pendidikan Dokter (MPPD) RS.Wahidin Sp.KJ,
Sudirohusodo
Efektivitas Cognitive Behavior Therapy dr. Mirna M.Zain,
(CBT) Pada Pasien Depresi Dengan dr. Erlyn Limoa,
Risiko Bunuh Diri Ph.D,Sp.KJ
Gangguan Afektif Bipolar Komorbid dr.Lilik Haryani,
Dengan Gangguan Kepribadian Ambang Prof.dr.Andi Jayalangkara
(Borderline Personality Disorder) Fokus Tanra,Ph.D,Sp.KJ (K),
Pada Tatalaksana: Self Harm Dan dr.Rinvil
Gangguan Impuls Seksual Renaldi,M.Kes.,Sp.KJ (K)
A&R
Profil Sosiodemografik Mahasiswa dr. Ahmad Andi Sameggu
Program Profesi Dokter Spesialis Fakultas Dr. dr. Saidah Syamsuddin,
Kedokteran Unhas Terhadap Burnout Sp.KJ
Syndrome Dan Distress Psikologis
Efikasi Terapi Holtikultura Terhadap dr. Andi Nursabhrina
Perbaikan Gejala Klinis Dan Kualtias Julianti
Hidup Pasien Skizofrenia dr.A. Suheyra Syauki,
M.Kes.Sp.KJ
The Effectiveness of the Combination dr. Iwan Honest
Therapy of Risperidone, Group Dr. dr. H. M Faisal Idrus,
Psychotherapy and Occupational Therapy Sp.KJ(K)
on Cognitive Functions and the Quality of dr. Erlyn Limoa, Sp.KJ,
Life of Schizophrenia Patients Ph.D
Dr. dr. Saidah Syamsuddin,
Sp.KJ
Dr. dr. Sonny T Lisal,
Sp.KJ
dr. Idham Jaya Ganda
dr. Jumraini Tammasse,
Sp.S
The Side Effect of Haloperidol in dr. Yazzit Mahri
Schizophrenic Patients: Analysis of Red Prof. dr. A. Jayalangkara
Blood Cell Distribution Width (RDW) and Tanra Ph.D, Sp.KJ (K) dr.
Mean Platelet Volume (MPV) Values Hawaidah, Sp.KJ (K) Dr.
dr. Saidah Syamsuddin,
Sp.KJ
Dr. dr. Sonny T Lisal,
Sp.KJ
Electroconvulsive shock restores the dr. Ilhamuddin A. Azis, dr.
decreased coverage of brain blood vessels Erlyn Limoa, Ph.D, Sp.KJ,
by astrocytic endfeet and ameliorates Prof. dr. A. Jayalangkara
depressive-like behavior Tanra, Ph.D, Sp.KJ (K),
 Total Jumlah Peserta Didik yang Karya Ilmiahnya terkait dengan penelitian dosen 10
* Yang dimaksud penelitian dosen adalah penelitian yang usulan penelitiannya diajukan oleh dosen yang
bersangkutan.

7.2.3 Sebutkan karya dosen atau peserta didik program studi yang telah memperoleh Paten/Hak atas Kekayaan Intelektual (HaKI)
atau karya yang mendapat pengakuan/penghargaan dari lembaga nasional/internasional selama tiga tahun terakhir.

Karya*
No Nama
Karya yang mendapat pengakuan/penghargaan
Paten / HAKI
dari Lembaga Nasional / Internasional
e-Poster Profil Efek Samping Sindrom
1. dr. Novianti Hajai Ekstrapiramidal Pasien Psikotik Dengan Terapi
Risperidone dan Olanzapine

2. dr. Erwiani Sutono Technology in Healthcare

Sistemic Lupus Eritematosus Comorbid

3. dr. Santiwati Anda Suspect Neuroleptic Malignant Syndrome

Association between Cathecol -O-

dr. Santiwati Anda Methyltransferase (COMT) V al 158 Met
4.
Polymorphisms and Psychosocial Stressors in
Torajanese Schizophrenic Patients
Black Seed (Nigella sativa) as Adjuvant
dr. Sri Purwatiningsih Therapy Improves Clinical, Cognitive and
5.
Extrapyramidal Symptoms During Risperidone
Treatment in Schizophrenia
The Efficacy of Vitamin D3 as Adjuvant
6 dr. Ekachaeryanti Zain Therapy in The Improvement of Depressive
Symptoms
Pengaruh Penggunaan Monitor Nadi Pada
7 dr. Ekachaeryanti Zain Terapi Relaksasi Terhadap Perbaikan Gejala
Klinis Pasien dengan Gangguan Cemas
Program computer: Deteksi
Dr.dr. Saidah Kejiwaaan: Kamu Hanya Stress,
8. Kamu Tidak Gila, Kamu Bisa
Syamsuddin,Sp.KJ
Sembuh Dari Gangguan Jiwa
9 dr. Rinvil Renaldi, Video Kuliah - ADHD
M.Kes, Sp.KJ(K)

(Departemen Ilmu Kedokteran Jiwa belum ada yang mendapatkan Paten/hak atas kekayaan intelektual (HAKI))

7.3 Kegiatan Pelayanan/Pengabdian kepada Masyarakat

Tuliskan kegiatan pelayanan/pengabdian kepada masyarakat (PkM) yang sesuai dengan bidang keilmuan PS selama tiga
tahun terakhir yang dilakukan oleh dosen di RS Pendidikan PS dengan mengikuti format tabel berikut.

Jumlah
Waktu Tempat
Jumlah Dosen Peserta
No. Judul Kegiatan PkM Kegiatan Kegiatan Didik yang
yang Terlibat
PkM PkM Terlibat
(1) (2) (3) (4) (5) (6)
 Peserta, Webinar PDSKJI malang, Update
1. Tatalaksana Dangguan Bipolar di masa 2020 1
Malang
pandemi covid 19
Peserta, Psychiatry update on depression
2. 2020 Daring 1
and bipolar disorder
 Peserta, Recent update in the treatment of
bipolar
3. Peserta, Benefit and sharing case of long 2020 Daring 1
acting injektable antipsychotic in treatment
bipolar
Peserta, Penerapan pembelajaran daring
dengan aplikasi sikola pada sekolah
4. pascasarjana UNHAS 2020 Makassar 1

Peserta, bimbingan teknis pengukuran

tingkat kesiapan inovasi bagi para peneliti
5. UNHAS 2020 1
Makassar

Stop stigma negatif pasien covid 19, Koran

6. fajar 2020 1 1
Makassar

Penguji, NBE FK UGM Yogyakarta

7. 2020 1
Daring
Penguji, NBE Bandung
8. 2020 1
Makassar
Penguji, NBE FK USU
9. 2020 Medan 1

Pengabdian Masyarakat, Pemateri Menjaga

kesehatan mental anak selama
10. pembelajaran jarak jauh di masa pandemi 2020 1
Makassar

Pengabdian Masyarakat, Pemateri

mendidik anak dengan baik, banar dan
11. menyenangkan sekolah Islam Athirah 2020 1
Makassar

Pengabdian Masyarakat, Pemateri

12. Mengenali tandda-tanda ADHD 2020 1
Makassar
Pengabdian Masyarakat, Pemateri
Membantu
13. 2020 1
anak menumbuhkan kepercayaan dirinya Makassar

Pengabdian Masyarakat, Pemateri Cara

tepat memarahi anak saat mereka berbuat
14. salah 2020 1
Makassar

Pengabdian Masyarakat, Pemateri

15. 2020 1
Membangaun kedekatan pada anak Makassar
Pengabdian Masyarakat, Pemateri
Mengatasi anak usia sekolah yang masih
16. mengompol 2020 Makassar 1

Pengabdian Masyarakat, Pemateri

Mengatur jadwal kegiatan anak selama
17. dirumah 2020 1
Makassar

Pemateri, Mengatasi anak yang selalu

19. konsumtif 2020 1
Makassar
Pemateri, Cara tepat mambantu anak
20. dengan bipolar disorder 2020 1
Makassar
 Seminar Edukasi-Kohati 2019; Komisariat
kedokteran gigi universitas hasanuddin,
22. november 2019 2019 1
Makassar

Peserta, Workshop spritual dan religius

23. psychiatry 2019 1
Solo
Pemateri dan panitia pada kegiatan
Pengabdian Masyarakat Deteksi Dini
24. Gangguan Jiwa dan NAPZA di Tana 2019 Toraja 18 20
Toraja, 29 November 2019-1Desember
2019

Konas IX PDSKJI sebagai Juri Makalah

25. bebas dan Research Award 2019 1
Balikpapan
Peserta, paradigma intersubjektif untuk
26. psikoanalisis 2019 1
Jakarta
Panitia, Simposium Konas IX PDSKJI
27. 2019 1
Balikpapan
Pemateri, Sumbangsih dan bakti dalam
penyuluhan mental pada kaum muda lewat
28. ceramah di GKY Palopo SULSEL 2019 1
Palopo

6 th Congress Of ASCNP Fukoka

29. 2019 1
Jepang
ASCPN ASEAN Yogyakarta
32. 2019 8 12
Yogyakarta
Panitia Workshop Psikoterapi dinamik
33. 2019 Makassar 5 17

Pengabdian Masyarakat, Pemateri

34. Kegawatdaruratan Psikiatri 2019 1
Makassar
Pemateri, Sosialisasi pencegahan dan
pengendalian masalah kesehatan jiwa di
35. Kab Soppeng 2019 1
Soppeng

Pemateri, Pelatihan penatalaksanaan kasus

36. gangguan jiwa di FKTP di BBPK 2019 Makassar 3
Makassar
Bakti Sosial Departemen Psikiatri Fakultas
Kedokteran Universitas Hasanuddin :
37. Generasi Muda yang Bahagia, Tangguh 2018 Gowa 2 7
dan Sehat Jiwa Menghadapi Perubahan
Dunia
Peserta, PIT PDSKJI 2018 Quality in
Psychiatry Education, Research and
38. services 2018 2
Banten

Panitia, dan peseerta Seminar bedah kasus

CLP dari berbagai bidang spesialis
40. kedokteran”bridging the gap between 2018 1
mentaldisorders and physical disease Makassar

Peserta, Psychiatry CME Current View and

41. Perspective of Benzodiazepine 2018 Makassar 9 18

WFSBP 2018 KOBE

42. 2018 1
Jepang
 Pemateri, PIT PDSKJI 2018, Tanggerang
43. Banten 2018 1
Banten
Peserta, PIT PDSKJI 2018, Tanggerang
44. Banten 2018 2
Banten
Peserta, pelatihan konselor UNHAS
46. 2018 1
Makassar
Panitia, Bakti Sosial Hari Kesehatan
Dunia; Generasi muda yang bahagia,
48. tangguh dan sehat jiwa 2018 Gowa 3

Pengabdian Masyarakat, Pemateri

pelatihan deteksi dini dan penatalaksanaan
49. Gangguan Jiwa bagi tenaga kesehatan 2018 1
dokter di FKTP, DINKES Sinjai Sinjai

Pengabdian Masyarakat, Pemateri

Psychiatry CME, Current View and New
50. Perspective of Benzodiazepine 2018 1
Makassar

Pemateri, Depression is The Sillent Killer

51. 2018 Makassar 1

Pemberdayaan perempuan dan

52. perlindungan anak kota makassar 2018 Makassar 1

Total N=52

7.4 Kegiatan Kerjasama dengan Instansi Lain

7.4.1 Tuliskan instansi dalam negeri yang menjalin kerjasama* yang terkait dengan program studi dalam tiga tahun terakhir.
Kurun Waktu Kerjasama
No. Nama Instansi Jenis Kegiatan Manfaat yang Telah Diperoleh
Mulai Berakhir
(1) (2) (3) (4) (5) (6)
Stase pendidikan, Pemanfaatan RSUP Dr. Wahidin
RSUP Dr. Wahidin penelitian dan Masih Sudirohusodo sebagai lahan
1 Maret 2006
Sudirohusodo pelayanan berlangsung praktik pendidikan, penelitian dan
kesehatan pengabdian masyarakat
Stase pendidikan, Pemanfaatan RS Ibnu Sina
Penelitian dan Masih sebagai lahan praktik pendidikan,
2 RS Ibnu Sina Agustus 2006
pelayanan berlangsung penelitian dan pengabdian
kesehatan masyarakat .
Stase pendidikan, Pemanfaatan RS Labuang Baji
Penelitian dan Masih sebagai lahan praktik pendidikan,
3 RS Labuang Baji Maret 2010
pelayanan berlangsung penelitian, dan pengabdian
kesehatan masyarakat
Stase pendidikan, Pemanfaatan RS Akademis
Penelitian dan Masih sebagai lahan praktik pendidikan,
4. RS Akademis 2016
pelayanan berlangsung penelitian, dan pengabdian
kesehatan masyarakat
Pemanfaatan RSUD Ternate
RS. H. Chasan Boesoirie Stase Residen sebagai lahan praktik pendidikan,
5. 2015 2019
Ternate semester 5,6, 7 penelitian, dan pengabdian
masyarakat peserta didik
 Pemanfaatan RSUD Morowali
Stase residen Masih sebagai lahan praktik pendidikan,
6. RSUD Morowali 1 Maret 2014
semester 5,6,7 berlangsung penelitian, dan pengabdian
masyarakat peserta didik
Pemanfaatan RSUD Kolonodale
Stase Residen November Masih sebagai lahan praktik pendidikan,
7. RSUD Kolonodale
semester 5,6,7 2016 berlangsung penelitian, dan pengabdian
masyarakat peserta didik
Stase pendidikan, Pemanfaatan RSKD Dadi Prov
RSKD Dadi Prov Sulawesi Penelitian dan November Masih Sulawesi Selatan sebagai lahan
8.
Selatan pelayanan 2017 berlangsung praktik pendidikan, penelitian dan
kesehatan pengabdian masyarakat
Stase pendidikan, Pemanfaatan BNN Badokka Prov
Penelitian dan Sulawesi Selatan sebagai lahan
9. BNN Badokka 2011 2019
pelayanan praktik pendidikan, penelitian dan
kesehatan pengabdian masyarakat
Stase pendidikan, Pemanfaatan RS DAYA Prov
Penelitian dan Masih Sulawesi Selatan sebagai lahan
10. RS DAYA 2016
pelayanan berlangsung praktik pendidikan, penelitian dan
kesehatan pengabdian masyarakat
Stase pendidikan, Pemanfaatan RSUD Poso sebagai
RSUD Poso Penelitian dan lahan praktik pendidikan,
11 2018 2019
pelayanan penelitian dan pengabdian
kesehatan masyarakat
Pemanfaatan RSUD Anuntaloko
Stase pendidikan,
RSUD Anuntaloko Kabupaten Parigi Moutong
Penelitian dan Masih sebagai lahan praktik pendidikan,
12 Kabupaten Parigi Moutong 2020
pelayanan berlangsung penelitian dan pengabdian
kesehatan masyarakat
Stase pendidikan, Pemanfaatan RSUD Mokopido
RSUD Mokopido Toli- Penelitian dan Masih
13 2020 Toli-Toli sebagai lahan praktik
Toli
pelayanan berlangsung pendidikan, penelitian dan
kesehatan pengabdian masyarakat
Catatan : * dokumen pendukung disediakan pada saat asesmen lapangan

7.4.2 Tuliskan instansi luar negeri yang menjalin kerjasama* yang terkait dengan program studi dalam tiga tahun terakhir.
Kurun Waktu Kerjasama
No. Nama Instansi Jenis Kegiatan Manfaat yang TelahDiperoleh
Mulai Berakhir
(1) (2) (3) (4) (5) (6)
Stase pendidikan, Pemanfaatan Kyoto University
Kyoto University Penelitian dan sebagai lahan praktik pendidikan,
1. 2016 2019
pelayanan penelitian dan pengabdian
kesehatan masyarakat

Catatan : * dokumen pendukung disediakan pada saat asesmen lapangan

7.4.3 Kunjungan kuliah tamu selama 3 tahun terakhir

No. Tanggal Kegiatan Nama Acara

1. 22 Februari 2019 Kuliah Tamu Psikiatri Anak dan Remaja oleh Dr.dr.Veranita
Pandia,Sp.KJ(K),M.Kes dan Psikiatri Adiksi oleh dr. Luh
Nyoman Alit Aryani,Sp.Kj(K)
2. 03 Maret 2019 Visiting Lecture by Prof. Anthony Albert Grace,Ph.D
(Department of Neuroscience, University of Pittsburgh)
 3. 07 Agustus 2019 Special Lecture by Prof.Masatoshi Inagaki (Shimane University)
Sucide Prevention Among Patients Admitted to Emergency
Departments for Suicidal Behavior
4. 21 Agustus 2019 Kuliah Tamu “Terapi Realitas pada Depresi” oleh Dr. dr. Gusti
Ayu Maharatih, Sp.KJ (K), M.Kes
5. 8-9 Februari 2020 Workshop Psikoterapi Dinamik oleh dr. Sylvia D.Elvira,
Sp.KJ(K) dan dr.Petrin Redayani L,Sp.KJ(K),MPd

7.5 Perolehan dan penggunaan dana untuk kegiatan penelitian dan pengabdian masyarakat

No. Nama Dosen Judul Proposal Usulan Dana Keterangan

dr. Andi Suheyra Syauki, Efektivitas Repetitive Rp.100.000.000 Tidak lolos
M.Kes Sp.KJ Transcranial Magnetic
Stimulation (rTMS)
Dr.dr. Sonny Teddy Dibandingkan Dengan
Lisal,Sp.KJ Fluoxetine Terhadap
Peningkatan BDNF
Pada Depresi Pasca
dr. Rinvil Renaldi, Stroke Iskemik
M.Kes.,SpKJ(K)
2. dr. Rinvil Renaldi, M.Kes, Perbandingan Kadar Rp.100.000.000 Tidak lolos
Sp.KJ(K) Kortisol Rambut
Dr. dr. H. M. Faisal Idrus, Sebelum dan Setelah
Sp.KJ(K) Terapi Metylphenidate
dr. A. Suheyra Syauki, M.Kes, Pada Pasien Dengan
Sp.KJ Gangguan Pemusatan
Perhatian dan
Hiperaktivitas (GPPH)
3. dr. Erlyn Limoa, Ph.D, Penambahan Probiotik Rp.100.000.000 Tidak lolos
Sp.KJ Sebagai Terapi
Tambahan Pada Pasien
Dr. dr Saidah Syamsuddin, Skizofrenia yang
Sp.KJ Mendapatkan Terapi
Antipsikotik Atipikal
4. Dr.dr. H.M. Faisal Idrus, Kadar Interleukin 6 dan Rp.100.000.000 Tidak lolos
Sp.KJ(K) 8 Pada Pasien
dr. Andi Suhera Syauki, M.kes, Gangguan Pemusatan
SpKJ Perhatian dan
dr. Rinvil Renaldi, M.Kes, Hiperaktivitas (GPPH)
Sp.KJ(K)
5 Dr.dr. Sonny Teddy
Analisis Hubungan Rp.100.000.000 Tidak lolos
Lisal,Sp.KJ Antara Polimorfisme
Prof.dr.A.jayalangkara Gen Reseptor
Tanra,Ph.D,Sp.KJ(K) Cathecol-o-Methyl
Transferase (COMT)
rs740603 dan rs4818
dengan Skizofrenia
yang Dalam Populasi
Masyarakat Toraja
6 Dr. dr Saidah Syamsuddin, Hubungan Antara Rp.100.000.000 Tidak lolos
Sp.KJ Polimorfisme Gen
Reseptor Cathecol-O-
dr. Erlyn Limoa, Ph.D, Methyl Transferase
Sp.KJ (COMT) VAL158MET
dengan Resppm Terapi
dan Fungsi Kognitif
Pasien Skizofrenia
Yang Mendapatkan
TErapi Risperidon
Received: 31 March 2020 Accepted: 5 July 2020
DOI: 10.1002/kjm2.12280

ORIGINAL ARTICLE

QT interval prolongation noted in one percent of 2553 Asian

patients with schizophrenia: Findings from the REAP-AP
survey
1 1 2 3
Seon-Cheol Park | Bong Ju Lee | Jae Hong Park | Hiroaki Kawasaki |
4 4 5 6 7
Ajit Avasthi | Sandeep Grover | Andi J. Tanra | Shih-Ku Lin | Afzal Javed |
8 9 10 11
Chay Hoon Tan | Norman Sartorius | Naotaka Shinfuku | Yong Chon Park
1
Department of Psychiatry, Inje University Haeundae Paik Hospital, Busan, Republic of Korea
2
Department of Psychiatry, College of Medicine, Dong-A University, Busan, Republic of Korea
3
Department of Psychiatry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
4
Department of Psychiatry, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
5
Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
6
Psychiatric Center, Taipei City Hospital, Taipei, Taiwan
7
Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan
8
Department of Pharmacology, National University Hospital, Singapore, Singapore
9
Association for the Improvement of Mental Health Programmes, Geneva, Switzerland
10
Department of Social Welfare, School of Human Sciences, Seinan Gakuin University, Fukuoka, Japan
11
Department of Neuropsychiatry, Hanyang University Guri Hospital, Guri, Republic of Korea

Correspondence
Seon-Cheol Park, Department of Psychiatry, Abstract
Inje University Haeundae Paik Hospital,
Although the association between antipsychotic use and corrected QT interval (QTc)
875, Haeun-daero, Haeundae-gu, Busan
48108, Korea. prolongation has been repeatedly confirmed, the relationship has been rarely studied
Email: cogito-ergo-sum@hanmail.net
in a practical setting. Using data from the Research on Asian Psychotropic Prescrip-
Funding information tion Patterns for Antipsychotics (REAP-AP) survey, our study aimed to investigate
Korea government (MSIT), Grant/Award
the prevalence and clinical correlates of QTc prolongation in 2553 Asian patients with
Number: 2019R1A2C1090146
schizophrenia. After adjusting for the potential effect of confounding factors, the
baseline and clinical characteristics of the schizophrenia patients with and without
QTc prolongation were compared using analyses of covariance and binary logistic
analyses. In addition, a binary logistic analysis model with a forward selection method
was used to identify the distinctive clinical correlates of QTc prolongation. QTc pro-
longation was noted in 1.1% of Asian patients with schizophrenia. Schizophrenia
patients were characterized by lower proportions of disorganized speech and nega-
tive symptoms; higher use of amisulpride and clozapine; and higher proportions
of rigidity, hypercholesterolemia, and sedation than those without QTc
prolongation.
Finally, a binary logistic mode showed that amisulpride, clozapine, rigidity,
and

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.
Kaohsiung J Med Sci. 2020;1–8. wileyonlinelibrary.com/journal/kjm2 1
2 PARK ET AL.
hypercholesterolemia might be the distinctive clinical correlates of QTc prolongation
in Asian patients with schizophrenia. These findings indicate the clinical implications
that the uses of amisulpride and clozapine and the occurrences of rigidity and
hypercholester- olemia may be potential risk factors
schizophrenia patients.
KEYWOR DS
Asian, hypercholesterolemia, rigidity, QTc prolongation, schizophrenia
1 | I NT R O D U C
T IO N
A dose-response relationship exists between antipsychotic drugs and
potential prolongation of the rate-corrected QT interval (QTc).1 Inhibi-
tion of the hERG-encoded potassium channels has been proposed as
a possible mechanism of the potential effects of most antipsychotics
2,3
on QTc prolongation. QTc prolongation may be caused by antipsy-
chotics, such as chlorpromazine, haloperidol, pimozide, quetiapine, ris-
peridone, thioridazine, and ziprasidone; and antidepressants, such as,
bupropion, duloxetine, fluoxetine, and paroxetine.4 In addition, QTc
prolongation has been observed in some newer antidepressants rather
5
than tricyclic antidepressants. However, an association between anti-
psychotic polypharmacy and QTc prolongation has been inconsis-
tently reported.1 Moreover, in a study with a large sample population
of 2366 subjects, it was reported that age, sex, alcohol misuse, and
concurrent intake of the implicated drug acted as mediating variables
6
between first generation antipsychotic use and QTc interval. A QTc
interval of >500 ms is considered to be a risk factor for torsade de
pointes, which is a life-threatening arrhythmia, associated with sudden
7
cardiac death. However, the prevalence and clinical correlates of
QTc prolongation have rarely been reported, especially in patients
with schizophrenia in a practical clinical situation. The Research on
Asian Psychotropic Prescription Patterns for Antipsychotics (REAP-
8,9
AP) survey is the largest survey in the realm of psychiatry in Asia.
this study, using data from the REAP-AP survey, we aimed to evaluate
the prevalence and clinical correlates of QTc prolongation in Asian
patients with schizophrenia.
2 | S UB JEC T S AN D M ET HOD S
2.1 | Study participants and design
As described earlier,
8,9
an aim of the REAP-AP survey was to investi-
gate psychotropic prescription patterns and their clinical correlates
as well as explore ways to improve prescription patterns in patients
with schizophrenia in Asian countries/special administrative areas.
During the study period of March–June 2016, 3744 consecutive
patients with schizophrenia were enrolled from 71 REAP-AP4 survey
centers in 15 Asian countries and areas, namely Bangladesh, China,
Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Myanmar, Paki-
stan, Singapore, Sri Lanka, Taiwan, Thailand, and Vietnam. The
United Nations classification was used to categorize the 15 Asian
for QTc prolongation of
countries/special administrative areas into three groups as follows:
Eastern Asia (China, Hong Kong, Japan, Korea, and Taiwan); South-
ern Asia (Bangladesh, India, Pakistan, and Sri Lanka); and Southeast-
ern Asia (Indonesia, Malaysia, Myanmar, Singapore, Thailand, and
Vietnam). The World Bank list of economies was used to classify the
15 Asian countries/special administrative areas into three groups
based on income as follows: high income (Hong Kong, Japan, Korea,
Singapore, and Taiwan); upper middle income (China, Malaysia, and
Thailand); and lower middle income (Bangladesh, India, Indonesia,
Myanmar, Pakistan, Sri Lanka, and Vietnam). The institutional review
boards of Taipei City Hospital, Taipei, Taiwan (receipt number:
TCHIRB-10412128-E) and other centers approved the protocol for
the REAP-AP survey. All study participants, or their authorized rep-
resentatives, provided written informed consent prior to participa-
tion. Prior to initiation of the study, a conference meeting was held
to improve the consistency of data collection and diagnosis of
schizophrenia among the survey centers. Demographic data and clin-
ical and treatment-related details as per protocol were collected by
trained study coordinators supervised by clinical psychiatrists at the
survey centers. Data on the study subjects were collected using the
predefined questionnaires as per protocol and stored on the REAP-
AP study website.
We selected participants who met all the following inclusion
criteria, to ensure appropriate analyses of the data obtained from the
In REAP-AP survey: (a) schizophrenia diagnosed with the International
Classification of Diseases, 10th revision (ICD-10),
10
(b) antipsychotic
drugs used for pharmacotherapy, and (c) availability of the presence
or absence of QTc prolongation, which was recorded by a standard
12-lead electrocardiography with a paper speed of 25 mm/s. The QTc
1/2
interval was calculated by Bazett's formula: QTc = QT/RR , and QTc
prolongation was defined as a duration of >450 ms in men and
7,11
>470 ms in women.
2.2 | Statistical analysis
Thus, 2553 Asian patients with schizophrenia were included for the
comparison of the baseline and clinical characteristics of those with
and without QTc prolongation. Independent t-tests were used for
continuous variables and χ2 tests were used for discrete variables;
and the baseline and clinical characteristics of schizophrenia patients
with and without QTc prolongation were compared. Moreover,
covariance analyses were performed for continuous variables, and
PARK ET AL. 3

TA BL E 1 Baseline characteristics of schizophrenia patients with QTc prolongation (n = 27)

Case BMI Psychopathological

2 a
number Age Sex (kg/m ) characteristics Psychotropic medications Other adverse effects
1 14 Male 25.63 Disorganized behavior Olanzapine 20 mg Weight gain
2 58 Male n/a Disorganized behavior, negative Olanzapine 10 mg None
symptoms
3 61 Male 22.60 Negative symptoms Olanzapine 20 mg Hypercholesterolemia
4 66 Female 22.02 Hallucination Sulpride 800 mg, estazolam 1 mg Hypercholesterolemia
5 50 Female 26.89 Hallucination Aripiprazole 15 mg, estazolam Impaired glucose tolerance
2 mg
6 40 Female 24.63 Delusion, hallucination Zotepine 200 mg, clonazepam Constipation, oversedation
2.5 mg
7 59 Female 22.48 Delusion, hallucination Clozapine 200 mg, lorazepam Blurred vision
2 mg
8 48 Female 25.60 Hallucination Clozapine 300 mg, clonazepam Constipation, excessive
2 mg salivation, postural
hypotension, urinary difficulty,
blurred vision
9 71 Female 26.93 Hallucination Clozapine 300 mg Constipation
10 56 Female 23.73 Delusion, hallucination, verbal Clozapine 350 mg, flunitrazepam Constipation, impaired glucose
aggression 2 mg tolerance,
hypercholesterolemia
11 30 Male 24.13 Delusion, hallucination Clozapine 350 mg, valproate Tremor, constipation,
1000 mg oversedation
12 62 Female 23.01 Delusion Olanzapine 20 mg, ziprasidone Constipation, dry mouth,
160 mg, clonazepam 2 mg, impaired glucose tolerance,
Zopiclone 7.5 mg hypercholesterolemia
13 63 Male 29.90 Delusion Amisulpride 400 mg, Akathisia
trihexyphenidyl 8 mg
14 61 Female 29.16 Delusion, hallucination Amisulpride 400 mg, Valproate Rigidity, tremor, constipation,
1000 mg, Escitalopram 10 mg hypercholesterolemia,
oversedation
15 52 Female 26.98 Delusion, hallucination, Clozapine 275 mg, valproate Rigidity, tremor
disorganized speech 1000 mg, trihexyphenidyl 4 mg
16 78 Female 25.71 Delusion, hallucination, negative Risperidone 4 mg, trihexyphenidy Rigidity, hypercholesterolemia,
symptoms, verbal aggression 2 mg oversedation
17 24 Female 27.21 Delusion, hallucination, negative Zotepine 400 mg, carbamazepine Rigidity, akathisia, constipation
symptoms, verbal aggression 600 mg,
trihexyphenidy 5 mg
18 56 Female 18.56 Hallucination, negative symptoms Olanzapine 20 mg, Rigidity, constipation
trihexyphenidy 2 mg
19 43 Female 23.60 Hallucination, negative symptoms Amisulpride 800 mg, Rigidity, tremor, constipation
trihexyphenidy 2 mg
20 53 Female 25.35 Delusion, hallucination Amisulpride 800 mg, Rigidity, tremor, constipation
trihexyphenidy 10 mg
21 69 Female 24.65 Negative symptoms Risperidone 3 mg, Constipation, excessive
chlorpromazine 250 mg, salivation, dry mouth, postural
valproate 500 mg, duloxetine hypotension, blurred vision,
40 mg, oxazepam 30 mg impaired glucose tolerance,
weight gain
22 41 Male 36.49 Delusion, hallucination Clozapine 25 mg, risperidone Hypocholesterolemia, weight
4 mg, trihexyphenidy 4 mg gain
23 38 Female 21.64 Negative symptoms Clozapine 275 mg, Excessive salivation
trihexyphenidy 4 mg
24 58 Female n/a Disorganized speech Clozapine 300 mg, fluoxetine Constipation
40 mg, clonazepam 1 mg,

(Continues)
4 PARK ET AL.

TA BL E 1 (Continued)

Case BMI Psychopathological

2 a
number Age Sex (kg/m ) characteristics Psychotropic medications Other adverse effects
25 49 Female 21.27 Delusion, hallucination Clozapine 450 mg, fluoxetine Rigidity, tremor
40 mg, trihexyphenidy 15 mg
26 43 Male 19.33 Delusion, hallucination Amisupride 800 mg, clonazepam Rigidity, akinesia, dystonia,
3 mg, trihexyphenidy 2 mg excessive salivation,
oversedation
27 43 Female 23.73 Hallucination, disorganized Clozapine 200 mg, risperidone Tremor, akathisia, constipation,
speech, verbal aggression, 2 mg, trihexyphenidy 2 mg sexual dysfunction,
physical aggression hypercholesterolemia

Abbreviations: BMI, body mass index; QTc, QT interval.

a
Except QTc prolongation.

binary logistic analyses were performed for discrete variables after
adjusting for the potential effects of confounding factors. A binary
logistic analysis model, with a forward selection method to avoid
multicollinearity, was used to identify the distinctive clinical correlates
for QTc prolongation. Statistical significance was set at P < .01 (two-
tailed) as we aimed to exclude familywise errors due to multiple com-
parisons. All statistical analyses were conducted using IBM SPSS 24
(IBM Co., Armonk, New York).
3 | RE SU L T S
As shown in Table 1, the prevalence of QTc prolongation was 1.1%
(n = 27) among 2553 Asian patients with schizophrenia. The baseline
characteristics (ie, age, sex, body mass index
psychopatholgical characteristics, psychotropic medications, and other
side effects) of schizophrenia patients with QTc prolongation were
presented. In addition, as shown in Table 2, participants with QTc pro-
longation were characterized by a significantly older age (t = 4.191,
2
P < .0001) and female sex (χ = 11.595, P = .001), and a higher propor-
tion of them were inpatients (χ 2 = 11.899, P = .001) than those with-
out QTc prolongation. Moreover, participants with QTc prolongation
significantly differed from those without QTc prolongation with
2
respect to the distribution of the duration of illness (χ
2
P < .0001), regional group (χ = 22.517, P < .0001), and income group
(χ
2
= 26.752, P < .0001). After adjusting for the effect of age, sex,
region group, income group, inpatient, and duration of illness for con-
trolling potential effects of confounding factors on the differences in
clinical characteristics of the study participants with and without QTc
prolongation, those with QTc prolongation were characterized by sig-
nificantly lower proportions of disorganized speech (adjusted odds
ratio [aOR] = 0.290, P = .029) and negative symptoms (aOR = 0.345,
P = .025); higher use of amisulpride (aOR = 4.632, P = .005) and cloza-
pine (aOR = 2.974, P = .010); and higher proportions of rigidity
(aOR = 4.440, P = .001), hypercholesterolemia (aOR = 3.699,
P = .005), and sedation (aOR = 4.955, P = .005) than those without
QTc prolongation. Although the difference was not statistically signifi-
cant, the use of antipsychotic polypharmacy was lower in those with
QTc prolongation than in those without QTc prolongation
(aOR = 0.345, P = .014). In addition, between those with and without
QTc prolongation, there were no differences in terms of the uses of
anticonvulsant (aOR = 0.775, P = .620), antidepressant (aOR = 1.226,
P = .720), anxiolytic (aOR = 0.806, P = .610), and antiparkinsonian
drugs (aOR = 1.487, P = .325).
Finally, as shown in Table 3, initial covariates selected for a binary
logistic model included disorganized speech, negative symptoms, ami-
sulpride, clozapine, rigidity, hypercholesterolemia, and sedation,
whereas QTc prolongation was defined as a dependent variable. In
addition, the potential effects of age, sex, region group, income group,
inpatient/outpatient status, and duration of illness on the binary logis-
tic model were controlled. All study participants were included in the
binary logistic model. The binary logistic model was validated by the
Hosmer–Lemeshow goodness-of-fit test (χ 2 = 6.885, df = 8, P = .549).
2
[kg/m ], As a result of forward selection to avoid multicolinearity, the model
explained a 27.9% (Nagelkerke's R2) variability in QTc prolongation
and showed that use of amisulpride (aOR = 5.355, P = .010) and cloza-
pine (aOR = 4.652, P = .004), rigidity (aOR = 4.926, P = .004), and
hypercholesterolemia (aOR = 6.000, P = .001) were distinctive corre-
lates for QTc prolongation. By contrast, disorganized speech, negative
symptoms, and sedation were not significantly related to QTc
prolongation.
= 33.269,
4 | D I S CU
SSI O N
In this study, we report that the prevalence of QTc prolongation in
Asian patients with schizophrenia is 1.1% and hypothesize that this
prevalence may indicate the necessity of extra clinical attention for
patients with schizophrenia, especially those treated with antipsy-
chotics and other psychotropic drugs, and are thus at risk of QTc pro-
longation. A prospective observational study by Ali et al showed that
out of 405 patients who used psychotropic medications for seven or
more days and were over 18 years, 23 (5.7%) patients presented with
12
QTc prolongation. A one sample t test of our results and Ali et al's
results showed no significant difference in the prevalence rates of the
12
two studies (t = 1.478, P = .379). In addition, a study by
Rettenbacher et al13 reported no significant differences in QTc
intervals or QTc variability between 61 schizophrenia patients and 31
PARK ET AL. 5

TA BL E 2 Clinical characteristics of schizophrenia patients with and without QTc prolongation (n = 2553)

QTc prolongation

Total sample Presence Absence Statistical Unadjusted Adjusted

a
(n = 2553) (n = 27) (n = 2526) coefficients P-value P-value
Baseline characteristics
Age, mean (SD) years 39.7 (13.1) 51.3 (14.5) 39.6 (13.5) t = 4.191 <.0001 —
2
Female, n (%) 1070 (41.9) 20 (74.1) 1050 (41.6) χ = 11.595 .001 —
2
Body mass index, mean (SD) kg/m 23.8 (4.7) 24.9 (3.7) 23.8 (4.6) t = 1.148 .251 415
b 2
Regional group χ = 22.517 <.0001 —
Eastern Asia, n (%) 826 (32.4) 20 (74.1) 806 (31.9)
Southeastern Asia, n (%) 1014 (39.7) 6 (22.2) 1008 (39.9)
Southern Asia, n (%) 713 (27.9) 1 (3.7) 712 (28.2)
c 2
Income group χ = 26.752 <.0001 —
High income, n (%) 773 (30.3) 20 (74.1) 753 (29.8)
Upper middle income, n (%) 385 (15.1) 4 (14.8) 281 (15.1)
Lower middle income, n (%) 1395 (54.6) 3 (11.1) 1392 (55.1)
2
Inpatient, n (%) 1539 (60.3) 25 (92.6) 1514 (59.9) χ = 11.899 .001 —
2
Duration of illness χ = 33.269 <.0001 —
<3 months, n (%) 136 (5.3) 0 (0.0) 136 (5.4)
3-6 months, n (%) 98 (3.8) 1 (3.7) 97 (3.8)
6-12 months, n (%) 139 (5.4) 0 (0.0) 139 (5.5)
1-5 years, n (%) 496 (19.4) 1 (3.7) 495 (19.6)
5-10 years, n (%) 492 (19.3) 2 (7.4) 490 (19.4)
10-20 years, n (%) 627 (24.6) 5 (18.5) 622 (24.6)
>20 years, n (%) 565 (22.1) 18 (66.7) 547 (21.7)
Psychopathological characteristics
2
Delusions, n (%) 1207 (47.3) 14 (51.9) 1193 (47.2) χ = 0.229 0.632 .661
2
Hallucinations, n (%) 1271 (49.8) 19 (70.4) 1252 (49.6) χ = 4.626 .031 .160
2
Disorganized speech, n (%) 824 (32.3) 4 (14.8) 820 (32.5) χ = 3.806 .051 .029
2
Catatonic behavior, n (%) 485 (19.0) 3 (11.1) 482 (19.1) χ = 1.103 .294 .636
2
Negative symptoms, n (%) 977 (38.3) 7 (25.9) 970 (38.4) χ = 1.760 .185 .025
2
Verbal aggression, n (%) 722 (28.3) 4 (14.8) 718 (28.4) χ = 2.440 .118 .640
2
Physical aggression, n (%) 609 (23.9) 1 (3.7) 608 (24.1) χ = 6.100 .014 .155
d
Psychotropic drug using patterns
2
Amisulpride, n (%) 119 (4.7) 5 (23.8) 114 (4.5) χ = 11.792 .001 .005
2
Clozapine, n (%) 416 (16.3) 11 (40.7) 405 (16.0) χ = 11.957 .001 .010
2
Olanzapine, n (%) 598 (23.4) 5 (18.5) 593 (23.5) χ = 0.366 .545 .582
2
Risperidone, n (%) 923 (36.2) 4 (14.8) 919 (36.4) χ = 5.383 .020 .108
2
Antipsychotic polypharmacy, n (%) 1023 (40.1) 6 (22.2) 1017 (40.3) χ = 3.620 .057 .014
2
Anticonvulsant, n (%) 396 (15.5) 5 (18.5) 396 (15.5) χ = 0.188 .664 .620
2
Antidepressant, n (%) 284 (11.1) 4 (14.8) 280 (11.1) χ = 0.376 .540 .720
2
Anxiolytic, n (%) 881 (34.5) 11 (40.7) 870 (34.4) χ = 0.469 .493 .610
2
Antiparkinson drugs, n (%) 868 (34.0) 13 (48.1) 855 (33.8) χ = 2.435 .119 .325
Chlorpromazine equivalent, 594.7 (562.6) 579.7 (259.9) 594.9 (625.4) t = −0.126 .900 .445
mean (SD)
Imipramine equivalent, mean (SD) 18.5 (89.6) 19.1 (49.8) 18.5 (107.4) t = 0.029 .977 .981
Diazepam equivalent, mean (SD) 10.1 (43.4) 10.8 (18.5) 10.1 (51.0) t = 0.072 .942 .826
Levodopa equivalent, mean (SD) 36.4 (83.8) 56.1 (91.2) 36.2 (71.2) t = 1.299 .194 .694

(Continues)
6 PARK ET AL.

TA BL E 2 (Continued)

QTc prolongation

Total sample Presence Absence Statistical Unadjusted Adjusted

a
(n = 2553) (n = 27) (n = 2526) coefficients P-value P-value
Drug-induced adverse events
2
Rigidity, n (%) 322 (12.8) 9 (39.1) 313 (12.5) χ = 14.443 <.0001 .001
2
Akinesia, n (%) 182 (7.2) 1 (4.5) 181 (7.3) χ = 0.240 .624 .989
2
Tremor, n (%) 469 (18.6) 7 (30.4) 462 (18.5) χ = 2.159 .142 .679
2
Akathisia, n (%) 210 (8.3) 3 (13.6) 207 (8.3) χ = 0.814 .367 .351
2
Dystonia, n (%) 68 (2.7) 1 (4.5) 67 (2.7) χ = 0.287 .592 .332
2
Constipation, n (%) 588 (23.3) 15 (60.0) 573 (23.0) χ = 18.977 <.0001 .135
2
Excessive salivation, n (%) 342 (13.6) 4 (16.0) 338 (13.5) χ = 0.129 .720 .925
2
Dry mouth, n (%) 400 (15.8) 3 (12.0) 397 (15.9) χ = 0.280 .596 .651
2
Postural hypotension, n (%) 109 (4.3) 2 (8.0) 107 (4.3) χ = 0.821 .365 .392
2
Dysuria, n (%) 78 (3.1) 2 (8.3) 76 (3.1) χ = 2.196 .138 .111
2
Blurred vision, n (%) 149 (5.9) 3 (12.0) 146 (5.9) χ = 1.665 .197 .374
2
Sexual dysfunction, n (%) 130 (5.5) 1 (4.2) 129 (5.5) χ = 0.081 .776 .992
2
Impaired glucose tolerance, n (%) 138 (5.6) 4 (16.7) 134 (5.5) χ = 5.649 .017 .783
2
Hypercholesterolemia, n (%) 192 (7.8) 9 (36.0) 183 (7.5) χ = 27.754 <.0001 .005
2
Weight gain, n (%) 280 (11.5) 3 (13.0) 277 (11.5) χ = 0.057 .812 .222
2
Sedation, n (%) 255 (10.1) 5 (20.8) 250 (10.0) χ = 3.099 .078 .005

Abbreviations: QTc, QT interval.

a
Adjusted for the effects of age, sex, regional group, income group, inpatient, and duration of illness.
b
Defined by the United Nations classification: Eastern Asia (China, Hong Kong, Japan, Korea, and Taiwan); Southern Asia (Bangladesh, India, Pakistan,
and Sri Lanka); and Southeastern Asia (Indonesia, Malaysia, Myanmar, Singapore, Thailand, and Vietnam).
c
Defined by the World Bank list of economies: high income (Hong Kong, Japan, Korea, Singapore, and Taiwan); upper middle income (China, Malaysia,
and Thailand); and lower middle income (Bangladesh, India, Indonesia, Myanmar, Pakistan, Sri Lanka, and Vietnam).
d
Defined by the Anatomical Therapeutic Chemical (ATC) classification system: antipsychotics (N05A), mood stabilizers (N03A), antidepressants (N06A),
anxiolytics (N05B and N05C), and antiparkinsonian drugs (N04).

TA BL E 3 Binary logistic model for the distinctive clinical correlates of QTc prolongation (n = 2553)
a a
B SE Wald Adjusted P-value Adjusted odds ratio 95% confidence interval
Amisulpride 1.676 0.650 6.666 .010 5.355 1.498-19.138
Clozapine 1.537 0.530 8.400 .004 4.652 1.645-13.157
Rigidity 1.595 0.549 8.437 .004 4.926 1.680-14.448
Hypercholesterolemia 1.792 0.522 11.797 .001 6.000 2.158-16.680

Abbreviation: QTc, QT interval.

a
Adjusted for the effects of age, sex, regional group, income group, inpatient, and duration of illness.

sex- and age- matched healthy controls. It is hypothesized that the
prevalence of QTc prolongation may be affected by previously
established risk factors, such as the use of certain antipsychotics and
newer antidepressants, rather than the psychiatric diagnoses them-
selves. The known risk factors for torsade de pointes are in line with
our findings regarding the increased risk of QTc prolongation due to
significantly older age, being female, and increased duration of illness
14
in patients with schizophrenia. In addition, we found that the major-
ity of patients with QTc prolongation were from countries classified
as high income. This finding may at first seem counter-intuitive; how-
ever, the demographics of participants from high-income countries
consisted mainly of elderly, female patients, who were taking ami-
sulpride and clozapine, sometimes in combination with newer antide-
pressants. The aforementioned clinical characteristics are all known
risk factors of QTc prologation. As such, we hypothesize that these
demographic and clinical characteristics influenced the increased inci-
dence of QTc prolongation in participants from high-income
countries.
With regard to the psychopathological characteristics, we found
that patients with schizophrenia without QTc prolongation are more
likely to present with disorganized speech and negative symptoms
than those with QTc prolongation. The findings cannot be simply
PARK ET AL.
explained. We hypothesize that this is because of the difference in
pharmacological antipsychotic treatment between these two groups.
In additional statistical analyses, patients with disorganized speech
had significantly higher prescription rates of haloperidol (χ 2 = 39.574;
2
P < .0001) and levopromazine (χ = 28.224; P < .0001), than those
without disorganized speech. Meanwhile, those with negative symp-
toms had significantly higher prescription rates of blonanserin
2 2
(χ = 16.169; P < .0001), and levopromazine (χ = 11.199; P = .001)
than those without negative symptoms. It has been reported that hal-
operidol, levopromazine, blonaserin, and levopromazine are associated
15
with QTc prolongation. Thus, our hypothesis is that these prescrip-
tion patterns for antipsychotics may play the role of an intervening
variable that results in an inverse correlation between QTc prolonga-
tion and disorganized speech/negative symptoms.
We found that a significantly higher use of amisulpride was
linked to an increased incidence of QTc. This is supported by a
16
meta-analysis by Smith et al, which showed that amisulpride has a
greater effect on QTc prolongation than other commonly used anti-
17
psychotics. Conversely, Merill et al reported that clozapine cannot
be independently associated with QTc prolongation, but rather the
combined effects of clozapine and other QTc prolongation-associ-
ated risk factors are what may contribute to QTc prolongation. With
regard to the patterns of psychotropic drug treatment, we found no
significant difference between patients in the QTc prolongation and
without QTc prolongation groups. Patients with QTc prolongation
tended to use less antipsychotic polypharmacy compared to those
without QTc prolongation. However, a systematic review
18
Takeuchi et al showed that it remains unclear whether antipsy-
chotic polypharmacy worsens QTc prolongation. Thus, despite that,
our results between groups are not statistically significant, it indi-
cates that the effect of antipsychotic polypharmacy on QTc requires
more research. It is currently hypothesized that the relationship
between QTc prolongation and antipsychotic polypharmacy might
be affected by combining its effects with other risk factors (ie, psy-
chotropic prescription patterns and other side effects). We found no
specific differences between other psychotropic medications and
QTc prolongation.
Furthermore, our binary logistic model showed that amisulpride,
clozapine, rigidity, and hypercholesterolemia have distinctive correla-
tions with QTc prolongation. A relationship between QTc prolonga-
tion and hypercholesterolemia can be partly supported by the
19
following findings: A study by Szabo et al, showed that patients with
hyperlipidemia have greater levels of the longest QT interval and QT
dispersion. As mentioned earlier, amisulpride is characterized by its
greater effects on QTc prolongation compared to other commonly
used antipsychotics.
15
Lin et al,
20
reported that clozapine may be one
of predictive factors for QTc prolongation in schizophrenia patients
17
treated with antipsychotics. Studies by Merrill et al and Warner et
21
al, reported that the potential effects of clozapine on QTc prolonga-
tion may be due to the combined effects of all the possible risk factors
associated with clozapine rather than an independent effect on QTc
prolongation. Thus, based on our binary logistic model, we hypothe-
size that clozapine may be distinctively associated with QTc
7
prolongation in terms of its interaction with other psychotropic medi-
cations and other adverse effects.
Furthermore, our findings here indicate a possible relationship
between QTc prolongation and rigidity. This relationship may be
partly explained by the dose–response effects of olanzapine on QT
intervals and prolactin levels reported by Suzuki et al.22
This study has several limitations. First, the REAP-AP survey was
not an epidemiological study in the strictest sense. This is a limitation
with respect to the possible generalization or extrapolation of our
findings. Second, there was a significant size difference between the
two groups—those who presented with QTc prolongation and those
who did not present with QTc prolongation—which were compared.
This means that the statistical analysis was not robust as it was based
on the small number of cases with QTc prolongation (n = 27) and the
large sample size of the comparison group (n = 2526) comprising
patients who did not show QTc prolongation. Third, although a con-
sensus meeting was held prior to the initiation of our study, the inter-
rater reliability for recording of the psychopathological characteristics
and the adverse effects were not evaluated. Fourth, in our findings,
although the prescribing patterns of psychotropic medications were
reported, prescribing periods of psychotropic medications were not
evaluated. Thus, it cannot be guaranteed that a potential effect of
psychotropic medications on the QTc interval has been incompletely
estimated. Fifth, physical diseases of the study subjects were thor-
oughly evaluated. Thus, the potential effects of the physical disease
on QTc prolongation were not evaluated in our study. Further studies
by on antipsychotics-induced QTc prolongation may be warranted using
the detailed information of both prescribing patterns and periods.
In conclusion, despite the limitations, our study revealed that QTc
prolongation was prevalent in 1.1% of Asian patients with schizophre-
nia. The clinical profile of patients with schizophrenia with QTc pro-
longation was characterized by old age, higher incidence among
women, high blood cholesterol levels, lower proportions of disorga-
nized speech and negative symptoms, increased usage of amisulpride
and clozapine, and higher proportions of rigidity, and hypercholester-
olemia than those without QTc prolongation. Moreover, our binary
logistic regression model suggests that amisulpride, clozapine, rigidity,
and hypercholesterolemia might be the greatest potential risk factors
for QTc prolongation in Asian patients with schizophrenia.
OR CI D
Seon-Cheol Park https://orcid.org/0000-0003-3691-4624
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interval prolongation noted in one percent of 2553 Asian
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 Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-186 https://doi.org/10.24869/psyd.2020.176 Original
paper
© Medicinska naklada - Zagreb,
Croatia

RELATIONSHIP BETWEEN BODY MASS INDEX AND

EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH
SCHIZOPHRENIA: THE RESEARCH ON ASIAN PSYCHOTROPIC
PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)
1 2 3 3 4
Seon-Cheol Park , Adarsh Tripathi , Ajit Avasthi , Sandeep Grover , Andi J. Tanra , Takahiro A.
5 6 7 8 9 10 11
Kato , Toshiya Inada , Kok Yoon Chee , Mian-Yoon Chong , Shu-Yu Yang , Sih-Ku Lin , Kang Sim ,
12 13 14 15 16
Yu-Tao Xiang , Afzal Javed , Norman Sartorius , Naotaka Shinfuku & Yong Chon Park
1
Department of Psychiatry, Inje University Haeundae Paik Hospital, Busan, Republic of Korea
2
Department of Psychiatry, King George’s Medical University, Chowk, Lucknow, India
3
Department of Psychiatry, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
4
Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
5
Department of Neuropsychiatry, Graduate School of Medicine, Kyushu University, Fukuoka, Japan
6
Department of Psychiatry and Psychobiology, Nagoya University, Graduate School of Medicine, Nagoya, Japan
7
Tunku Abdul Rahman Institute of Neuroscience, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
8
Chang Gung Memorial Hospital, Chiayi, and Chang Gung University School of Medicine, Taiwan
9
Deparment of Pharmacy, Songde Branch, Tapei City Hospital, Tapei, Taiwan
10
Psychiatric Center, Taipei City Hospital, Taipei, Taiwan
11
West Region, Institute of Mental Health and Yong Loo Lin School of Medicine, National University of Singapore,
Singapore, Singapore
12
Faculty of Health Sciences, Unit of Psychiatry, Institute of Translational Medicine, University of Macau,
Macau SAR, China
13
Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan
14
Association for the Improvement of Mental Health Programmes, Geneva, Switzerland
15
Department of Social Welfare, School of Human Sciences, Seinan Gakuin University, Fukuoka, Japan
16
Department of Neuropsychiatry, Hanyang University Guri Hospital, Guri, Republic of Korea

received: 15.2.2020; revised: 5.3.2020; accepted: 23.5.2020

SUMMARY
Background: Although an inverse relationship between body mass index (BMI) and Parkinson disease (PD) has been repeatedly
re- ported, to our knowledge, the relationship between BMI and antipsychotic-induced extrapyramidal symptoms (EPS) has rarely
been stu- died in patients with schizophrenia. Our study aimed to evaluate the relationship between BMI and EPS in patients with
schizophrenia.
Subjects and methods: Using data from the Research on Asian Psychotropic Prescription Patterns for Antipsychotics (REAP-AP)
study, we compared the prevalence of EPS in 1448 schizophrenia patients stratified as underweight, normal range, overweight pre-
obese, overweight obese I, overweight obese II, and overweight obese III according to the World Health Or ganization (WHO)
classification system for body weight status, and with underweight, normal range, overweight at risk, overweight obese I, and
overweight obese II according to the Asia-Pacific obesity classification.
Results: In the first step of the WHO classification system for body weight status, adjusting for the potential effects of confoun-
ding factors, the multinomial logistic regression model revealed that underweight was significantly associated with greater rates of
bradykinesia and muscle rigidity, and a lower rate of gait disturbance. In the second step of the Asia-Pacific obesity classification,
adjusting for the potential effects of confounding factors, the multinomial logistic regression model revealed that underweight was
significantly associated with a higher rate of muscle rigidity.
Conclusion: Findings of the present study consistently revealed that underweight was associated with a greater rate of muscle
rigidity in a stepwise pattern among Asian patients with schizophrenia. Although the mechanism underlying the inverse relationship
between BMI and muscle rigidity cannot be sufficiently explained, it is speculated that low BMI may contribute to the development of
muscle rigidity regardless of antipsychotic "typicality" and dose in patients with schizophrenia.

Key words: antipsychotics - Asian, body mass index (BMI) - extrapyramidal symptoms (EPS) - muscle rigidity - schizophrenia

* * * * *
INTRODUCTION
An inverse relationship between body mass index
(BMI) and Parkinson disease (PD) has been reported by
previous studies, despite several controversies. Low BMI
has been regarded as a risk factor for PD regardless of
the confounding factors including smoking, caffeine
and alcohol (Logroscino et al. 2007, Noyce et al. 2017).
5-hydroxytryptamine-1A (5-HT1A) receptor agonist can
reduce the motor deficits in PD as well as antipsychotic-

176
 Seon-Cheol Park, Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J. Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon
Chong, Shu-Yu Yang, Sih-Ku Lin, Kang Sim, Yu-Tao Xiang, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park:
RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
THE RESEARCH ON ASIAN PSYCHOTROPIC PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)
Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-186
induced extrapyramidal symptoms (EPS) in schizo-
phrenia because serotonergic input from the dorsal
raphe nucleus can modulate dopaminergic neurons of
the substantia nigra. Hence, 5-HT1A receptor agonist has
been regarded as a promising therapeutic agent for PD
and schizophrenia (Haleem 2015, Ohno 2011). Also,
from the viewpoint of neuro-inflammation, the micro-
glial activation associated with both PD and EPS can be
a cause for prostaglandin release (Arora et al. 2018).
Furthermore, because the facilitatory role of dopamine
D2 receptor agonists on movement can be potentiated by
blocking the cannabinoid CB1 receptor, the endogenous
cannabinoid system has been suggested as a novel thera-
peutic target for dopamine-related diseases including
PD and psychosis (De Fonseca et al. 2001). It can, there-
fore, be speculated that common biological underpin-
nings may be shared by both core parkinsonian symp-
toms in PD and antipsychotic-induced EPS in schizo-
phrenia. However, to our knowledge, the relationship
between BMI and antipsychotic-induced EPS has been
rarely studied. Therefore, using data from the Research
on Asian Psychotropic Prescription Patterns for Anti-
psychotics (REAP-AP) study, the largest international
collaborative psychiatric survey in Asia (Park et al.
2018), we aimed to clarify the relationship between BMI
and EPS in Asian patients with schizophrenia. Among
Asian patients with schizophrenia, BMI groups were
categorized according to the World Health Organization
(WHO) classification system for body weight status
(World Health Organization 1998) and the Asia-Pacific
obesity classification (International Obesity Task Force
2000). Additionally, we aimed to compare findings re-
garding the relationship between BMI and EPS accor-
ding to the different obesity classification systems.
SUBJECTS AND METHODS
As described elsewhere (Park et al. 2018), in the
fourth REAP-AP, a consecutive recruitment of 3,744
patients with schizophrenia was conducted from 71
survey centers in 15 Asian countries including Bangla-
desh, China, Hong Kong, India, Indonesia, Japan, Korea,
Malaysia, Myanmar, Pakistan, Singapore, Sri Lanka,
Taiwan, Thailand and Vietnam from March to June 2016.
The institutional review boards of Taipei City Hospital,
Taipei, Taiwan (receipt number: TCHIRB-10412128-E)
and other survey centers approved the study protocols
and informed consent forms. All study subjects signed
the informed consent form prior to their participation in
the study. Using the predefined case report form, the
baseline characteristics and pharmacotherapy-related
details were collected by the study coordinators, under
the supervision of clinical psychiatrists. In our study, the
analysis of data from the REAP-AP study was per-
formed, and the subjects who met the following inclu-
sion criteria were selected: (i) a diagnosis of schizo-
phrenia according to the International Classification of
th
Diseases, 10 Revision (ICD-10) (World Health Organi-
zation 1992), (ii) pharmacotherapy with antipsychotics,
and (iii) availability of the complete Drug-induced
Extrapyramidal Symptom Scale (DIEPSS) data (Inada
2009, Kim et al. 2002). Finally, we included 1448
schizophrenia patients recruited from India, Indonesia,
Japan, Taiwan and Malaysia.
In the first step, BMI, defined as weight in kilograms
2
(kg) divided by height in meters squared (m ), was used
to categorize schizophrenia patients into 6 groups ac-
cording to the WHO classification system for body
weight status (World Health Organization 1998) as
2
follows: underweight (<18.50 kg/m ), normal range
2
(18.50–24.99 kg/m ), overweight (pre-obese (25.00–
2
29.99 kg/m )), overweight obese I (30.00–34.99 kg/m ),
2
overweight obese II (35.00–39.99 kg/m ), and
2
overweight
2
obese III (>40.00 kg/m ). However, compared with Euro-
peans, Asians who exhibit risks associated with obesity
are increased in those with lower BMIs, and Pacific
Islanders exhibit lower body fat levels for the same BMI.
Therefore, in the second step, schizophrenia patients were
categorized into 5 groups according to the Asia-Pacific
obesity classification (International Obesity Task Force
2
2000) as follows: underweight (<18.50 kg/m ); normal
2
range (18.50–22.99 kg/m ); overweight at risk (23.00–
2 2
24.99 kg/m ); overweight obese I (25.00–29.9 kg/m );
2
and overweight obese II (>30.00 kg/m ).
The DIEPSS was used to evaluate the antipsychotic-
induced EPS among the study subjects. All the DIEPSS
items, which are gait, bradykinesia, sialorrhea, muscle
rigidity, tremor, akathisia, dystonia, dyskinesia and ove-
rall severity, were rated on a 5-point Likert scale with
scores 0 (normal) to 4 (severe). The inter-rater reliabi-
lity, test-retest reliability and concurrent validity were
assessed. According to the confirmed metric characte-
ristics, the presence of gait, bradykinesia, sialorrhea,
muscle rigidity, tremor, akathisia, dystonia, dyskinesia
and overall severity was indicated by a score of 2 or
higher in each of the items and the presence of parkinso-
nism was indicated by a total sum score of 5 or higher in
5 items including gait, bradykinesia, sialorrhea, muscle
rigidity and tremor (Inada 2009, Kim et al. 2002).
The Brief Psychiatric Rating Scale (BPRS) (Leucht
et al. 2005, Overall & Gorham 1962), the Charlson Co-
morbidity Index (CCI) (Charlson et al. 1987, Quan et al.
2005) and the Anatomical Therapeutic Chemical (ATC)
classification (World Health Organization 2019) were
used to evaluate the psychiatric symptoms, quantify the
comorbid physical disease and classify the used psycho-
tropic drugs among the study subjects, respectively. The
BPRS items - somatic concern, anxiety, emotional with-
drawal, conceptual disorganization, feelings of quilt, ten-
sion, mannerism and posturing, grandiosity, depressed
mood, hostility, suspiciousness, hallucinatory behavior,
motor retardation, uncooperativeness, unusual thought
177
 Seon-Cheol Park, Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J. Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon
Chong, Shu-Yu Yang, Sih-Ku Lin, Kang Sim, Yu-Tao Xiang, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park:
RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
THE RESEARCH ON ASIAN PSYCHOTROPIC PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)
Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-186
content, blunted affect, excitement and disorientation -
were rated on a 7-point Likert scale from scores 1 (not
present) to 7 (very severe) (Leucht et al. 2005, Overall
& Gorham 1962). The CCI evaluated the comorbid
physical diseases based on their weight and was regar-
ded as a predictive factor for long-term outcome. Also,
in our study, the CCI level was classified into 3 groups
according to 1- and 2-year survival rates: 0-1, 2-3 and 4-
5 (Charlson et al. 1987, Quan et al. 2005). Both the
BPRS and the CCI were validated and confirmed by the
study findings (Charlson et al. 1987, Leucht et al. 2005,
Overall & Gorham 1962, Quan et al. 2005). In addition,
based on the ATC classification system (World Health
Organization 2019), psychotropic drugs were classified
into antipsychotics (N05A), anticonvulsants (antiepilep-
tics; N03A), antidepressants (N06A), anxiolytics (N05B
and N05C) and antiparkinsonian drugs (N04). Accor-
ding to the definition of Tandon and coworkers (2010),
antipsychotic medications were dichotomized into first-
or second-generation antipsychotics in an association
with "atypicality", which is defined as a favorable anti-
psychotic effect with a reduced risk of EPS.
In the first step for the WHO obesity classification,
using analysis of covariance (ANCOVA) for continuous
2
variables and the chi-squared (Ȥ ) test for discrete vari-
ables, baseline characteristics and antipsychotic-induced
EPS in schizophrenia patients with underweight, normal
range, pre-obese, obese I, obese II, and obese III were
compared. Multinomial logistic regression analyses were
used to adjust for the potential effect of confounding
factors in terms of the differences in the proportions of
antipsychotic-induced EPS according to the WHO
obesity classification. In the second step for the Asia-
Pacific obesity classification, using ANCOVA for con-
2 tage representation of the country (Ȥ =62.437, P<0.0001),
tinuous variables and the Ȥ test for discrete variables,
baseline characteristics and antipsychotic-induced EPS in
schizophrenia patients with underweight, normal range, at
risk, obese I, and obese II were compared. Multinomial
logistic regression analyses were used to adjust for the
potential effect of confounding factors in terms of the
differences in the proportions of antipsychotic-induced
EPS according to the Asia-Pacific Obesity classification.
Statistical significance was set at P<0.05 (two-tailed) for
all the tests. All statistical analyses were conducted using
IBM SPSS 24 (IBM Co., Armonk, NY, USA).
RESULTS
As shown in Table 1, among 1448 Asian patients
with schizophrenia, the percentages of underweight,
normal range, pre-obese, obese I, obese II, and obese III
were 8.4% (n=122), 56.1% (n=812), 25.3% (n=366),
7.4% (n=107), 1.7% (n=25), and 1.1% (n=16), res-
pectively. The percentage representation of the country
2
(Ȥ =60.692, P<0.0001), regional classification
2
(Ȥ =21.989, P=0.015), income group (Ȥ =32.548,
2 obese II, aOR=0.436, P=0.094) were significantly
2
P<0.0001), enroll- ment as an outpatient (Ȥ =41.957,
P<0.0001), duration
178
2
of illness (Ȥ =60.630, P<0.0001), duration of untreated
2
psychosis (Ȥ =20.028, P=0.029), antidepressants
2
(Ȥ =21.864, P<0.0001), age (F=1767.2, P<0.0001) and
BPRS total score (F=1325.9, P<0.0001) were signifi-
cantly different among schizophrenia patients with nor-
mal range, pre-obese, obese I, obese II, and obese III in
terms of the WHO classification system for body weight
status. Multinomial logistic regression analyses were
used to adjust for the potential effects of age, regional
classification, income group, enrollment as an outpa-
tient, duration of illness, duration of untreated psychosis,
antidepressants and BPRS total score. Additionally,
underweight was defined as the reference category of
the BMI classification in the multinomial logistic re-
gression analyses. After adjusting for the effect of con-
founding factors, the presence of gait disturbance (nor-
mal range, adjusted odds ratio aOR=0.626, P=0.248;
pre-obese, aOR=0.644, P=0.335; obese I, aOR=0.395,
P=0.151; obese II, aOR=3.868, P=0.041; obese III,
aOR=0.770, P=0.821), bradykinesia (normal range,
aOR=0.518, P=0.035; pre-obese, aOR=0.246, P=0.671;
obese I, aOR=0.387, P=0.054; obese II, aOR=1.451,
P=0.544; obese III, aOR=1.704, P=0.474), and muscle
rigidity (normal range, aOR=0.432, P=0.004; pre-obese,
aOR=0.717, P=0.308; obese I, aOR=0.333, P=0.031;
obese II, aOR=0.596, P=0.523; obese III, aOR=0.344,
P=0.333) were significantly different among the divided
patient groups based on the WHO classification system
for body weight status.
As shown in Table 2, the percentages of under-
weight, normal range, at risk, obese I, and obese II were
8.4% (n=122), 37.1% (n=537), 19.0% (n=275), 25.3%
(n=366), and 10.2% (n=148), respectively. The percen-
2
2
regional classification (Ȥ =23.577, P=0.003), income
2
group (Ȥ =32.841, P<0.0001), enrollment as an outpatient
2 2
(Ȥ =42.164, P<0.0001), duration of illness (Ȥ =54.674,
2
P<0.0001), antidepressants (Ȥ =21.484, P<0.0001), and
age (F=3557.8, P<0.0001) were significantly different
among schizophrenia patients with underweight, normal
range, at risk, obese I, and obese II in terms of the Asia-
Pacific obesity classification. Multinomial logistic re-
gression analyses were used to adjust for the potential
effects of age, regional classification, income group, en-
rollment as an outpatient, duration of illness, and anti-
depressants. Additionally, underweight was defined as
the reference category for the BMI classification in
multinomial logistic regression analyses. After adjusting
for the effect of confounding factors, the presence of
muscle rigidity (normal range, aOR=0.569, P=0.035; at
risk, aOR=0.387, P=0.003; obese I, aOR=0.241,
P=0.715; obese II, aOR=0.430, P=0.034) and akathisia
(normal range, aOR=0.641, P=0.176; at risk,
aOR=0.440, P=0.034; obese I, aOR=0.643, P=0.214;
different among the divided patient groups based on the
Asia- Pacific obesity classification system.
 Table 1. Antipsychotic-induced extrapyramidal symptoms divided into groups according to the World Health Organization (WHO) classification system for body
weight status in Asian patients with schizophrenia (n=1448)

Seon-Cheol Park, Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J. Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon
RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
Overweight: Overweight: Overweight: Overweight:
Underweight Normal range Statistical Unadjusted Adjusted

Chong, Shu-Yu Yang, Sih-Ku Lin, Kang Sim, Yu-Tao Xiang, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park:
Pre-obese Obese I Obese II Obese III
(n=122) (n=812) coefficient P-value P-value*
(n=366) (n=107) (n=25) (n=16)

THE RESEARCH ON ASIAN PSYCHOTROPIC PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)

Age, mean (SD) years 35.4 (13.7) 38.4 (12.9) 39.2 (11.5) 41.5 (12.1) 38.5 (11.3) 36.9 (7.1) F=1767.2 <0.0001 -
2
Male, n (%) 69 (56.6) 504 (62.1) 234 (63.9) 53 (49.5) 13 (52.0) 10 (62.5) Ȥ =9.506 0.091 -
2
Country Ȥ =60.692 <0.0001 -
India, n (%) 36 (29.5) 226 (27.8) 125 (34.2) 31 (29.0) 5 (20.0) 3 (18.8)
Indonesia, n (%) 52 (42.6) 293 (36.1) 85 (23.2) 18 (16.8) 9 (36.0) 6 (37.5)
Japan, n (%) 7 (5.7) 83 (10.2) 41 (11.2) 10 (9.3) 4 (16.0) 0 (0.0)
Malaysia, n (%) 21 (17.2) 105 (12.9) 67 (18.3) 29 (27.1) 5 (20.0) 3 (18.0)
Taiwan, n (%) 6 (4.9) 105 (12.9) 48 (13.1) 19 (17.8) 2 (0.1) 4 (0.3)
2

Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-

Regional classification** Ȥ =21.989 0.015 -
East Asian, n (%) 13 (10.7) 188 (23.2) 89 (24.3) 29 (27.1) 6 (24.0) 4 (25.0)
Southeast Asian, n (%) 73 (59.8) 398 (49.0) 152 (41.5) 47 (43.9) 14 (56.0) 9 (56.3)
South Asian, n (%) 36 (29.5) 226 (27.8) 125 (34.2) 31 (29.0) 5 (20.0) 3 (18.8)
2
Income group*** Ȥ =32.548 < 0.0001 -
High, n (%) 13 (10.7) 188 (23.2) 89 (24.3) 29 (27.1) 6 (24.0) 4 (25.0)
Upper middle, n (%) 21 (17.2) 105 (12.9) 67 (18.3) 29 (27.1) 5 (20.0) 3 (18.8)

186
Lower middle, n (%) 88 (72.1) 519 (63.9) 210 (57.4) 49 (45.8) 14 (56.0) 9 (56.3)
2
Employment, n (%) 19 (15.6) 155 (19.1) 79 (21.6) 22 (20.6) 1 (4.0) 3 (18.8) Ȥ =6.214 0.286 -
2
Outpatient, n (%) 58 (47.5) 340 (51.7) 238 (65.0) 78 (72.9) 21 (84.0) 10 (62.5) Ȥ =41.957 <0.0001 -
2
Duration of illness Ȥ =60.630 <0.0001 -
< 1 year, n (%) 26 (21.3) 158 (19.3) 33 (9.0) 8 (7.5) 2 (8.0) 0 (0.0)
1-5 years, n (%) 33 (27.0) 177 (21.8) 79 (21.6) 20 (18.7) 6 (24.0) 2 (12.5)
5-10 years, n (%) 28 (23.0) 136 (16.7) 65 (17.8) 12 (11.2) 7 (28.0) 2 (12.5)
> 10 years, n (%) 35 (28.7) 341 (42.0) 189 (51.6) 67 (62.6) 10 (40.0) 12 (75.0)
2
DUP Ȥ =20.028 0.029 -
< 3 months, n (%) 43 (35.2) 318 (39.2) 132 (36.1) 44 (41.1) 16 (64.0) 6 (37.5)
3-12 months, n (%) 51 (41.8) 232 (28.6) 124 (33.9) 37 (34.6) 4 (16.0) 5 (31.3)
> 1 year, n (%) 28 (23.0) 262 (32.3) 110 (30.1) 26 (24.3) 5 (20.0) 5 (31.3)
According to the WHO classification system for body weight status, the body mass index was classified into the underweight (<18.50), normal weight (18.50-24.99),
overweight: pre-obese (25.00-29.99), overweight: obese I (30.00-34.99), overweight: obese II (35.00-39.99), and overweight: obese III (>40.00)
* Adjusted for the effects of age, regional classification, income group, enrollment as an outpatient, duration of illness, DUP, total score on the BPRS, and antidepressants;
Underweight was defined as the reference category of the BMI classification in the multinominal logistic regression analyses.
** Defined by United Nations classification: East Asia (Japan and Taiwan), South Asia (India) and Southeast Asia (Indonesia and Malaysia)
*** Defined by the World Bank list of economies : high income (Japan and Taiwan), upper middle income (Malaysia) and lower middle income (India and Indonesia)
BMI - body mass index; BPRS - Brief Psychiatric Rating Scale; CCI - Charlson comorbidity index; DUP - duration of untreated psychosis; FGA - first-generation
antipsychotics; SGA - second-generation antipsychotics; WHO - World Health Organization; a - normal range; b - pre-obese; c - obese I; d - obese II; e - obese III
179
 Table 1. Continues
180

Overweight: Overweight: Overweight: Overweight:

Seon-Cheol Park, Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J. Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon
RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
Underweight Normal range Statistical Unadjusted Adjusted
(n=122) (n=812) Pre-obese Obese I Obese II Obese III coefficient P-value P-value*

Chong, Shu-Yu Yang, Sih-Ku Lin, Kang Sim, Yu-Tao Xiang, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park:
(n=366) (n=107) (n=25) (n=16)
2
Cigarette smoking Ȥ =10.847 0.370 -

THE RESEARCH ON ASIAN PSYCHOTROPIC PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)

Current, n (%) 29 (24.8) 260 (33.1) 95 (27.1) 28 (26.7) 6 (25.0) 4 (25.0)
Previous, n (%) 12 (10.3) 59 (7.5) 33 (9.4) 8 (7.6) 3 (12.5) 3 (18.8)
No, n (%) 76 (65.0) 466 (59.4) 222 (63.4) 69 (65.7) 15 (62.5) 9 (56.3)
2
CCI level Ȥ =16.645 0.341 -
0-1, n (%) 101 (82.8) 627 (77.2) 275 (75.1) 73 (68.2) 16 (64.0) 15 (93.8)
2-3, n (%) 19 (15.6) 162 (20.0) 85 (23.2) 29 (27.1) 8 (32.0) 1 (6.3)
4-5, n (%) 2 (1.6) 23 (2.8) 6 (1.6) 5 (4.7) 1 (4.0) 0 (0.0)
BPRS, mean (SD) 35.9 (13.9) 35.4 (13.3) 34.0 (12.6) 31.8 (11.8) 35.4 (13.3) 38.3 (14.1) F=1325.9 <0.0001 -
Psychotropic drugs

Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-

2
FGA, n (%) 41 (33.6) 283 (34.9) 133 (36.3) 35 (32.7) 13 (52.0) 8 (50.0) Ȥ =5.259 0.385 -
2
SGA, n (%) 104 (85.2) 677 (83.4) 307 (83.9) 94 (87.9) 19 (76.0) 11 (68.8) Ȥ =5.345 0.375 -
2
Antiparkinson, n (%) 49 (40.2) 308 (37.9) 124 (33.9) 48 (44.9) 11 (44.0) 2 (12.5) Ȥ =9.675 0.085 -
2
Anticonvulsants, n (%) 9 (7.4) 72 (8.9) 35 (9.6) 12 (11.2) 2 (8.0) 2 (12.5) Ȥ =1.422 0.922 -
2
Anxiolytics, n (%) 41 (33.6) 264 (32.5) 93 (25.4) 33 (30.8) 6 (24.0) 4 (25.0) Ȥ =7.317 0.198 -
2
Antidepressants, n (%) 9 (7.4) 53 (6.5) 53 (14.5) 14 (13.1) 2 (8.0) 2 (12.5) Ȥ =21.864 <0.0001 -
2 a
Gait, n (%) 9 (7.8) 66 (8.1) 28 (7.7) 5 (4.7) 6 (24.0) 2 (12.5) Ȥ =10.874 0.054 0.254

186
b
0.331
c
0.151 d
0.041
e
0.820
2 a
Bradykinesia, n (%) 18 (14.8) 89 (11.0) 46 (12.6) 8 (7.5) 5 (20.0) 3 (18.8) Ȥ =6.094 0.297 0.036
b
0.242
c
0.054 d
0.541
e
0.472
2 a
Sialorrhea, n (%) 9 (7.4) 67 (8.3) 27 (7.4) 8 (7.5) 3 (12.0) 2 (12.5) Ȥ =1.349 0.930 0.482
b
0.665
c
0.639 d
0.241
e
0.958
According to the WHO classification system for body weight status, the body mass index was classified into the underweight (<18.50), normal weight (18.50-24.99),
overweight: pre-obese (25.00-29.99), overweight: obese I (30.00-34.99), overweight: obese II (35.00-39.99), and overweight: obese III (>40.00)
* Adjusted for the effects of age, regional classification, income group, enrollment as an outpatient, duration of illness, DUP, total score on the BPRS, and antidepressants;
Underweight was defined as the reference category of the BMI classification in the multinominal logistic regression analyses.
** Defined by United Nations classification: East Asia (Japan and Taiwan), South Asia (India) and Southeast Asia (Indonesia and Malaysia)
*** Defined by the World Bank list of economies : high income (Japan and Taiwan), upper middle income (Malaysia) and lower middle income (India and Indonesia)
BMI - body mass index; BPRS - Brief Psychiatric Rating Scale; CCI - Charlson comorbidity index; DUP - duration of untreated psychosis; FGA - first-generation
antipsychotics; SGA - second-generation antipsychotics; WHO - World Health Organization; a - normal range; b - pre-obese; c - obese I; d - obese II; e - obese III
 Table 1. Continues
Overweight: Overweight: Overweight: Overweight:

Seon-Cheol Park, Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J. Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon
RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
Underweight Normal range Statistical Unadjusted Adjusted
Pre-obese Obese I Obese II Obese III
(n=122) (n=812) coefficient P-value P-value*

Chong, Shu-Yu Yang, Sih-Ku Lin, Kang Sim, Yu-Tao Xiang, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park:
(n=366) (n=107) (n=25) (n=16)
2 a
Rigidity, n (%) 25 (20.5) 88 (10.8) 47 (27.5) 7 (6.4) 3 (12.0) 1 (6.3) Ȥ =13.628 0.021 0.005 b

THE RESEARCH ON ASIAN PSYCHOTROPIC PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)

0.251 c
0.032 d
0.537
e
0.347
2 a
Tremor, n (%) 20 (16.4) 136 (16.7) 72 (19.7) 16 (15.0) 4 (16.0) 3 (18.8) Ȥ =2.142 0.829 0.336
b
0.048 c
0.433 d
0.345
e
0.829
2 a
Akathisia, n (%) 15 (12.3) 59 (7.3) 28 (7.7) 5 (4.7) 2 (8.0) 0 (0.0) Ȥ =6.634 0.249 0.156 b
0.664

Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-

c
0.120 d
0.776
e
0.999
2 a
Dystonia, n (%) 9 (7.4) 37 (4.6) 20 (5.5) 1 (1.5) 1 (4.0) 0 (0.0) Ȥ =6.675 0.246 0.087 b
0.361 c
0.996 d
0.869
e
0.999
2 a

186
Dyskinesia, n (%) 4 (3.3) 43 (5.3) 14 (3.8) 3 (2.8) 2 (8.0) 0 (0.0) Ȥ =4.128 0.531 0.323
b
0.896 c
0.976 d
0.219
e
0.999
2 a
Overall, n (%) 23 (18.9) 134 (16.5) 63 (17.2) 15 (14.0) 5 (20.0) 2 (12.5) Ȥ =1.449 0.919 0.554 b
0.783
c
0.518 d
0.598
e
0.915
2 a
Parkinsonism, n (%) 25 (34.7) 131 (31.7) 68 (34.3) 16 (33.3) 5 (33.3) 3 (37.5) Ȥ =0.638 0.986 0.411
b
0.730
d
0.556
e
0.989
According to the WHO classification system for body weight status, the body mass index was classified into the underweight (<18.50), normal weight (18.50-24.99),
overweight: pre-obese (25.00-29.99), overweight: obese I (30.00-34.99), overweight: obese II (35.00-39.99), and overweight: obese III (>40.00)
* Adjusted for the effects of age, regional classification, income group, enrollment as an outpatient, duration of illness, DUP, total score on the BPRS, and antidepressants;
Underweight was defined as the reference category of the BMI classification in the multinominal logistic regression analyses.
** Defined by United Nations classification: East Asia (Japan and Taiwan), South Asia (India) and Southeast Asia (Indonesia and Malaysia)
*** Defined by the World Bank list of economies : high income (Japan and Taiwan), upper middle income (Malaysia) and lower middle income (India and Indonesia)
BMI - body mass index; BPRS - Brief Psychiatric Rating Scale; CCI - Charlson comorbidity index; DUP - duration of untreated psychosis; FGA - first-generation
antipsychotics; SGA - second-generation antipsychotics; WHO - World Health Organization; a - normal range; b - pre-obese; c - obese I; d - obese II; e - obese III
181
 Table 2. Antipsychotic-induced extrapyramidal symptoms divided into groups according to the Asia-Pacific obesity classification in Asian patients with schizophrenia
182

(n=1448)

Seon-Cheol Park, Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J. Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon
RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
Overweight: Overweight: Overweight:
Underweight Normal range Statistical Unadjusted Adjusted

Chong, Shu-Yu Yang, Sih-Ku Lin, Kang Sim, Yu-Tao Xiang, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park:
At risk Obese I Obese II
(n=122) (n=537) coefficient P-value P-value*
(n=275) (n=366) (n=148)

THE RESEARCH ON ASIAN PSYCHOTROPIC PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)

Age, mean (SD) years 35.4 (13.7) 38.1 (13.2) 39.0 (12.4) 39.2 (11.5) 40.5 (11.6) F=3557.8 <0.0001 -
2
Male, n (%) 69 (56.6) 333 (62.0) 171 (62.2) 234 (63.9) 76 (51.4) Ȥ =8.519 0.074 -
2
Country Ȥ =62.437 <0.0001 -
India, n (%) 36 (29.5) 138 (25.7) 88 (32.0) 125 (34.2) 39 (26.4)
Indonesia, n (%) 52 (42.6) 207 (38.5) 86 (31.3) 85 (23.2) 33 (22.3)
Japan, n (%) 7 (5.7) 64 (11.9) 19 (6.9) 41 (11.2) 14 (9.5)
Malaysia, n (%) 21 (17.2) 63 (11.7) 42 (15.3) 67 (18.3) 37 (25.0)
Taiwan, n (%) 6 (4.9) 65 (12.1) 40 (14.5) 48 (13.1) 25 (16.9)

Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-

2
Regional classification** Ȥ =23.577 0.003 -
East Asian, n (%) 13 (10.7) 129 (24.0) 59 (21.5) 89 (24.3) 39 (26.4)
Southeast Asian, n (%) 73 (59.8) 270 (50.3) 128 (46.5) 152 (41.5) 70 (47.3)
South Asian, n (%) 36 (29.5) 138 (25.7) 88 (32.0) 125 (34.2) 39 (26.4)
2
Income group*** Ȥ =32.841 <0.0001 -
High, n (%) 13 (10.7) 129 (24.0) 59 (21.5) 89 (24.3) 39 (26.4)
Upper middle, n (%) 21 (17.2) 63 (11.7) 42 (15.3) 67 (18.3) 37 (25.0)

186
Lower middle, n (%) 88 (72.1) 345 (64.2) 174 (63.3) 210 (48.6) 72 (48.6)
2
Employment, n (%) 19 (15.6) 100 (18.6) 55 (20.0) 79 (21.6) 26 (17.6) Ȥ =2.847 0.584 -
2
Outpatient, n (%) 58 (47.5) 268 (49.9) 152 (55.3) 238 (65.0) 109 (73.6) Ȥ =42.164 <0.0001 -
2
Duration of illness Ȥ =54.674 <0.0001 -
< 1 year, n (%) 26 (21.3) 108 (20.1) 50 (18.2) 33 (9.0) 10 (6.8)
1-5 years, n (%) 33 (27.0) 121 (22.5) 56 (20.4) 79 (21.6) 28 (18.9)
5-10 years, n (%) 28 (23.0) 85 (15.8) 51 (18.5) 65 (17.8) 21 (14.2)
> 10 years, n (%) 35 (28.7) 223 (41.5) 118 (42.9) 189 (51.6) 89 (60.1)
2
DUP Ȥ =14.492 0.070 -
< 3 months, n (%) 43 (35.2) 210 (39.0) 108 (39.3) 132 (36.1) 66 (44.6)
3-12 months, n (%) 51 (41.8) 152 (28.3) 80 (29.1) 124 (33.9) 46 (31.1)
> 1 year, n (%) 28 (23.0) 175 (32.6) 87 (31.6) 110 (30.1) 36 (24.3)
According to the WHO classification system for body weight status, the body mass index was classified into the underweight (<18.50), normal weight (18.50-24.99),
overweight: pre-obese (25.00-29.99), overweight: obese I (30.00-34.99), overweight: obese II (35.00-39.99), and overweight: obese III (>40.00)
* Adjusted for the effects of age, regional classification, income group, enrollment as an outpatient, duration of illness, DUP, total score on the BPRS, and antidepressants;
Underweight was defined as the reference category of the BMI classification in the multinominal logistic regression analyses.
** Defined by United Nations classification: East Asia (Japan and Taiwan), South Asia (India) and Southeast Asia (Indonesia and Malaysia)
*** Defined by the World Bank list of economies : high income (Japan and Taiwan), upper middle income (Malaysia) and lower middle income (India and Indonesia)
BMI - body mass index; BPRS - Brief Psychiatric Rating Scale; CCI - Charlson comorbidity index; DUP - duration of untreated psychosis; FGA - first-generation
antipsychotics; SGA - second-generation antipsychotics; WHO - World Health Organization; a - normal range; b - at risk; c - obese I; d - obese II
 Table 2. Continues

Seon-Cheol Park, Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J. Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon
RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
Overweight: Overweight: Overweight:
Underweight Normal range Statistical Unadjusted Adjusted
At risk Obese I Obese II

Chong, Shu-Yu Yang, Sih-Ku Lin, Kang Sim, Yu-Tao Xiang, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park:
(n=122) (n=537) coefficient P-value P-value*
(n=275) (n=366) (n=148)
2
Cigarette smoking Ȥ =15.014 0.059 -

THE RESEARCH ON ASIAN PSYCHOTROPIC PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)

Current, n (%) 29 (24.8) 186 (35.9) 74 (27.7) 95 (27.1) 38 (26.2)
Previous, n (%) 12 (10.3) 41 (7.9) 18 (6.7) 33 (9.4) 14 (9.7)
No, n (%) 76 (65.0) 291 (56.2) 175 (65.5) 222 (63.4) 93 (64.1)
2
CCI level Ȥ =18.255 0.108 -
0-1, n (%) 101 (82.8) 422 (78.6) 205 (74.5) 275 (75.1) 104 (70.3)
2-3, n (%) 19 (15.6) 96 (17.9) 66 (24.0) 85 (23.2) 38 (25.7)
4-5, n (%) 2 (1.6) 19 (3.6) 4 (1.5) 6 (1.6) 6 (4.1)
BPRS, mean (SD) 35.9 (1.4) 35.9 (0.7) 34.5 (1.0) 34.0 (0.8) 33.0 (1.2) F=1.635 0.163 -

Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-

Psychotropic drugs
2
FGA, n (%) 41 (33.6) 186 (34.5) 98 (35.6) 133 (36.3) 56 (37.8) Ȥ =0.915 0.922 -
2
SGA, n (%) 104 (85.2) 446 (83.1) 231 (84.0) 307 (83.9) 124 (83.8) Ȥ =0.406 0.982
-
2
Antiparkinson, n (%) 49 (40.2) 203 (37.8) 105 (38.2) 124 (33.9) 61 (41.2) Ȥ =3.363 0.499 -
2
Anticonvulsants, n (%) 9 (7.4) 47 (8.8) 25 (9.1) 35 (9.6) 16 (10.8) Ȥ =1.133 0.889 -
2
Anxiolytics, n (%) 41 (33.6) 171 (31.8) 93 (33.8) 93 (25.4) 43 (29.1) Ȥ =7.065 0.132 -

186
2
Antidepressants, n (%) 9 (7.4) 37 (6.9) 16 (5.8) 53 (14.5) 18 (12.2) Ȥ =21.484 <0.0001 -
Gait, n (%) 41 (33.6) 171 (31.8) 93 (33.8) 93 (25.4) 43 (29.1)
2
Ȥ =0.403 0.982 0.942 a
0.923 b
0.657 c
0.449 d
Bradykinesia, n (%) 18 (14.8) 64 (11.9) 25 (9.1) 46 (12.6) 16 (10.8)
2
Ȥ =3.325 0.505 0.335 a
0.118 b
0.801 c
0.551 d
Sialorrhea, n (%) 9 (7.4) 48 (8.9) 19 (6.9) 27 (7.4) 13 (8.8)
2
Ȥ =1.466 0.833 0.507 a
0.914 b
0.969 c
0.735 d
According to the WHO classification system for body weight status, the body mass index was classified into the underweight (<18.50), normal weight (18.50-24.99),
overweight: pre-obese (25.00-29.99), overweight: obese I (30.00-34.99), overweight: obese II (35.00-39.99), and overweight: obese III (>40.00)
* Adjusted for the effects of age, regional classification, income group, enrollment as an outpatient, duration of illness, DUP, total score on the BPRS, and antidepressants;
Underweight was defined as the reference category of the BMI classification in the multinominal logistic regression analyses.
** Defined by United Nations classification: East Asia (Japan and Taiwan), South Asia (India) and Southeast Asia (Indonesia and Malaysia)
*** Defined by the World Bank list of economies : high income (Japan and Taiwan), upper middle income (Malaysia) and lower middle income (India and Indonesia)
BMI - body mass index; BPRS - Brief Psychiatric Rating Scale; CCI - Charlson comorbidity index; DUP - duration of untreated psychosis; FGA - first-generation
antipsychotics; SGA - second-generation antipsychotics; WHO - World Health Organization; a - normal range; b - at risk; c - obese I; d - obese II; e - obese II
183
 Table 2. Continues
184

Seon-Cheol Park, Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J. Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon
RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
Overweight: Overweight: Overweight:
Underweight Normal range Statistical Unadjusted Adjusted
At risk Obese I Obese II

Chong, Shu-Yu Yang, Sih-Ku Lin, Kang Sim, Yu-Tao Xiang, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park:
(n=122) (n=537) coefficient P-value P-value*
(n=275) (n=366) (n=148)
Rigidity, n (%) 25 (20.5) 65 (12.1) 23 (8.4) 47 (12.8) 11 (7.4)
2
Ȥ =15.017 0.004 0.035 a

THE RESEARCH ON ASIAN PSYCHOTROPIC PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)

0.003 b
0.241 c
0.034 d
Tremor, n (%) 20 (16.4) 95 (17.7) 41 (14.9) 72 (19.7) 23 (15.5)
2
Ȥ =2.980 0.561 0.635 a
0.835 b
0.217 c
0.811 d
Akathisia, n (%) 15 (12.3) 43 (8.0) 16 (5.8) 28 (7.7) 7 (4.7)
2
Ȥ =6.988 0.137 0.176 a
0.034 b
0.214 c

Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-

0.094 d
Dystonia, n (%) 9 (7.4) 28 (5.2) 9 (3.3) 20 (5.5) 2 (1.4)
2
Ȥ =7.708 0.103 0.511 a
0.134 b
0.721 c
0.069 d
Dyskinesia, n (%) 4 (3.3) 27 (5.0) 16 (5.8) 14 (3.8) 5 (3.4)
2
Ȥ =2.661 0.616 0.442 a
0.283 b
0.607 c

186
0.727 d
Overall, n (%) 23 (18.9) 84 (15.6) 50 (18.2) 63 (17.2) 22 (14.9)
2
Ȥ =1.698 0.791 0.624 a
0.926 b
0.951 c
d
0.997
Parkinsonism, n (%) 25 (34.7) 91 (34.1) 40 (27.4) 68 (34.3) 24 (33.8)
2
Ȥ =2.499 0.646 0.612 a
0.246 b
0.809 c
0.965 d
According to the WHO classification system for body weight status, the body mass index was classified into the underweight (<18.50), normal weight (18.50-24.99),
overweight: pre-obese (25.00-29.99), overweight: obese I (30.00-34.99), overweight: obese II (35.00-39.99), and overweight: obese III (>40.00)
* Adjusted for the effects of age, regional classification, income group, enrollment as an outpatient, duration of illness, DUP, total score on the BPRS, and antidepressants;
Underweight was defined as the reference category of the BMI classification in the multinominal logistic regression analyses.
** Defined by United Nations classification: East Asia (Japan and Taiwan), South Asia (India) and Southeast Asia (Indonesia and Malaysia)
*** Defined by the World Bank list of economies : high income (Japan and Taiwan), upper middle income (Malaysia) and lower middle income (India and Indonesia)
BMI - body mass index; BPRS - Brief Psychiatric Rating Scale; CCI - Charlson comorbidity index; DUP - duration of untreated psychosis; FGA - first-generation
antipsychotics; SGA - second-generation antipsychotics; WHO - World Health Organization; a - normal range; b - at risk; c - obese I; d - obese II
 Seon-Cheol Park, Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J. Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon
Chong, Shu-Yu Yang, Sih-Ku Lin, Kang Sim, Yu-Tao Xiang, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park:
RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
THE RESEARCH ON ASIAN PSYCHOTROPIC PRESCRIPTION PATTERNS FOR ANTIPSYCHOTICS (REAP-AP)
Psychiatria Danubina, 2020; Vol. 32, No. 2, pp 176-186
DISCUSSION
In summary, in terms of the WHO classification
system for body weight status, underweight (rather than
normal range, pre-obese, obese I, obese II, or obese III)
was associated with greater rates of bradykinesia and
muscle rigidity and lower rates of gait disturbance
among Asian patients with schizophrenia. Furthermore,
in terms of the Asia-Pacific obesity classification, under-
weight (rather than normal range, at risk, obese I, or
obese II) was associated with greater rates of muscle
rigidity and akathisia. Although different obesity classi-
fication systems were used, our findings consistently
revealed that underweight was associated with a greater
rate of muscle rigidity, in a stepwise pattern, among the
1448 Asian patients with schizophrenia.
Previous investigations on the relationship between
BMI and muscle rigidity have been rare and insuf-
ficient. Since muscle rigidity is regarded as a typical of
PD, based on the speculations about the relationship
between BMI and PD (Logroscino et al. 2007, Noyce et
al. 2017), an inverse relationship between BMI and
muscle rigidity can be elucidated. First, the alterations
in the autonomic nervous system, which are associated
with appetite or metabolism regulation, may increase
the vulnerability to muscle rigidity. The appetite and
weight regulation is closely implicated in hypothalamus.
Also, schizophrenia patients usually have structural and
functional disturbances in the hypothalamus (Klomp et
al. 2012). Thus, there is a possibility that the hypotha-
lamic disturbances may precede the decrease in BMI
and vulnerability to muscle rigidity in patients with
schizophrenia. Second, increased body fat may have a
protective effect on the vulnerability to EPS in patients
with schizophrenia (Cheshire & Wszolek 2005).
Namely, the levels of circulating and central insulin,
which can be affected by the high level of BMI, may
reduce neurodegeneration (Craft and Watson 2004).
Third, brain-derived neurotrophic factor (BDNF) and
regulatory-associated protein of mTOR (RAPTOR) have
been proposed as the candidate genes for the link
between BMI and PD (Logroscino et al. 2007, Noyce et
al. 2017). Since BDNF is a potential therapeutic agent
for neurodegenerative diseases (Nagahara & Tuszynski
2011) and RAPTOR contributes to the links between the
mTOR pathway, macroautophagy, and PD (Bove et al.
2011), these genes may also be associated with the
inverse relationship between BMI and muscle rigidity.
Fourth, poor nutrition-related weight loss, anemia, and
other physical complications might be a contributory
factor to the occurrence of muscle rigidity.
Our study has several limitations. First, the REAP-
AP was designed as a cross-sectional study. The infe-
rences about temporal causality were limited. Second,
physical activity may be inversely associated with both
BMI and EPS (Xu et al. 2010). Third, the possibility
that statistical significance may be different from
clinical significance cannot be excluded. The potential
effects of physical activity on the relationship between
BMI and EPS were not adjusted in our study. Despite
these limitations, our study sufficiently demonstrates
that the BMI is inversely related with muscle rigidity
in Asians with schizophrenia. Our findings suggest
that low BMI may be a risk factor for motor rigidity
irrespective of antipsychotic "typicality" and dose in
patients with schizophrenia.
CONCLUSION
Findings of the present study consistently revealed
that underweight was associated with a greater rate of
muscle rigidity in a stepwise pattern among Asian
patients with schizophrenia. Although the mechanism
underlying the inverse relationship between BMI and
muscle rigidity cannot be sufficiently explained, it is
speculated that low BMI may contribute to the
development of muscle rigidity regardless of anti-
psychotic "typicality" and dose in patients with
schizophrenia.
Acknowledgements:
This work was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korea
government (MSIT) (2019R1A2C1090146).
Conflict of interest: None to declare.
Contribution of individual authors:
Seon-Cheol Park: analyzed the data, wrote the first
draft of the manuscript, revision of manuscript,
agree with results and conclusions and accept final
manuscript.
Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Andi J.
Tanra, Takahiro A. Kato, Toshiya Inada, Kok Yoon
Chee, Mian-Yoon Chong, Shu-Yu Yang, Sih-Ku Lin,
Kang Sim, Yu-Tao Xiang & Afzal Javed: revision of
manuscript, agree with results and conclusions and
accept final manuscript.
Norman Sartorius, Naotaka Shinfuku & Yong Chon
Park: conceived and designed the study, revision of
manuscript, agree with results and conclusions and
accept final manuscript.
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RELATIONSHIP BETWEEN BODY MASS INDEX AND EXTRAPYRAMIDAL SYMPTOMS IN ASIAN PATIENTS WITH SCHIZOPHRENIA:
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PCN
Psychiatry and
Clinical Neurosciences
REGULAR ARTIC LE

Network analysis of the depressive symptom profiles in Asian

patients with depressive disorders: Findings from the Research
on Asian Psychotropic Prescription Patterns for Antidepressants
(REAP-AD)
Seon-Cheol Park, MD, PhD ,1* Eun Young Jang, PhD,2 Yu-Tao Xiang, MD, PhD,3 Shigenobu Kanba, MD, PhD,4
Takahiro A. Kato, MD, PhD ,4 Mian-Yoon Chong, MD, PhD,5 Shih-Ku Lin, MD, PhD,6 Shu-Yu Yang, PhD,7
Ajit Avasthi, MD, PhD,8 Sandeep Grover, MD, PhD ,8 Roy A. Kallivayalil, MD, PhD,9 Pichet Udomratn, MD, PhD,10
Kok Yoon Chee, MD, PhD,11 Andi J. Tanra, MD, PhD,12 Chay-Hoon Tan, MD, PhD,13 Kang Sim, MD, PhD,14
Norman Sartorius, MD, PhD,15 Yong Chon Park, MD, PhD16 and Naotaka Shinfuku, MD, PhD17
Aim: We aimed to estimate the network structures of orders overall. A community-detection algorithm estimated
depressive symptoms using network analysis and evaluated that when excluding psychomotor disturbance as an outlier,
the geographic regional differences in theses network struc- the other nine symptoms formed the largest clinically mean-
tures among Asian patients with depressive disorders. ingful cluster. Geographic and economic variations in net-
Methods: Using data from the Research on Asian Psycho- works of depressive symptoms were evaluated.
tropic Prescription Patterns for Antidepressants (REAP-AD), Conclusion: Our findings demonstrated that the typical
the network of the ICD-10 diagnostic criteria for depressive symptoms of the ICD-10 diagnostic criteria for depressive
episode was estimated from 1174 Asian patients with episode are the most centrally situated within the network of
depressive disorders. The node strength centrality of all depressive symptoms. Furthermore, our findings suggested
ICD-10 diagnostic criteria for a depressive episode was esti- that cultural influences related to geographic and economic
mated using a community-detection algorithm. In addition, distributions of participants could influence the estimated
networks of depressive symptoms were estimated sepa- depressive symptom network in Asian patients with depres-
rately among East Asian patients and South or Southeast sive disorders.
Asian patients. Moreover, networks were estimated sepa-
rately among Asian patients from high-income countries and Keywords: Asian, depressive disorders, depressive symptoms, net-
those from middle-income countries. work analysis, node strength centrality.
Results: Persistent sadness, fatigue, and loss of interest http://onlinelibrary.wiley.com/doi/10.1111/pcn.12989/full
were the most centrally situated within the network of
depressive symptoms in Asian patients with depressive dis-

1
Department of Psychiatry, Inje University Haeundae Paik Hospital, Busan, Republic of Korea
2
Department of Counseling Psychology, Honam University College of Humanities and Social Sciences, Gwangju, Republic of Korea
3
Faculty of Health Sciences, University of Macau, Macau, China
4
Department of Neuropsychiatry, Graduate School of Medicine, Kyushu University, Fukuoka, Japan
5
Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung & Chang Gung University School of Medicine, Linkou, Taiwan
6
Psychiatry Center, Tapei City Hospital, Taipei, Taiwan
7
Department of Pharmacy, Taipei City Hospital and Fu Jen University, Taipei, Taiwan
8
Department of Psychiatry, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
9
Pushpagiri Institute of Medical Sciences, India
10
Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
11
Tunku Abdul Rahman Institute of Neurosciences, Kuala Lumpur, Malaysia
12
Faculty of Medicine, Department of Psychiatry, Hasanuddin University, Makassar, Indonesia
13
Department of Pharmacology, National University Hospital, Singapore
14
Institute of Mental Health, Buangkok Green Medical Park, Singapore
15
Association for the Improvement of Mental Health Programmes, Geneva, Switzerland
16
Department of Neuropsychiatry, Hanyang University Guri Hospital, Guri, Republic of Korea
17
Department of Social Welfare, School of Human Sciences, Seinan Gakuin University, Fukuoka, Japan
* Correspondence: Email: cogito-ergo-sum@hanmail.net

344 © 2020 The Authors

Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.

Psychiatry and Clinical Neurosciences 74: 344–353, 2020

PCN Psychiatry and
Clinical Neurosciences
The heterogeneity of depressive syndrome can be due to the poly-
thetic and operational definition of ‘depressive syndrome’ from the
viewpoint of a categorical approach rather than a dimensional
approach.1,2 Thus, the heterogeneity of depressive syndrome can be
criticized in terms of Wittgenstein’s ‘game’ analogy as follows:
Whereas cases of depressive syndrome are not commonly
underpinned with an ‘essence,’ they are connected by the ‘family
resemblance,’ which denotes extensions of meaning.3 Thus, although
a simpler definition of ‘major depressive disorder’ (MDD) that elimi-
nates the four somatic symptoms from its diagnostic criteria in the
4 5–7
DSM-IV has been proposed, the definition was not further simpli-
fied during the DSM-5 revision process.
As shown in Table 1, according to the ICD-10,8 the
operational diagnostic criteria for depressive episode consists of
(i) the typical
symptoms, including depressed symptoms, loss of interest, and
reduced energy; and (ii) the other common symptoms, including
reduced con-
centration and attention, reduced self-esteem and self-confidence,
ideas of guilt and unworthiness, bleak and pessimistic views of the
future,
ideas or acts of self-harm or suicide, disturbed sleep, and disturbed
appetite. The severity of depressive episodes varies with the
number and severity of depressive symptoms. According to the
DSM-5,9 the operational diagnosis of MDD consists of: (i) the
presence of at least one of the core symptoms of depressed mood and
loss of interest or pleasure; and (ii) the presence of five or more of
the core symptoms and the other depressive symptoms, including
weight loss or gain,
insomnia or hypersomnia, psychomotor agitation or retardation,
fatigue or loss of energy, feelings of worthlessness or excessive guilt,
dimin- ished ability to concentrate or indecisiveness, and recurrent
thoughts of death or recurrent suicidal ideation. As shown in Table 1,
the main dif- ferences in the ICD-10 criteria for depressive episodes
and DSM-5 criteria for MDD are as follows: First, the DSM-5
criteria for depres- sive mood cover the two symptoms of depressive
mood and bleak and pessimistic views for the future included in the
ICD-10 criteria. Hope- lessness, which can be partly consistent with
bleak and pessimistic views in the ICD-10 criteria, has been newly
added as a subjective descriptor to depressive moods in the revision
from DSM-IV to DSM-
10
5. Second, in the ICD-10 criteria, low self-esteem, low self-
reproach, suicidality, and vegetative symptoms are regarded as
better indicators
Table 1. DSM-5 criteria for major depressive disorder vs ICD-10
criteria for depressive episodes
DSM-5 † ICD-10 ‡
Depressed mood Depressed mood
Markedly diminished interest or pleasure† Loss of interest and
Significant weight loss or weight gain enjoyment‡
Insomnia or hypersomnia Reduced energy and
Psychomotor agitation or retardation diminished activity‡
Fatigue or loss of energy Reduced concentration
Feelings of worthlessness or excessive or and attention
inappropriate guilt Reduced self-esteem and
Diminished ability to think or self-confidence
concentrate, or indecisiveness
Ideas of guilt and
Recurrent thoughts of death, recurrent unworthiness
suicidal ideation, or a suicide attempt Bleak and pessimistic
views of the future
Ideas or acts of self-harm
or suicide
Disturbed sleep
Diminished appetite
† ‡
Core symptoms of the DSM-5 criteria for major depressive disorder.
Network analysis of depressive symptoms
for severity than other symptoms, whereas all symptoms are equally
treated in the DSM-5 criteria.
11
In terms of the heterogeneity of the depressive syndrome,
227 different symptom combinations fulfilling the DSM-5 diagnostic
criteria for MDD can be theoretically calculated.12,13 However, in
actual clinical practice, among 1566 patients with MDD in the Rhode
Island Methods to Improve Diagnostic Assessment and Services
(MIDAS) project
13
and 853 patients with MDD in the Clinical
Research Center for Depression (CRESCEND) study,14 only 170 and
only 119 different symptom combinations were identified, respec-
tively. It is thus plausible that interrelated symptom constellations can
be established within the psychopathology of depressive syndrome.
The network approach has recently been suggested as a compu-
tational method to explain the complexity of psychiatric disorders, for
the following reasons15,16: First, the pathways between variables can
be explored and novel and interesting relationships can be identified
by visualization methods used in network psychiatry. Second, the
properties of the network as a whole can be evaluated using the net-
work approach. Third, the variables that are disproportionally related
with the network’s adaptive functioning can be identified by network
psychiatry. Thus, the network approach has been used to reveal a col-
lection of interrelated symptoms within an entire network.
17,18
More-
over, the network analysis approach focuses on the network of
relationships among symptoms but not the observation for manifesta-
tions of an underlying disease.17 While the standard reductionist
model is based on the typical top-down process that ‘symptoms are
the constituent factors of an underlying disease,’ the network analysis
approach basically assumes the bottom-up process that ‘symptoms
and associations among them are the disease itself.’19,20 Therefore,
while the structural equation model states that the common influence
of a latent variable can explain the covariance of constituent symp-
toms, the network analysis approach states that a network of symptom
components is regarded as a psychiatric constitute.21–23 From the
viewpoint of the Wittgensteinian analogy of the language game, cases
of the depressive syndrome are connected by the extension of mean-
ing but not underlying essence. Existence of the relevance of the men-
tal process for a distinctive diagnostic entity may be denied in terms
3
of the heterogeneity of the depressive syndrome. Hence, unlike the
structural equation model, the network analysis approach can present
a novel aspect of the intertwined and interrelated symptoms within
the network of depressive symptoms consistent with nominalism but
24,25
not essentionalism. From the perspective of a network approach,
it is speculated that the central symptoms may be more influential
than peripheral symptoms and facilitate the interrelated symptoms
within the entire network.26–28 Fried et al.29 reported that the DSM
symptoms are not more central than non-DSM symptoms within a
network of depressive symptoms, based on a study of 3462 outpa-
tients with depressive disorders in the Sequenced Treatment Alterna-
tives to Relieve Depression (STAR*D) study. In addition, the findings
29
of Fried et al. have been replicated among 5952 Han Chinese
women who fulfilled the DSM-IV criteria for MDD.30
A strong connection of depressive symptoms or emotions has
been suggested as an appropriate method for exploring the
organization of symptomatology in depressive disorders.31,32 Moreover,
it has been suggested that the patho-facilitative or patho-reactive
influences of spe- cific cultures can result in international differences
33
in clinical manifesta- tions of depressive disorders. Hence, using data
from the Research on Asian Psychotropic Prescription Patterns for
Antidepressants (REAP- AD) survey, which is one of the largest
international research collabora- tions within Asia,34–37 we aimed to
estimate the network structures of depressive symptoms and evaluate
the geographic regional differences in these network structures among
Asian patients with depressive disorders.
Methods
Core symptoms of the ICD-10 criteria for depressive episode.
Study overviews and participants As described elsewhere,34–37 in the REAP-AD survey, 2470 psychiat-
ric patients who had been treated with antidepressants were recruited
Psychiatry and Clinical Neurosciences 74: 344–353, 2020 345
Network analysis of depressive symptoms
from 10 Asian countries or special administrative regions – China,
Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore,
Taiwan, and Thailand – during the survey period from March to June
2013. Antidepressants were defined as psychoanaleptics, which were
coded as N06A in the Anatomical and Therapeutic Chemical (ATC)
classification system. The group comprising preparations used in the
treatment of endogenous and exogenous depression was denoted as
N06A antidepressants.38 A consensus meeting was held to ensure the
consistency of evaluating the clinical characteristics of the study par-
ticipants before the initiation of the REAP-AD study. To estimate the
network structures of data from the REAP-AD in this study, we
selected those participants who fulfilled the following criteria:
(i) diagnosis of a depressive episode (F32) or recurrent depressive
8
disorder (F33) according to the ICD-10 by the psychiatrists; and
(ii) availability of the presence or absence of the 10 depressive symp-
tom profiles defined by the ICD-10 diagnostic criteria for depression.8
Consequently 1174 Asian patients with depressive episode or recur-
rent depressive disorder were included for network analyses of
depressive symptoms.
Depressive symptom profiles and geographic and
economic classifications of countries
8 large effect (0.7).46 Epskamp et al.47 recommended only interpreting
Based on the ICD-10 diagnostic criteria for depression, each of the
10 depressive symptoms was evaluated as present or absent within
each participant. The depressive symptom profiles listed in the
National Institute for Health and Care Excellence (NICE) guidelines
for depression were persistent sadness or low mood (SAD), loss of
interest or pleasure (INT), fatigue or low energy (FAT), disturbed
sleep (SLE), poor concentration or indecisiveness (CON), low self-
confidence (SEL), decreased or increased appetite (APE), suicidal
thoughts or acts (SUI), agitated or slowed movements (AGI), and
guilt or self-blame (GUI).39 According to the ICD-10 diagnostic
criteria for depression,8 persistent sadness or low mood, loss of inter-
est or pleasure, and fatigue or low energy were regarded as the most
typical symptoms of depressive disorders.
According to the United Nations (UN) classification, 10
countries or special administrative regions (SAR) were geographically
classified into East Asia (China, Hong Kong, Japan, Korea, and
Taiwan) and South or Southeast Asia (India, Indonesia, Malaysia,
Singapore, and Thailand). Using the World Bank income
designation, countries or SAR were also economically classified into
high- (Hong Kong, Japan, Korea, Singapore, and Taiwan) and
middle-income countries (China, India, Indonesia, Malaysia, and
Thailand).
Statistical analysis
40
Using the R-package qgraph, the network structures of the
10 depressive symptom profiles listed in the NICE guidelines for
depression were estimated. All the depressive symptoms were consid-
ered to be dichotomized-categorical data. Network analyses were per-
formed using polychoric correlations. Depressive symptom network
structures, which consisted of both nodes (symptoms) and edges
(associations among symptoms), were estimated in Asians overall and
East Asians and South or Southeast Asians separately. Furthermore,
the network structures were estimated in Asian patients from high-
income countries and those from middle-income countries separately.
False positive edges were controlled using the least absolute shrink-
41
age and selection operator (LASSO). Thus, the very small edges
were set exactly to zero. Using the graphical LASSO (GLASSO) pro-
cedures in a network in which the edges were partial correlation coef-
ficients, the average edge was defined as the relationship level
between two symptoms, while controlling for all other relationships
within the network. Using shrinkage parameters, the extended Bayes-
ian information criterion was minimized and the underlying network
42,43
structures were recovered. Using the Fruchterman–Reingold algo-
rithm, the stronger connected nodes were placed closer together and
the network was represented graphically. Using a modularity-based
community-detecting algorithm, we investigated whether nodes
346
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Clinical Neurosciences
clustered together. Using the spin-glass algorithm, we tested whether
the number and weighted strength of edges within a cluster exceeded
those within another cluster in terms of the communities in the net-
work.44 Additionally, the spin-glass community function of the R-
package igrah was applied over the GLASSO network (weights = null,
vertex = null, parupdate = false, gamma = 0.5, start temperature = 1,
stop temperature = 0.01, cooling factor = 0.99, spins = 17).
45
In terms of the centrality of all depressive symptoms, the node
strength centrality was defined as the sum of all associations of a
given node with all other nodes. Additionally, the closeness centrality
was defined as a measure of how close a symptom was to all other
symptoms. The betweenness centrality was defined as the shortest
length of a path connecting any two nodes. As the node strength cen-
trality was a common and stable central metric and was substantially
correlated with the closeness centrality or betweenness centrality, the
most central symptoms within the network structures of the 10 depres-
sive symptom profiles were estimated mainly based on node strength
centrality. Centrality stability was operationally defined by the corre-
lation stability coefficient (CS-coefficient), as the CS-coefficient den-
oted the maximum proportion of cases that could be eliminated to
obtain a 95% probability that the ranking correlation between the
original network and the case-subset network would amount to a very
centrality indices with a CS-coefficient above 0.25, but preferentially
above 0.5. Using 95% nonparametric bootstrap confidence intervals
(1000 bootstrap samples) of the difference between each pair of cen-
trality indices, significant differences among centrality indices were
calculated.
Ethics
All the institutional review boards of the Psychiatric Center, Taipei
City Hospital, Taipei, Taiwan (receipt number: TCHIRB-1020206-E)
and other participating survey centers approved the study protocol
and informed consent forms. All participants signed the written
informed consent forms before participation in this survey.
Results
The 1174 Asian patients with depressive disorders included in the
present study consisted of 240 Chinese, 38 Hong Kongese, 142 Japa-
nese, 173 Korean, 38 Singaporean, 130 Indian, 111 Malaysian,
145 Thai, 50 Taiwanese, and 107 Indonesian individuals. Thus,
according to the UN classification, the numbers of Asians overall and
East Asians and South or Southeast Asians were 1174 (100%),
643 (54.8%), and 531 (45.2%), respectively. According to the World
Bank income designation, Asian patients from high- and middle-
income countries were 441 (37.6%) and 773 (62.4%), respectively.
The mean age of the participants was 48.3 (SD = 16.9) years. More
than half of the participants were female (n = 696, 59.3%). A diagno-
sis of depressive episode (F32) was made in three-quarters (n = 881,
75.0%), whereas a diagnosis of recurrent depressive disorder (F33)
was made in one-quarter (n = 293, 25.0%) of the cohort. In terms of
treatment setting, the proportions of public and private settings were
74.5% (n = 875) and 25.5% (n = 299), respectively. In terms of hospi-
tal settings, the proportions of psychiatric, general, university-
affiliated psychiatric, and university-affiliated general hospitals were
37.5% (n = 440), 10.8% (n = 127), 6.7% (n = 79), and 45.0%
(n = 528), respectively. The abbreviations and the presence rates of
the depressive symptom profiles are reported in Table 2.
Estimating a network of depressive symptom profiles in
Asian patients with depressive disorder overall
As shown in Figure 1, a psychopathological network consisting of the
10 depressive symptom profiles listed in the ICD-10 diagnostic
criteria for depression was constructed in 1174 Asian patients with
depressive disorders, and 29 (64.4%) of the possible 45 edges were
estimated to be above zero. The three strongest associations within
the network were between INT and SUI, SEL and AGI, and FAT and
Psychiatry and Clinical Neurosciences 74: 344–353, 2020
PCN Psychiatry and
Clinical Neurosciences Network analysis of depressive symptoms

Table 2. Rate of each of the ICD-10 depressive symptom profiles based on geographic and economic classifications of Asian countries, n (%)

Geographic classification Economic classification

Asians overall East South or HIC MIC

Depressive symptoms Abbreviations (n = 1174) (n = 643) Southeast (n = 531) (n = 441) (n = 733)
Persistent sadness or low SAD 859 (73.2) 484 (75.3) 375 (70.6) 341 (77.3) 518 (70.7)
mood
Loss of interest or pleasure INT 623 (53.1) 353 (54.9) 270 (50.8) 209 (47.4) 414 (56.5)
Fatigue or low energy FAT 536 (45.7) 310 (48.2) 226 (42.6) 206 (46.7) 330 (45.0)
Disturbed sleep SLE 748 (63.7) 406 (63.1) 342 (64.4) 265 (60.1) 483 (65.9)
Poor concentration or CON 348 (29.6) 143 (22.2) 205 (38.6) 89 (20.2) 259 (35.3)
indecisiveness
Low self-confidence SEL 268 (22.8) 157 (24.4) 111 (20.9) 98 (22.2) 170 (23.2)
Poor or increased appetite APE 384 (32.7) 215 (33.4) 169 (31.8) 120 (27.2) 264 (36.0)
Suicidal thoughts or acts SUI 268 (22.8) 158 (24.6) 110 (20.7) 87 (19.7) 181 (24.7)
Agitation or slowing of AGI 267 (22.7) 160 (24.9) 107 (20.2) 141 (32.0) 126 (17.2)
movements
Guilt or self-blame GUI 185 (15.8) 122 (19.0) 63 (11.9) 61 (13.8) 124 (16.9)
HIC, high-income country; MIC, middle-income country.

Strength

CON SAD

AGI FAT

SEL
INT
FAT
APE
INT
SEL
GUI
GUI

APE
CON

SUI
SUI
SAD SLE

SLE AGI

0.00 0.25 0.50 0.75

Fig.1 Network analysis of the depressive symptom profiles in Asian patients with depressive disorder overall (n = 1174). AGI, agitated or slowed movements; APE,
decreased or increased appetite; CON, poor concentration or indecisiveness; FAT, fatigue or low energy; GUI, guilt or self-blame; INT, loss of interest or pleasure;
SAD, persistent sadness or low mood; SEL, low self-confidence; SLE, disturbed sleep; SUI, suicidal thoughts or acts.

GUI. A community-detection analysis estimated that the 10
depressive symptoms were organized into two clinically
meaningful clusters. With AGI being largely isolated, the largest
cluster included the other nine depressive symptoms.
Node strength centralities of the 10 depressive symptoms are
shown in Figure 1. SAD had the greatest node strength centrality in
the network and was considered the most important symptom within
the network. Following SAD, FAT and INT were most significantly
centrally situated. In contrast, due to its virtual disconnection within
the network, AGI had the lowest node strength centrality. The
betweenness and closeness centralities for the 10 depressive symptom
profiles are visualized in Figure S1. An excellent level of stability
was reported for node strength centrality (i.e., CS-coefficient = 0.594),
although both betweenness (i.e., CS-coefficient = 0.050) and close-
ness (i.e., CS-coefficient = 0.050) centralities demonstrated low levels
of stability.
Estimating a network of depressive symptom profiles
based on the geographic classification of Asian
countries
As shown in Figure 2a, a network consisting of the 10 depressive
symptom profiles was constructed in 643 East Asian patients with
depressive disorders, and 34 (75.6%) of the possible 45 edges were
estimated to be above zero. The three strong associations were rev-
ealed between SEL and GUI, SUI and GUI, and FAT and APE within

Psychiatry and Clinical Neurosciences 74: 344–353, 2020 347

Network analysis of depressive symptoms PCN Psychiatry and
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(a) Strength

GUI
SEL
INT FAT

CON SUI

AGI GUI
APE

SEL
FAT
SUI INT

SAD

APE CON
SAD
SLE

SLE AGI

0.00 0.25 0.50 0.75 1.00

(b) Strength

SAD
CON
SEL
AGI
INT
FAT
APE FAT

SEL GUI

INT CON
SAD
APE
GUI
SUI

SLE AGI

SUI SLE

0.0 0.5 1.0 1.00

Fig.2 Network structure and node strength centrality of depressive symptom profiles based on the geographic classification of Asian countries: (a) East Asian patients
with depressive disorder (n = 643) and (b) South or Southeast Asian patients with depressive disorder (n = 531). AGI, agitated or slowed movements; APE, decreased
or increased appetite; CON, poor concentration or indecisiveness; FAT, fatigue or low energy; GUI, guilt or self-blame; INT, loss of interest or pleasure; SAD, persistent
sadness or low mood; SEL, low self-confidence; SLE, disturbed sleep; SUI, suicidal thoughts or acts.

the network. A community-detection analysis estimated a single clini-
cally meaningful cluster consisting of all 10 depressive symptom
profiles.
As shown in Figure 2a, by inspecting the node strength centrali-
ties of the 10 depressive symptom profiles, GUI, FAT, and SUI were
reported as the top three central symptoms within the network. In
contrast, AGI was the least centrally situated symptom within the net-
work. The betweenness and closeness centralities for the 10
depressive symptom profiles are shown in Figure S2. An
interpretable level of stability was reported by node strength
centrality (i.e., CS-coeffi-
cient = 0.360), although low levels of stability were reported for both
betweenness (i.e., CS-coefficient = 0.049) and closeness (i.e., CS-
coefficient = 0.128) centralities.
As shown in Figure 2b, a network consisting of the 10 depres-
sive symptom profiles was constructed in 531 South or Southeast
Asian patients with depressive disorders; 33 (73.3%) of the possible
45 edges were estimated to be above zero. The three strongest
associations were noted between SAD and APE, SAD and SEL,
and SEL and GUI within the network. A community-detection anal-
ysis estimated that the 10 depressive symptoms were organized into
three clinically meaningful clusters. Cluster A included five symp-
toms: INT, FAT, CON, SEL, and AGI. Cluster B included another
three symptoms: SAD, SLE, and APE. Cluster C included two
symptoms: SUI and GUI. As shown in Figure 2b, by inspecting the
node strength centralities of the 10 depressive symptom profiles,
SAD, SEL, and INT were reported as the top three central symp-
toms within the network. In contrast, SLE was the least centrally
situated within the network. The betweenness and closeness central-
ities for the 10 depressive symptom profiles are depicted in
Figure S3. However, an interpretable level of stability was reported
by the node strength (i.e., CS-coefficient = 0.345), although low
levels of stability were reported for both betweenness (i.e., CS-
coefficient < 0.0001) and closeness (i.e., CS-coefficient = 0.087)
centralities.

348 Psychiatry and Clinical Neurosciences 74: 344–353, 2020

PCN Psychiatry and
Clinical Neurosciences Network analysis of depressive symptoms
(a) Strength
SEL
GUI

SUI
GUI
FAT CON

APE

INT SUI INT

AGI
FAT

APE SEL
CON
SAN

SAD SLE

AGI

SLE
0.0 0.2 0.4 0.6

(b) Strength
CON
SAD

FAT
FAT AGI
INT

SEL SEL

APE
APE INT
GUI

CON

SAD GUI SLE

SUI

SLE AGI

SUI 0.0 0.3 0.6 0.9

Fig.3 Network structure and node strength centrality of depressive symptom profiles based on the economic classification of Asian countries: Asian patients from
(a) high-income countries (n = 441) and (b) middle-income countries (n = 733). AGI, agitated or slowed movements; APE, decreased or increased appetite; CON, poor
concentration or indecisiveness; FAT, fatigue or low energy; GUI, guilt or self-blame; INT, loss of interest or pleasure; SAD, persistent sadness or low mood; SEL, low
self-confidence; SLE, disturbed sleep; SUI, suicidal thoughts or acts.

Estimating a network of depressive symptom profiles
based on the economic classification of Asian countries
As shown in Figure 3a, a network consisting of the 10 depressive
symptom profiles was constructed in 441 high-income-country Asian
patients with depressive disorders, and 22 (48.9%) of the possible
45 edges were estimated to be above zero. The three strongest associ-
ations were found between SEL and GUI, SUI and GUI, and INT and
CON within the network. A community-detection analysis estimated
that the 10 depressive symptoms were organized into three clinically
meaningful clusters. Cluster A included five symptoms: INT, FAT,
CON, APE, and AGI. Cluster B included another three symptoms:
SEL, SUI, and GUI. Cluster C included one symptom: SAD. As
shown in Figure 3a, by inspecting the node strength centralities of the
10 depressive symptom profiles, GUI, SUI, and CON were reported
as the top three central symptoms within the network. In contrast,
AGI was the least centrally situated symptom within the network.
The betweenness and closeness centralities for the 10 depressive
symptom profiles are shown in Figure S4. An interpretable level of
stability was reported by the node strength centrality (i.e., CS-
Psychiatry and Clinical Neurosciences 74: 344–353, 2020
coefficient = 0.283), although low levels of stability were reported for
both betweenness (i.e., CS-coefficient = 0.127) and closeness
(i.e., CS-coefficient = 0.128) centralities.
As shown in Figure 3b, a network consisting of the 10 depressive
symptom profiles was constructed in 773 middle-income-country
Asian patients with depressive disorders; 29 (64.4%) of the possible
45 edges were estimated to be above zero. The three strongest associ-
ations were noted between SAD and SLE, INT and SEL, and SAD
and APE within the network. A community-detection analysis esti-
mated that the 10 depressive symptoms were organized into one clini-
cally meaningful cluster including all symptoms. As shown in
Figure 3b, by inspecting the node strength centralities of the
10 depressive symptom profiles, SAD, FAT, and INT were reported
as the top three central symptoms within the network. In contrast,
AGI was the least centrally situated within the network. The between-
ness and closeness centralities for the 10 depressive symptom profiles
are depicted in Figure S5. However, interpretable levels of stability
were reported for the node strength (i.e., CS-coefficient = 0.283) and
closeness (i.e., CS-coefficient = 0.283) centralities, although a low
349
Network analysis of depressive symptoms PCN Psychiatry and
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level of stability was reported for the betweenness centrality (i.e., CS-
coefficient = 0.050).
Discussion
In summary, in Asian patients with depressive disorders overall,
SAD, FAT, and INT were among the top three central symptoms
within the network of ICD-10 depressive symptoms. Although these
top-three central symptoms of Asian patients with depressive disor-
ders overall were equal to the three typical symptoms of the ICD-10
8
diagnostic criteria for depressive episode, the top three central symp-
toms varied within each of the networks of depressive symptoms in
East, South, or Southeast Asian patients with depressive disorders. In
East Asian patients, GUI, FAT, and SUI were the top three central
symptoms within the network. In South Asian patients, SAD, SLE,
and AGI were the top three central symptoms within the network. In
Southeast Asian patients, SAD, SEL, and CON were the top three
central symptoms within the network.
Typical symptoms of the diagnostic criteria for
suicidal rate in men as compared to women globally,55 the reverse pat-
tern has been reported among women in rural areas in Mainland
China. Namely, a preponderance of women who completed suicides is
56
a phe- nomenon limited to China. Second, as compared to American
outpa- tients with MDD, Korean outpatients with MDD were
characterized by more prevalent suicidality and hypochondriasis, and
less prevalent depressed mood.57 Third, in terms of the ‘intersection of
a collectivistic society encountering an individualistic performance-
based system,’ modern-type depression (MTD) has been concurrently
proposed as a culture-specific phenomenon that is prevalent in the
younger Japanese generation. MTD is characterized by mild to
moderate depressive epi- sodes combined with fatigue, blaming others,
impulsive suicidal actions, and so forth.58,59 Importantly, religious
affiliations have been proposed as the most important cultural factor
for affecting human experience, behavior, and illness patterns.60
Although religious affiliations and other cultural contexts have been
influenced by colonization, globalization, and industrialization,33 from
the viewpoint of the Freudian theory, it has been suggested that the
structure of neurotic depression can be continu- ally affected by
Confucianism under the influences of the Sinosphere in
61

depressive episode as the most central symptoms East Asians. Moreover, it is known that Confucianism has the paradox-
within the network of depressive symptoms network. These findings can be influenced by the following cultural
The ICD-10 diagnostic criteria for depressive episodes were fac- tors: First, Chinese women constituted the most substantial
supported by the network of depressive symptoms in Asian patients portion of
with depres- sive disorders overall (n = 1174), as indicated by an East Asians among our study participants. Contrary to the
excellent level of node strength centrality stability. First, all the typical higher
symptoms of the ICD-10 diagnostic criteria for depressive episodes
350
were the most cen- trally situated within the network structure of
depressive symptoms. Sec- ond, within the network of depressive
symptom profiles, loss of interest/ pleasure and fatigue/loss of energy
of the typical symptoms contributed to forming strong associations
with other depressive symptoms. Third, a community-detection
analysis revealed that, excluding psychomotor dis- turbances, a
depressive symptom constellation consisted of all other nine depressive
symptoms. These findings partly supported the actual exis- tence of the
ICD-10 diagnostic criteria for depressive episode as an inter- related
symptom organization. Thus, our findings can support the provisional
ICD-11 diagnostic criteria for single-episode depressive
disorder,48 which is characterized by the depressive symptom profiles
that are similar to the ICD-10 diagnostic criteria.
However, as mentioned in the Introduction, it was repeatedly
reported that there were no significant differences in node strength
centralities between the DSM symptoms and non-DSM symptoms
within the network of depressive symptoms in patients with depres-
29,30
sive disorders. Since the network was estimated only using the
ICD-10 diagnostic criteria for a depressive episode, the differences in
node strength centralities in our study cannot be discussed. Despite
the differences in study samples, our findings were partly consistent
49
with the findings of Garabiles et al., in that fatigue was the most
centrally situated within the network of the Patient Health
Questionnaire-9 items in migrant Filipino domestic workers.

Geographic variations in networks of depressive

symptoms
The networks of depressive symptoms were estimated differently with
respect to geographic variations. Thus, we speculate that geographic
variations in the networks of depressive symptoms could be associ-
ated with cultural influences on depressive symptoms. Although the
heterogeneity of the culture and ethnicity diluted the effect of geo-
50–54
graphic differences in Asian countries, differences in network
structures might be mostly attributed to the pathoplastic effects that
denote the cultural contribution towards the modeling or plastering of
33
manifestations of the depressive symptomatology.
In East Asian patients with depressive disorders, GUI, FAT, and
SUI were the most centrally situated within the network of depressive
symptom profiles. However, SAD was not centrally situated within
the
ical effects of reducing suicidal ideations and increasing the stigma for
62
suicidal survivors. Thus, it is speculated that a unique
depressive
symptom constellation, centrally involving guilt, loss of interest, and
suicidality, is present in East Asian patients with depressive disorders.
Under the influence of Confucianism or Neo-Confucianism, it is
the
‘face’ rather than the ‘mood’ that matters most, resulting in the
suppres- sion of depressive symptoms. The ‘loss of face’ is a sign of
‘remorse’ or
‘guilt’ and
57
is sometimes accompanied by ‘suicidal ideas’ in
Koreans.
Similarly, ‘neurasthenia’ or the fatigue syndrome in the Chinese63 is
also strongly related to depression. Such are the unique cultural
expressions of distress and depression in this region.
In South or Southeast Asian patients with depressive
disorders, SAD, SEL, and INT were the most centrally situated within
the network
of depressive symptom profiles. In the South or Southeast Asian
region, the heterogeneity of the ethnicity and/or culture has been
remarkable. For example, despite being one country, India has more
than 100 differ-
ent ethnicities and more than eight religions, and Malaysia has more
64
than three ethnicities and more than five different religions. Thus,
although these findings cannot be simply explained, they may be
partly based on the report that depressive symptom profiles of South
Asians were charac- terized by significant preponderances of loss of
interest, poor concentra- tion, and poor appetite compared to those of
East and Southeast Asians in other findings of the REAP-AD
64
survey. In 488 Indian elderly patients with depression, ‘feeling
tired or having little energy’ was the most prevalent depressive
symptom, followed by ‘not being able to stop or control worry,’
‘trouble sleeping,’ ‘trouble relaxing,’ ‘worry too much about different
65
things,’ and others. Also, these findings suggest that rather than
fatigue or loss of energy, persistent sadness or low mood and loss of
interests or pleasure are the most central symptoms among the ICD-10
diagnostic criteria for depressive episodes for South or Southeast Asian
patients with depressive disorders. In terms of a strong association
between depressed mood and MDD, low socioeconomic status
and social isolation have been proposed as risk factors for depressed
mood.66
Thus, our findings suggest that approaches that address depressed-
mood- associated clinical factors may be helpful for evaluating and
treating South or Southeast Asian patients with depressive disorders.
Moreover, bleak and pessimistic views in the ICD-10 criteria may
be consistent with hopelessness, which has newly been added as a
subjective descrip- tor for depressed moods in the DSM-5 criteria.
Thus, despite the hetero- geneity of the ethnicity and culture, the
network structure of South or Southeast Asian patients with
depressive disorders may support the DSM-5 diagnostic criteria for
MDD.

Economic variations in networks of depressive

symptoms
Differences in geographic and economic classifications of Asian
countries/SAR were only based on the trade-off between China and
Psychiatry and Clinical Neurosciences 74: 344–353, 2020
PCN Psychiatry and
Clinical Neurosciences
Singapore in our study. Thus, the network structure of depressive
symptoms in East Asian patients with depressive disorders has been
similar to that in Asian patients from high-income countries, whereas
the network structure in South or Southeast Asian patients has been
similar to that in Asian patients of middle-income countries. Thus, as
mentioned earlier, the network structure of depressive symptom pro-
files in Asian patients of high-income countries may be partly
supported by clinical characteristics of Japanese or Korean patients
with depressive disorders57–59 and influenced by Confucianism or
Neo-Confucianism.61,62 Furthermore, the network structure in Asian
patients of middle-income countries may be partly supported by clini-
cal characteristics of Chinese, Indian, or Malaysian patients with
depressive disorders.56,64,65 Although completed suicides have been
predominant in Chinese women, suicidal ideation has been considered
to be an independent factor of depression outside of high-income
countries.66 Thus, based on this relationship between suicidal ideation
and depression outside of high-income countries, it is speculated that
SUI has been the second least central domain within the network
structure of depressive symptom profiles.
Limitations
Our study had several limitations as follows: First, the estimated net-
work structures can change within the clinical course of depressive
disorders. Reanalysis of the STAR*D clinical trial has reported that,
whereas energy-related symptoms are the most centrally situated at
baseline, mood-related symptoms are the most centrally situated at
the end-point.67 However, in our study, depressive disorder patients
with any clinical course were included as study participants. Second,
some of the ICD-10 depressive symptoms have been aggregated
(e.g., combining decreased and increased appetite). However, the
depression-related increase and decrease in appetite has been differen-
tiated in terms of the patterns of aberrant activity in reward and inter-
oceptive neurocircuitry.68 Thus, aggregated depressive symptoms
should be separated in further network analyses of depressive symp-
toms. Third, information for the outdegree centrality and indegree
centrality cannot be provided by the estimated centralities. Fourth,
since a low level of stability has been reported for the node strength
centrality (i.e., CS-coefficient = 0.046) in a network of depressive
symptom profiles in South Asian patients with depressive disorders, a
network has been estimated in South or Southeast Asian patients with
depressive disorders. Stability of the node strength centrality is
defined not by a proper sample size but by a criterion of CS-
47
coefficient > 0.25, whereas the sample size (n = 130) of South
Asian patients with depressive disorders was the smallest. Thus, the
possibility that the heterogeneity of the ethnicity and culture may
influence the network structure of depressive symptom profiles is not
excluded. Fifth, although the REAP-AD survey has recruited the
study participants with a convenient sampling method, a potentiality
of sampling bias cannot be excluded.
Conclusions
Despite these limitations, our study shows that the estimated network
of depressive symptoms among Asian patients with depressive disor-
ders supports the ICD-10 diagnostic criteria for depressive episode. In
addition, the provisionally defined ICD-11 diagnostic criteria for a
single-episode depressive disorder are supported by this study’s find-
ings. However, geographic variations in the networks of the depres-
sive symptoms were present. Herein, although the heterogeneity of
the ethnicity and culture may contribute to dilutions of geographic
differences in clinical manifestations of depressive disorders, cultural
contexts, including religious affiliations, can contribute to differences
in network structures of depressive symptoms among Asian patients
with depressive disorders. Most importantly, it is speculated that a
unique depressive symptom constellation may influence the network
structure of depressive symptom profiles, which is partly inconsistent
with the ICD-10 or DSM-5 criteria, in East Asian patients or high-
income-country patients with depressive disorders.
Psychiatry and Clinical Neurosciences 74: 344–353, 2020
Network analysis of depressive symptoms
Acknowledgments
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korean government (MSIT;
2019R1A2C1090146). We would like to thank Dr Jinseob Kim for
his valuable help with the network analysis.
Disclosure statement
The authors have no conflicts of interest to declare.
Author contributions
S-C.P., Y-T.X., S.K., M-Y.C., S-K.L., S-Y.Y., A.A., S.G., R.A.K.,
P.U., K.Y.C., A.J.T., C-H.T., K.S., N.S., Y.C.P., and N.S. designed
and conducted the study. S-C.P., E.Y.J., and Y.C.P. performed analy-
sis. S-C.P., E.Y.J., and Y.C.P. wrote the manuscript. All authors read
and approved the final manuscript.
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Supporting information
Additional Supporting Information may be found in the online ver-
sion of this article at the publisher’s web-site:

Figure S1. Node strength, betweenness, and closeness centralities of

the 10 depressive symptom profiles in Asian patients with depressive
disorder overall (n = 1174).
PCN Psychiatry and
Clinical Neurosciences Network analysis of depressive symptoms
Figure S2. Node strength, betweenness, and closeness centralities of Figure S4. Node strength, betweenness, and closeness centralities of
the 10 depressive symptom profiles in East Asian patients with the 10 depressive symptom profiles in Asian patients from high-
depressive disorder (n = 643). income countries (n = 441).

Figure S3. Node strength, betweenness, and closeness centralities of Figure S5. Node strength, betweenness, and closeness centralities of
the 10 depressive symptom profiles in South or Southeast Asian the 10 depressive symptom profiles in Asian patients from low-
patients with depressive disorder (n = 531). income countries (n = 733).

Psychiatry and Clinical Neurosciences 74: 344–353, 2020 353

Received: 5 April 2020 Accepted: 24 April 2020
DOI: 10.1111/appy.12393

ORIGINAL ARTICLE

Patterns of long acting injectable antipsychotic use and

associated clinical factors in schizophrenia among 15 Asian
countries and region
1 1 1
Chao Tian Tang MD | Ee Cheong Chua MD | Qian Hui Chew B.Soc.Sci(Hons) |
2 3 4
Yan-Ling He MD | Tian-Mei Si MD | Helen F.-K. Chiu MD |
5 6 6
Yu-Tao Xiang MD | Takahiro A. Kato MD, PhD | Shigenobu Kanba MD, PhD |
7 8 9
Naotaka Shinfuku MD, PhD | Min-Soo Lee MD | Seon-Cheol Park MD |
10 11 12
Yong-Chon Park MD | Mian-Yoon Chong MD | Shih-Ku Lin PhD |
12 13 14
Shu-Yu Yang PhD | Adarsh Tripathi MD | Ajit Avasthi MD |
14 15 16
Sandeep Grover MD | Roy A. Kallivayalil MD | Pichet Udomratn MD |
17 18 19
Kok Yoon Chee MD | Andi J. Tanra MD | Md Golam Rabbani MD |
20 21 21
Afzal Javed MD | Samudra Kathiarachchi MD | Dulshika Waas MD |
22 23 24
Wing Aung Myint MD | Norman Sartorius MD | Van Cuong Tran MD |
24 25 26
Kim Viet Nguyen MD | Chay-Hoon Tan MD | Ross J. Baldessarini MD |
Kang Sim MD1
1
Institute of Mental Health, Buangkok Green Medical Park, Singapore, Singapore
2
Department of Psychiatric Epidemiology, Shanghai Mental Health Center, Shanghai, China
3
Institute of Mental Health, Peking University, Beijing, China
4
Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China
5
Centre for Cognition and Brain Sciences, University of Macau, Macao SAR, China
6
Department of Neuropsychiatry, Graduate School of Medicine, Kyushu University, Fukuoka, Japan
7
Department of Psychiatry, Kobe University, Kobe, Japan
8
Department of Psychiatry, College of Medicine, Korea University, Seoul, South Korea
9
Department of Psychiatry, Inje University Haeundae Paik Hospital, Busan, South Korea
10
Department of Neuropsychiatry, Hanyang University Guri Hospital, Guri, South Korea
11
Department of Psychiatry, Kaoshiung Chang Gung Memorial Hospital and Chang Gung University School of Medicine, Kaohsiung, Taiwan
12
Department of Pharmacy, Taipei City Hospital and Fu Jen University, Taipei, Taiwan
13
Department of Psychiatry, King George's Medical University, Lucknow, India
14
Department of Psychiatry, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
15
Department of Psychiatry, Pushpagiri Institute of Medical Sciences, Tiruvalla, India
16
Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
17
Department of Psychiatry & Mental Health , Tunku Abdul Rahman Institute of Neurosciences, Kuala Lumpur, Malaysia
18
Department of Psychiatry, Hasanuddin University Faculty of Medicine, Makassar, Indonesia
19
Bangladesh Association of Psychiatrists, Dhaka, Bangladesh
20
Pakistan Psychiatric Research Center, Fountain House, Lahore, Pakistan
21
Department of Psychiatry, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
22
Mental Health Society, Myanmar Medical Association, Yangon, Myanmar
23
Association for the Improvement of Mental Health Programmes, Geneva, Switzerland

Asia Pac Psychiatry. 2020;e12393. wileyonlinelibrary.com/journal/appy © 2020 John Wiley & Sons Australia, Ltd 1 of 10
https://doi.org/10.1111/appy.12393
2 of 10 TANG ET AL.

24
Vietnam Psychiatric Association (VPA), Thuong Tin, Hanoi, Vietnam
25
Department of Pharmacology, National University Hospital, Singapore, Singapore
26
International Consortium for Mood & Psychotic Disorder Research , McLean Hospital, Belmont, Massachusetts

Correspondence
Kang Sim, Institute of Mental Health, Abstract
10, Buangkok View, Singapore 539747,
Introduction: Patterns of clinical use of long-acting injectable (LAI) antipsychotic
Republic of Singapore.
Email: kang_sim@imh.com.sg drugs in many countries, especially in Asia, for treatment of patients diagnosed with
chronic psychotic disorders including schizophrenia are not well established.
Methods: Within an extensive research consortium, we evaluated prescription rates
for first- (FGA) and second-generation antipsychotic (SGA) LAI drugs and their clinical
correlates among 3557 subjects diagnosed with schizophrenia across 15 Asian coun-
tries and region.
Results: Overall, an average of 17.9% (638/3557; range: 0.0%-44.9%) of treated sub-
jects were prescribed LAI antipsychotics. Those given LAI vs orally administered
agents were significantly older, had multiple hospitalizations, received multiple anti-
psychotics more often, at 32.4% higher doses, were more likely to manifest disorga-
nized behavior or aggression, had somewhat superior psychosocial functioning and
less negative symptoms, but were more likely to be hospitalized, with higher BMI,
and more tremor. Being prescribed an FGA vs SGA LAI agent was associated with
male sex, aggression, disorganization, hospitalization, multiple antipsychotics, higher
doses, with similar risks of adverse neurological or metabolic effects. Rates of use of
LAI antipsychotic drugs to treat patients diagnosed with schizophrenia varied by
more than 40-fold among Asian countries and given to an average of 17.9% of
treated schizophrenia patients. We identified the differences in the clinical profiles
and treatment characteristics of patients who were receiving FGA-LAI and SGA-LAI
medications.
Discussion: These findings behoove clinicians to be mindful when evaluating
patients' need to be on LAI antipsychotics amidst multifaceted considerations, espe-
cially downstream adverse events such as metabolic and extrapyramidal side effects.

KEYWOR DS
antipsychotic drugs, long-acting injectable, schizophrenia

1 | I NT R O D U C and hospitalization, and potential risk of suicide (Higashi et al., 2013).

T IO N There has been hope that use of long-acting injectable (LAI) or depot
preparations of antipsychotic medications would increase long-term-
Unreliable adherence to prescribed treatment is a major source of lim- treatment-adherence and enhance the effectiveness of treatment.
ited effectiveness of treatment in general, and is of particular concern Such agents started with esters of fluphenazine and haloperidol in the
for patients with schizophrenia and other severe, chronic psychiatric 1960s and 1970s, followed by additional esters as well as agents
disorders (García, Martínez-Cengotitabengoa, & López-Zurbano, 2016; made long-acting by other pharmacological mechanisms
Sendt, Tracy, & Bhattacharyya, 2015) Several large clinical studies (Baldessarini, 2013; Haddad, Brain, & Scott, 2014; Jann &
have documented low levels of long-term treatment adherence Penzak, 2018; Johnson, 2009). There was a resurgence of interest in
among patients diagnosed with schizophrenia. For example, the US LAI antipsychotics after the launch of risperidone in a LAI form based
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) on its incorporation into slowly hydrolyzed carbohydrate micro-
study found that 74% of subjects discontinued oral antipsychotic spheres (Sampson, Hosalli, Furado, & Davis, 2016). This was the first
medication within 18 months (Czobor, Van Dorn, & Citrome, 2015; second-generation depot antipsychotic developed, with similar prepa-
Lieberman et al., 2005). Potential consequences of such treatment rations involving other atypical antipsychotics, including aripiprazole,
nonadherence include markedly increased risks of clinical worsening
TANG ET AL.
olanzapine, and paliperidone (Baldessarini, 2013; Jann & some Asian regions, and that LAI preparations of both FGA and SGA
Penzak, 2018; Rauch & Fleischhacker, 2013). Studies of long-acting-
second-generation antipsychotics (SGAs) have shown consistent
superiority to placebo regarding relapse prevention and symptom
reduction in schizophrenia, as would be expected of clinically
employed treatments with regulatory approval (Keating et al., 2017;
Rauch & Fleischhacker, 2013; Titus-Lay, Ansara, Isaacs, & Ott, 2018).
However, anticipated superiority of LAI vs orally administered anti-
psychotic drug treatment has been found only in some trials—more
often in nonrandomized or retrospective trials, whereas prospective,
randomized trials have not consistently yielded significant differences
between oral and LAI treatments (Buckley, Schooler, & Goff, 2015;
Kirson et al., 2013; Kishimoto et al., 2018).
Reported benefits of treatment with LAI antipsychotics include
lower overall treatment costs, associated in large part with reduction
of costs of hospitalization (Marcus & Olfson, 2008). Clinical benefits
include reduced rates of refusal or discontinuation of treatment, with
more reliable delivery of active drug over time—all of which can con-
tribute to reduced risk of exacerbations of illness (Brissos, Veguilla, &
Taylor, 2014; Siegel, 2005; Subotnik et al., 2015). Treatment involving
injectable antipsychotic drugs can provoke concerns about perceived
intrusiveness and coercion (Patel, de Zoysa, Bernadt, Bindman, &
David, 2010) and such concerns can differ with cultural and other
sociological factors. Often they can be resolved successfully by
greater efforts to discuss pros and cons with patients and to involve
them more actively in treatment decisions (Brissos et al., 2014; Patel
et al., 2010). Physical discomfort and pain at the injection site also are
potential problems of LAI antipsychotics (Bloch, Mendlovic, & tional Review Board at each collaborating site. All participants were
Strupinsky, 2001).
In general, the numbers of well-designed, controlled, and ran-
domized treatment trials comparing orally administered with LAI
antipsychotics are relatively few, and comparisons of LAI prepara-
tions of FGA and SGA agents remain inadequate (Jann &
Penzak, 2018). Additionally, comparisons of such preparations given
at different intervals (from weekly to quarterly) are rare (Carr, Hall, &
Roche-Desilets, 2016). Moreover, information about current accep-
tance of LAI antipsychotics in various Asian cultures is very limited.
Reported rates of use of LAI antipsychotic agents in Western coun-
tries suggest wide regional differences, with usage rates ranging
from 8% to 35% among patients with schizophrenia (Barnes,
Shingleton-Smith, & Paton, 2009; Potkin, Bera, Zubek, & Lau, 2013;
Sneider, Pristed, Correll, & Nielsen, 2015). Our earlier survey, con-
ducted more than a decade ago in six Asian countries found an aver-
age usage rate of 15.3%, with a preference for older, FGA LAI agents
(Sim et al., 2004).
The preceding observations encouraged the present study of a
large sample of patients diagnosed with schizophrenia in 15 Asian
countries and region, to determine the rates of use of LAI prepara-
tions of both FGAs and SGAs in comparison to the use of orally
administered antipsychotic agents. We also sought to identify geo-
graphic and clinical factors that were associated with rates of LAI
usage. Based largely on informal clinical observations, we hypothe-
sized that LAI antipsychotic drug use is becoming more prevalent in
3 of 10
agents are being used.
2 | M ET HOD S
2.1 | Study sample and procedures
We evaluated data collected in 2016 from 3577 subjects with schizo-
phrenia in the Research on Asian Psychotropic prescription patterns
in Schizophrenia (REAP-SZ) project, a pharmaco-epidemiological study
initiated in 1999 (Chong, Tan, & Fujii, 2004). Data collected include
details of usage of both FGA and SGA LAI antipsychotics for patients
diagnosed with schizophrenia across 15 Asian countries and region
(Bangladesh, Hong Kong SAR, India, Indonesia, Japan, Malaysia,
Myanmar, Pakistan, PR China, RO Korea, Singapore, Sri Lanka, Taiwan,
Thailand, and Vietnam). Data collection followed the same protocol at
each site. We recruited consecutive subjects diagnosed with schizo-
phrenia by standard international criteria and receiving antipsychotic
drug treatment in various ambulatory and inpatient settings. Data
recorded included current age, sex, diagnosis, duration of illness, set-
ting of treatment (outpatient or inpatient), selected clinical features,
all medicines and doses prescribed by clinicians responsible for care of
the subjects. Diagnoses were confirmed at each site by experienced
project investigators, following ICD-10(World Health Organization
[WHO], 1992) or Diagnostic and Statistical Manual of Mental Disor-
ders (DSM-5) criteria. The study protocol was approved by an Institu-
fully informed of the aims of the study and provided written, informed
consent for anonymous and aggregate reporting of their findings.
Depot intramuscular injections of antipsychotics and their doses
within 30 days of admission were recorded. Daily doses of antipsy-
chotics, including LAI antipsychotics, were converted to approximate
chlorpromazine equivalents (CPZ-eq mg/day) using guidelines as
described previously (Baldessarini, 2013; Gardner, Murphy, O'Donnell,
Centorrino, & Baldessarini, 2010; Kane et al., 1998).
2.2 | Data analyses
Statistical analyses are based on the Statistical Package for the Social
Sciences (SPSS) (IBM Corp, 2015). Averages are reported as means
±SD or 95% confidence intervals (CI), and rates (%) as well as Odds
Ratios (OR) are reported with confidence intervals (CIs). Normality of
distributions of continuous measures was tested with the
Kolmogorov-Smirnovone-sample test before further analysis. Differ-
ences between subjects receiving a LAI antipsychotic or not were
tested by ANOVA (t-test) for normally distributed continuous data
and nonparametric Mann-WhitneyU tests for nonnormally distributed
continuous data; contingency tables (χ 2) were used for categorical var-
iables. Multivariate logistic regression modeling was used to test for
influences of adjust for relevant covariates and to determine factors
associated significantly and independently with LAI vs oral
 4 of 10
TAB L E 1 Characteristics of 15 samples of Asian schizophrenia patients treated with long-acting injected (LAI) or oral antipsychotics

Age Hospitalized First admission In remission LAI usage LAI use or LAI CPZ-eq Total CPZ-eq
Country Subjects (years) Males (%) (%) (%) (%) (%) [CI] (mg/day) (mg/day)
Bangladesh 50 33.4 ± 10.1 58.0 0.00 - 30.0 16.0 2.91 [1.08-7.85] 219 ± 57.9 580 ± 221
PR China 152 40.9 ± 16.0 65.1 90.8 36.2 48.7 0.66 0.01 [0.01-0.80] 375 ± 10.1 507 ± 277
Hong Kong 31 38.8 ± 13.9 58.1 100.0 9.70 71.0 6.50 1.06 [0.22-5.07] 219 ± 133 391 ± 213
India 475 36.0 ± 11.7 66.5 31.2 55.6 65.7 15.8 2.87 [1.45-5.69] 229 ± 99.9 396 ± 293
Indonesia 539 36.2 ± 10.4 64.0 50.5 45.6 59.7 8.30 1.39 [0.69-2.83] 216 ± 172 333 ± 211
Japan 219 46.6 ± 14.3 62.1 58.4 14.1 35.2 8.20 1.38 [0.62-3.07] 285 ± 91.6 530 ± 491
RO Korea 112 39.3 ± 12.1 44.6 5.40 33.3 42.0 13.4 2.37 [1.02-5.48] 425 ± 193 534 ± 470
Malaysia 292 39.2 ± 12.1 51.7 34.2 24.0 66.8 44.9 12.4 [6.21-24.6] 188 ± 122 345 ± 269
Myanmar 163 37.7 ± 11.2 65.6 55.2 42.2 37.4 6.10 1.00 138 ± 44.5 325 ± 112
Pakistan 287 37.2 ± 11.9 55.1 47.7 20.4 36.9 23.0 4.57 [2.28-9.17] 155 ± 103 647 ± 663
Singapore 160 47.9 ± 13.5 35.6 73.1 11.1 24.4 43.8 11.9 [5.84-24.2] 163 ± 103 397 ± 272
Sri Lanka 96 40.6 ± 13.1 60.4 52.1 34.0 30.2 38.5 9.60 [4.49-20.5] 199 ± 95.3 499 ± 424
Taiwan 392 47.5 ± 11.8 45.7 56.6 7.20 52.6 16.6 3.04 [1.52-6.08] 189 ± 116 341 ± 271
Thailand 319 39.4 ± 12.3 66.5 42.9 32.1 60.2 29.8 6.49 [3.28-12.8] 237 ± 125 414 ± 308
Vietnam 270 39.1 ± 11.7 67.4 100.0 33.3 16.7 0.00 - - 531 ± 336
Totals [95%CI] 3557 39.9 [37.8-47.0] 57.8 [52.5-63.1] 53.2 [36.8-69.7] 28.5 [20.4-36.6] 45.2 [35.8-54.5] 17.9 [9.69-26.0] - 231 [184-278] 451 [395-507]

Note: Data are means ± SD, or OR [with 95%CI]. OR for LAI usage compares with Myanmar as the reference country (OR = 1.00); all OR differ significantly from the null of 1.00, except for Hong Kong, Indonesia,
and Japan. Note that usage rates of LAI antipsychotics are highest in Malaysia (44.9% of schizophrenia patients), Singapore (43.8%), and Sri Lanka (38.5%), and lowest in Vietnam (0.00%) and PR China (0.70%).
CPZ-eq mg/day doses of LAI drugs and total doses of all antipsychotics are not significantly associated with the rate of use of LAI antipsychotics (r = 0.412 and 0.139; both P ≥ .14), nor are total daily doses and
doses of LAI agents correlated (r = 0.345, P = .23).

TANG ET AL.
TANG ET AL.
antipsychotic treatment or differences between subjects given LAI
FGA vs SGA agents. Statistical significance was set at P < .05.
3 | RE SU L T S
Of the 3577 subjects included, mean current age was 39.9 [CI:
37.8-47.0] years (Table 1, Figure 1). The majority of subjects were
male (57.8%) and currently hospitalized (53.2%). Usage of LAI antipsy-
chotics in the 3577 subjects averaged about 17.9% [CI: 9.69-26.0],
with wide international variations, ranging from 0% in Vietnam to
44.9% in Malaysia. The mean dose of LAI antipsychotics, as mg/day
approximately equivalent to orally administered chlorpromazine as a
standard comparator (CPZ-eq) averaged 231 [CI: 184-278] mg/day.
However, the total daily exposure to all antipsychotic drugs averaged
451 [395-507] CPZ-eq mg/day, or nearly twice-more than the dose
of LAI agents only, owing to the use of more than one type of drug in
many subjects (Table 2).
Subjects receiving any LAI (with or without oral supplements) vs
only orally administered antipsychotics were compared (Table 2). Use
of LAI agents differed from oral treatment only in several ways:
(a) demographic factors (older age, and a tendency toward more men
than women), (b) illness features (multiple hospitalizations, disorganized
and negative symptoms, verbal and physical aggression, but not in the
presence of hallucinations or delusions), (c) psychosocial functional
status (superior functioning), (d) treatment characteristics (use of more
than one antipsychotic, higher antipsychotic doses), and (e) risks of
adverse effects (higher BMI, more tremor and rigidity).
Multivariable logistic regression modeling identified several fac-
tors that were significantly and independently associated with the use
F I G U R E 1 Rates of usage of long-acting injected antipsychotic
drugs as percentage of treated schizophrenia patients in 15 Asian
countries, with 95% confidence intervals, ranked in descending order
5 of 10
of LAI antipsychotics. These included longer duration of illness, disor-
ganized behavior, lack of negative symptoms, and better social-
occupational functioning (Table 3).
We also compared characteristics of subjects who received FGAs
or SGAs in LAI formulations (Table 4). Those treated with FGA-LAI
agents were significantly more likely to be male, currently hospital-
ized, and to show more disorganized speech and behavior, with more
verbal or physical aggression. They were also more likely to be given
more than one antipsychotic drug and at higher average total daily
CPZ-eq doses.
Based again on multivariable logistic regression modeling, use of
FGA-LAIs vs SGA-LAIs were independently and significantly associ-
ated with: male sex, verbal aggression, disorganized speech, and cur-
rent psychiatric hospitalization (Table 5).
4 | D I S CU
SSI O N
Several findings from this large multicenter study of the use of LAI
antipsychotic drugs to treat schizophrenia patients in 15 countries
and region in Asia are noteworthy. Rates of use of such agents aver-
aged 17.9%, but varied by more than 40-fold among different coun-
tries, and were greatest in Malaysia and Singapore, and lowest in
Vietnam and China (Table 1). Subjects given LAI antipsychotics were
older, males, had more years of illness with multiple hospitalizations,
had more disorganized behavior, showed more verbal and physical
aggression, and had better psychosocial functioning. They were also
more likely to receive more than one antipsychotic drug (usually sup-
plemented with oral medication), and higher total daily CPZ-eq doses,
and are more likely to experience more adverse neurological effects,
including more tremor and muscular rigidity (Tables 2 and 3). We also
identified significant differences between subjects treated with older
(FGA) vs newer (SGA) antipsychotic agents in LAI preparations, includ-
ing more men, disorganized speech, verbal aggression, and current
hospitalization among those given FGA-LAIs(Tables 4 and 5).
The present findings can be compared to a similar, decade earlier
study in six Asian countries (Sim et al., 2004). Overall, the current find-
ings indicate a modest increase in use of LAI agents, from 15.3% to
17.9%, and from 15.3% (368 out of 2399 subjects) to 16.0% (171 out
of 1066 subjects) among the same six countries sampled at both
times. Our observed average prevalence of use of depot antipsy-
chotics in Asia is consistent with recent rates averaging 19.9% in sev-
eral Western countries: USA (8%), Denmark (16.7%), UK (35%)
(Barnes et al., 2009; Potkin et al., 2013; Sneider et al., 2015). As in the
present findings (Table 1), marked differences between countries and
regions also have been noted in other parts of the world
(Hálfdánarson et al., 2017; Oteri et al., 2016). Reasons for both the
generally limited acceptance of LAI antipsychotics and the high
regional differences in their use are not entirely clear. Patient factors
including age, sex, and clinical characteristics may contribute. For
example, patients who are unreliably adherent to prescribed oral
treatments and present disruptive or threatening behavior are more
likely to receive injectable drugs (Arango, Bombín, & González-
6 of 10 TANG ET AL.

TA BL E 2 Comparison of patients treated with LAI versus oral antipsychotics

2
Factor LAI Oral Statistic (t, U or χ ) or OR P-value
Subjects (n) 638 2919 - -
Male sex (%) 62.2 [58.3-66.0] 58.2 [56.4-60.0] 1.18 .06
Current age (years) 41.1 ± 11.8 39.6 ± 13.0 2.85 .004
CPZ-eq dose (mg/day) 535 ± 372 404 ± 351 8.14 <.001
Given ≥2 antipsychotics (%) 77.4 [74.0-80.6] 32.0 [30.3-33.7] 7.29 [5.96-8.92] <.001
2
Body-Mass Index (kg/m ) 24.5 ± 4.99 23.9 ± 4.62 3.01 .003
Hospitalized (%) 49.8 [45.9-53.8] 52.3 [50.5-54.2] 0.91 .25
First admission (%) 21.0 [16.7-25.9] 31.6 [29.3-34.0] 0.58 <.001
In remission (%) 51.3 [47.3-55.2] 48.5 [46.6-50.3] 1.12 [0.94-1.33] .20
Delusional (%) 45.5 [41.5-49.4] 41.7 [39.9-43.5] 1.17 [0.98-1.39] .08
Hallucinating (%) 47.6 [43.7-51.6] 45.9 [4.1-47.84] 1.07 [0.90-1.27] .43
Disorganized speech (%) 30.3 [26.7-34.0] 28.9 [27.3-30.6] 1.07 [0.88-1.28] .51
Disorganized behavior (%) 21.9 [18.8-25.4] 16.5 [15.2-17.9] 1.42 [1.15-1.75] .001
Negative symptoms (%) 27.4 [24.0-31.1] 37.5 [35.839.3] 0.63 [0.52-0.76] <.001
Dysfunctional (%) 38.6 [34.8-42.5] 46.7 [44.9-48.6] 0.72 [0.60-0.85] <.001
Verbal aggression (%) 29.6 [26.1-33.3] 23.9 [22.4-25.5] 1.34 [1.11-1.62] .003
Physical aggression (%) 25.2 [21.9-28.8] 19.5 [18.1-21.0] 1.39 [1.14-1.70] .001
Affective symptoms (%) 11.8 [9.36-14.5] 11.0 [9.92-12.2] 1.07 [0.82-1.40] .60
Extrapyramidal syndromes (%)
Any 35.3 [31.6-39.2] 28.3 [26.7-30.0] 1.38 [1.15-1.66] .001
Tremor 25.6 [22.2-29.2] 17.1 [15.7-18.5] 1.67 [1.36-2.04] <.001
Rigidity 14.3 [11.7-17.3] 10.5 [9.43-11.7] 1.42 [1.10-1.83] .007
Akathisia 5.81 [4.10-7.95] 6.95 [6.03-7.95] 0.83 [0.57-1.19] .30
Dystonias 1.61 [0.78-2.95] 2.28 [1.76-2.90] 0.70 [0.36-1.38] .30
Tardive dyskinesia 1.94 [1.00-3.36] 1.70 [1.26-2.25] 1.14 [0.60-2.16] .69
Akinesia 6.14 [4.38-8.33] 6.20 [5.34-7.17] 0.99 [0.69-1.42] .95

Note: Data are means ± SD, or % [with 95%CI], comparing schizophrenia patients treated with long-acting injected (LAI), alone or with orally administered
supplements vs oral antipsychotic drugs only. CPZ-eq = approximate mg/day equivalent of orally administered chlorpromazine. Dysfunction is for social or
occupational functions.

TA BL E 3 Factors associated with

Factor OR [95%CI] Wald test score P-value
treatment with LAI vs oral antipsychotics
Duration of illness
(vs >20 years) - 28.5 <.001
<3 months 2.33 [0.62-8.74] 1.57 .22
3-6 months 1.36 [0.35-5.35] 0.20 .66
0.5-1.0 year 4.35 [1.50-12.7] 7.28 .007
1-5 years 5.38 [1.85-15.7] 9.53 .002
5-10 years 7.45 [2.56-21.7] 13.6 <.001
10-20 years 7.47 [2.48-22.5] 12.8 <.001
Disorganized behavior 1.87 [1.41-2.49] 18.6 <.001
Negative symptoms 0.488 [0.365-0.653] 23.3 <.001
Dysfunction 0.554 [0.424-0.723] 18.9 <.001

Note: OR = Odds Ratio [with 95% CI] for treatment with LAI vs oral antipsychotics. Other factors not sig-
nificantly associated with antipsychotic treatment type include: male sex, being in a first lifetime hospitali-
zation, current age, currently in clinical remission, presence of delusions, hallucinations, disorganized
speech, verbal aggression, physical aggression, affective symptoms, or other symptoms. Disorganized
behavior includes catatonic features.
TANG ET AL. 7 of 10

TA BL E 4 Characteristics of schizophrenia patients given first- or second-generationlong-acting injected (LAI) antipsychotic drugs
2
Factors First-generation(FGA-LAI) Second generation (SGA-LAI) Statistics (t, U or χ ) or OR P-value
Subjects (n; % of LAIs) 543 (85.0) 95 (14.9) - -
Usage rate (% of all cases) 15.3 [14.1-16.5] 2.67 [2.17-3.26]
Age (years) 41.2 ± 11.7 41.0 ± 12.9 0.143 .89
Male sex (%) 64.5 [60.2-68.5] 49.5 [39.1-59.9] 1.85 [1.19-2.87] .005
Given ≥2 antipsychotics 82.9 [79.6-86.1] 46.3 [36.0-56.8] 5.61 [3.54-8.89] <.001
Total CPZ-eq dose (mg/day) 551 ± 380 446 ± 302 2.99 .003
Illness duration (years) 5.49 ± 1.25 5.53 ± 1.37 1.23 [1.18-1.28] .77
2
Body-Mass Index (kg/m ) 24.4 ± 4.97 25.2 ± 5.05 1.55 .12
Hospitalized (%) 52.1 [47.8-56.4] 36.8 [27.2-47.4] 1.87 [1.19-2.83] .006
In first hospitalization (%) 20.4 [17.1-24.1] 25.7 [16.9-35.2] 0.74 [0.33-1.69] .47
Currently in remission (%) 50.3 [46.0-54.6] 56.8 [46.3-67.0] 0.77 [0.50-1.19] .24
Delusional (%) 44.8 [40.5-49.0] 49.5 [39.1-59.9] 0.83 [0.54-1.28] .39
Hallucinating (%) 47.7 [43.4-52.0] 47.4 [37.0-57.4] 1.01 [0.66-1.57] .95
Disorganized speech (%) 33.0 [29.0-37.1] 14.7 [8.30-23.5] 2.85 [1.57-5.16] <.001
Disorganized behavior (%) 23.4 [19.9-27.2] 13.7 [7.49-22.3] 1.93 [1.04-3.57) .04
Negative symptoms (%) 26.3 [22.7-30.3] 33.7 [24.3-44.1] 0.70 [0.44-1.12] .14
Dysfunctional (%) 38.3 [34.2-42.5] 40.0 [30.1-50.6] 0.93 [0.60-1.45] .75
Verbal aggression (%) 33.0 [29.0-37.1] 10.5 [5.16-18.5] 4.18 [2.12-8.24] <.001
Physical aggression (%) 27.6 [23.9-37.1] 11.6 [5.92-19.8] 2.92 [1.51-5.62] .001
Affective symptoms (%) 11.0 [8.54-14.0] 15.8 [9.12-24.7] 0.66 [0.36-1.22] .19
Extrapyramidal syndromes (%)
Any 36.3 [32.2-40.6] 29.3 [20.3-39.8] 1.37 [0.85-2.23] .20
Rigidity 15.1 [12.2-18.4] 9.89 [4.62-17.9] 1.62 [0.78-3.36] .19
Akinesia 6.63 [4.66-9.10] 3.30 [0.69-9.33] 2.08 [0.63-6.92] .22
Tremor 26.2 [22.5-30.1] 22.0 [14.0-31.9] 1.26 [0.74-2.14] .40
Akathisia 5.28 [3.54-7.55] 8.89 [3.92-16.7] 0.57 [0.25-1.30] .18
Dystonia 1.89 [0.91-3.44] 0.00 [0.00-4.02] - -
Tardive dyskinesia 1.89 [0.91-3.44] 2.22 [0.27-7.80] - -
Systemic adverse effects (%)
Excess sedation 12.0 [9.35-15.1] 5.56 [1.83-12.5] 2.32 [0.91-5.93] .07
Weight-gain 12.7 [9.80-16.1] 12.5 [641-21.3.] 1.02 [0.51-2.03] .96
Constipation 23.1 [19.6-27.0] 17.6 [10.4-27.0] 1.41 [0.79-2.51] .24
Sialorrhea 14.3 [11.4-17.6] 7.69 [3.15-15.2] 2.00 [0.89-4.49] .09
Dry mouth Urinary 16.9 [13.8-20.4] 11.0 [5.40-19.3] 1.65 [0.82-3.31] .16
hesitancy Blurred 0.77 [0.21-1.97] 3.26 [0.68-9.23] - -
vision Postural 5.58 [3.77-7.91] 1.10 [0.03-5.97] - -
hypotension 5.35 [3.59-7.64] 0.00 [0.00-0.00] - -
Impaired glucose tolerance 9.00 [6.45-12.2] 3.53 [0.73-9.97] 2.71 [0.82-8.98] .09
Hypercholesterolemia 12.8 [9.74-16.5] 5.95 [1.96-13.3] 2.33 [0.90-6.02] .07

Note: Data are means ± SD or % or OR [95%CI]. CPZ-eq = Approximate oral chlorpromazine-equivalent dose (mg/day).
Abbreviations: LAI, long-acting injected; OR, Odds ratio.

Salvador, 2006; Belli & Ural, 2012). In addition, it is likely that other
factors including regional variances in healthcare systems such as
availability of drugs, pharmaco-economics, and prescribing habits of
psychiatrists may also play a role, including in Asian countries
(Si et al., 2011).
In the present sample, there is only a 4% greater proportion of
male patients given LAI antipsychotics (Table 2). In other studies, LAI
treatment was considerably more likely to involve male patients
(Decuypere, Sermon, & Geerts, 2017; Janzen, Bolton, Kuo, Leong, &
Alessi-Severini, 2020; Ostuzzi et al., 2018). Of note, similar portions
8 of 10
TA BL E 5 Factors associated with treatment with first- vs.
second-generation. long-acting injected antipsychotic drugs
Factor OR [95%CI] Statistic P-value
Male sex 2.22 [1.38-3.58] 10.85 .001
Verbal aggression 3.63 [1.60-8.24] 9.48 .002
Disorganized speech 2.21 [1.13-4.31] 5.38 .02
Hospitalized 1.73 [1.03-2.92] 4.26 .03
of patients given LAI (49.8%) and oral antipsychotics (52.3%) were
currently hospitalized (Table 2), if a major reason to employ LAI treat-
ments is to limit treatment nonadherence among ambulatory patients
(Panish, Karve, Candrilli, & Dirani, 2013; Verdoux et al., 2000; West
et al., 2008). Presumably, however, many patients required hospitali-
zation due to morbidity arising from treatment nonadherence, and
may have been started on a LAI regimen in anticipation of aftercare.
More broadly, important questions remain about the relative clinical
value of relying on LAI antipsychotic treatment compared to oral med-
ication, perhaps supplemented with closer clinical support and super-
vision, such as with assertive community treatment (ACT) programs
(Barnes et al., 2009; Jaeger & Rossler, 2010).
Particularly intriguing findings are that participants treated with
modern SGAs in LAI formulations were 1.79-timesless likely to receive
multiple antipsychotic drugs, and were exposed to 1.24-fold lower
total daily CPZ-eq doses than those given older FGAs (Table 4). That
is, the overall greater use of multiple antipsychotics and higher total
daily dose-exposure with LAI agents in general (Table 2) may be lim-
ited by use of SGA-LAIs. Similar findings have been reported previ-
ously (Ostuzzi et al., 2018). These differences may suggest hoped-for
clinical superiority of SGAs over FGAs, which has been difficult to
prove (Baldessarini, 2013). Despite the lower average dosing with
SGA-LAIs vs FGA-LAIs, risks of neurological and systemic adverse
effects were generally quite similar (Table 4). Lack of longitudinal data
preclude assessment of potentially important differential effects of
LAI vs oral, and of SGA-LAI vs FGA-LAI treatments on morbidity and
other critical aspects of clinical outcome. In addition, it is likely that
socioeconomic factors may have a major impact on rates of utilization
of older vs newer, more expensive pharmacotherapy which can also
impact clinical outcome (Nielsen, Jensen, Friis, Valentin,
Correll, 2015; Si et al., 2011).
4.1 | Limitations
There were several strengths and limitations to this study. It involved
a large and broadly representative sampling from 15 Asian countries
and region, with standardized methods of clinical assessment and
data-management. Major limitations include lack of extensive sam-
pling from well-characterized locations within individual countries to
address the effects of such factors as rural vs urban settings, academic
vs clinical healthcare programs, and the number of subjects treated
with LAI agents is small for some countries. Moreover, the study was
TANG ET AL.
cross sectional in nature and future efforts would want to consider
following up the subjects over their illness course and treatment pro-
spectively. Also, we did not capture details of healthcare financing
across countries which can be further examined in the context of
intercountry variations in psychotropic prescription patterns including
depot antipsychotics.
4.2 | Conclusion
In conclusion, we found that the rate of use of LAI antipsychotic prep-
arations had increased modestly (1.17-fold), from 15.3% to 17.9% of
treated schizophrenia patients over the last 12 years in Asia, with very
wide regional variations as have been reported in other world regions.
The use of LAI treatment was associated with more polytherapy and
higher average total daily antipsychotic drug doses, although less with
SGA-LAIs than with FGA-LAIs. These findings behoove clinicians to
be mindful when considering management options including LAI anti-
psychotic preparations in terms of balancing clinical benefits vs risks
over the treatment course of a potentially crippling illness.
C O NF L I C T OF I NT E R E
ST
The authors declare no potential conflict of interest.
A U T HO R CO NT RI B U
T I ON S
Chao T. Tang, Ee C. Chua, Qian H. Chew, and Kang Sim have made
substantial contributions to conception and design of this project
theme, acquisition of data, analysis and interpretation of the data,
drafting of the manuscript, revision of the paper for important intel-
lectual content, given final approval of the version to be published
and agreed to be accountable for all aspects of the work; all other co-
authors have made substantial contributions to acquisition of data or
analysis and interpretation of the data, revision of the paper for
important intellectual content, given final approval of the version to
be published and agreed to be accountable for all aspects of the work.
D A T A A VAILABILI TY ST A T EM E N
T
&
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
OR CI
D
Yu-Tao Xiang https://orcid.org/0000-0002-2906-0029
Naotaka Shinfuku https://orcid.org/0000-0002-7390-9077
Seon-Cheol Park https://orcid.org/0000-0003-3691-4624
Kang Sim https://orcid.org/0000-0003-3209-9626
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 Nordic Journal of Psychiatry

ISSN: 0803-9488 (Print) 1502-4725 (Online) Journal homepage: https://www.tandfonline.com/loi/ipsc20

Dyskinesia is most centrally situated in an

estimated network of extrapyramidal syndrome
in Asian patients with schizophrenia: findings
from research on Asian psychotropic prescription
patterns for antipsychotics

Seon-Cheol Park, Gyung-Mee Kim, Takahiro A. Kato, Mian-Yoon Chong, Shih-

Ku Lin, Shu-Yu Yang, Ajit Avasthi, Sandeep Grover, Roy Abraham Kallivayalil,
Yu-Tao Xiang, Kok Yoon Chee, Andi Jayalangkara Tanra, Chay Hoon Tan,
Kang Sim, Norman Sartorius, Naotaka Shinfuku, Yong Chon Park & Toshiya
Inada

To cite this article: Seon-Cheol Park, Gyung-Mee Kim, Takahiro A. Kato, Mian-Yoon Chong, Shih-
Ku Lin, Shu-Yu Yang, Ajit Avasthi, Sandeep Grover, Roy Abraham Kallivayalil, Yu-Tao Xiang, Kok
Yoon Chee, Andi Jayalangkara Tanra, Chay Hoon Tan, Kang Sim, Norman Sartorius, Naotaka
Shinfuku, Yong Chon Park & Toshiya Inada (2020): Dyskinesia is most centrally situated in an
estimated network of extrapyramidal syndrome in Asian patients with schizophrenia: findings
from research on Asian psychotropic prescription patterns for antipsychotics, Nordic Journal of
Psychiatry, DOI: 10.1080/08039488.2020.1777462
To link to this article: https://doi.org/10.1080/08039488.2020.1777462

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NORDIC JOURNAL OF PSYCHIATRY
https://doi.org/10.1080/08039488.2020.1777462

ARTICLE

Dyskinesia is most centrally situated in an estimated network of extrapyramidal

syndrome in Asian patients with schizophrenia: findings from research on Asian
psychotropic prescription patterns for antipsychotics
Seon-Cheol Parka , Gyung-Mee Kima , Takahiro A. Katob, Mian-Yoon Chongc,d, Shih-Ku Line, Shu-Yu Yangf,
Ajit Avasthig, Sandeep Groverg, Roy Abraham Kallivayalilh, Yu-Tao Xiangi, Kok Yoon Cheej,
Andi Jayalangkara Tanrak, Chay Hoon Tanl, Kang Simm, Norman Sartoriusn, Naotaka Shinfukuo ,
Yong Chon Parkp and Toshiya Inadaq
a
Department of Psychiatry, Inje University Haeundae Paik Hospital, Busan, Republic of Korea; bDepartment of Neuropsychiatry, Graduate
School of Medicine, Kyushu University, Fukuoka, Japan; cChang Gung Memorial Hospital, Chiayi, Taiwan; dSchool of Medicine, Chang Gung
University, Kwei-Shan, Taiwan; eDepartment of Psychiatry, Taipei City Hospital, Songde Branch, Taipei, Taiwan; fDepartment of Pharmacy,
Tapei City Hospital, Songde Branch, Tapei, Taiwan; gDepartment of Psychiatry, Post Graduate Institute of Medical Education and Research
(PGIMER), Chandigarh, India; hPushpagiri Institute of Medical Sciences, Tiruvalla, Kerala, India; iCenter for Cognition and Brain Sciences,
University of Macau, Macao SAR, China; jTunku Abdul Rahman Institute of Neuroscience, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia;
k
Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia; lDepartment of Pharmacology, National
University Hospital, Singapore, Singapore; mWest Region, Institute of Mental Health and Yong Loo Lin School of Medicine, National
University of Singapore, Singapore; nAssociation for the Improvement of Mental Health Programmes, Geneva, Switzerland; oDepartment of
Social Welfare, School of Human Sciences, Seinan Gakuin University, Fukuoka, Japan; pDepartment of Neuropsychiatry, Hanyang University
Guri Hospital, Guri, Republic of Korea; qDepartment of Psychiatry and Psychobiology, Nagoya University, Graduate School of Medicine,
Nagoya, Japan

ABSTRACT ARTICLE HISTORY

Background: Network analysis provides a new viewpoint that explicates intertwined and interrelated Received 26 December 2019
symptoms into dynamic causal architectures of symptom clusters. This is a process called Revised 28 April 2020
‘symptomics’ and is concurrently applied to various areas of symptomatology. Accepted 29 May 2020
Aims: Using the data from Research on Asian Psychotropic Prescription Patterns for
KEYWORDS
Antipsychotics
Extrapyramidal syndrome;
(REAP-AP), we aimed to estimate a network model of extrapyramidal syndrome in patients with dyskinesia; Drug-Induced
schizophrenia. Extrapyramidal Symptoms
Methods: Using data from REAP-AP, extrapyramidal symptoms of 1046 Asian patients with Scale; network analysis;
schizophre- nia were evaluated using the nine items of the Drug-Induced Extrapyramidal schizophrenia
Symptoms Scale
(DIEPSS). The estimated network of the ordered-categorical DIEPSS items consisted of nodes (symp-
toms) and edges (interconnections). A community detection algorithm was also used to identify
dis-
tinctive symptom clusters, and correlation stability coefficients were used to evaluate the
centrality stability.
Results: An interpretable level of node strength centrality was ensured with a correlation
coefficient.
An estimated network of extrapyramidal syndrome showed that 26 (72.2%) of all possible 35 edges
were estimated to be greater than zero. Dyskinesia was most centrally situated within the
estimated
network. In addition, earlier antipsychotic-induced extrapyramidal symptoms were divided into three
distinctive clusters – extrapyramidal syndrome without parkinsonism, postural instability and gait diffi-
culty-dominant parkinsonism, and tremor-dominant parkinsonism.
Conclusions: Our findings showed that dyskinesia is the most central domain in an estimated network
structure of extrapyramidal syndrome in Asian patients with schizophrenia. These findings are
consist-
ent with the speculation that acute dystonia, akathisia, and parkinsonism could be the risk factors of
tardive dyskinesia.

Background classified into three categories – dystonia, akathisia, and par-

First-generation antipsychotic drugs have higher affinity for
D2 dopamine receptors than second-generation antipsychotic
drugs, which have higher affinity for 5-HT2A receptors [1].
Antipsychotic-induced extrapyramidal syndrome is mediated
by D2 dopamine receptor antagonism in the substantia nigra
and striatum areas [2]. Early extrapyramidal syndrome is
kinsonism [3]. Tardive dyskinesia denotes persistent, involun-
tary, and repetitive choreoathetoid movement disorders that
are induced by antipsychotics and other dopamine receptor
blocking agents. Moreover, vesicular monoamine transporter
2 inhibitors, such as valbenazine, have been approved for
the treatment of tardive dyskinesia [4]. The three
CONTACT Seon-Cheol Park cogito-ergo-sum@hanmail.net Department of Psychiatry, Inje University Haeundae Paik Hospital, 875, Haeun-daero,
Haeundae-gu, Busan, 48108, Republic of Korea
2020 The Nordic Psychiatric Association
2 S.-C. PARK ET AL.
extrapyramidal symptoms are strongly associated with a
negative subjective response to antipsychotics and poor
treatment outcomes among patients with schizophrenia [2].
In addition, the quality of life of patients and their families,
which is linked to long-term treatment adherence, is affected
by extrapyramidal syndrome [5,6]. Moreover, according to
longitudinal trends of 484 patients with schizophrenia, there
is a negative relationship between drug-induced extrapyram-
idal symptoms and psychosocial aspects [7].
To facilitate the clinical and pharmacological approaches
for extrapyramidal syndrome, estimating their latent struc-
ture is needed. Network analysis is an analytical method to
estimate the map of a collection of interrelated symptoms
and explicate dynamic causal architectures of symptom clus-
ters [8]. From a topological perspective, a network’s structure
consists of nodes (symptoms) and edges (inter-connections).
According to graph theory, different spatial and functional
characteristics that demonstrate information about the rela-
tionships between the nodes within an estimated network
are represented [9,10]. Since centrality is based on the overall
interconnections of a symptom within an estimated network,
central symptoms may have greater influence than periph-
eral symptoms. It is speculated that intertwined symptoms
are more easily activated by symptoms that are centrally sit-
uated within the entire network. In terms of centrality, node
strength, closeness, and betweenness are defined as the sum
of all associations of a given node with all other nodes, the
measure of how close a symptom is to all other symptoms,
and the shortest length of a path connecting any two nodes,
respectively [11,12]. Thus, the network structures of psycho-
pathology among patients with schizophrenia have been
estimated below. Alogia and avolition have been the most
central domains among the negative symptoms of schizo-
phrenia. Furthermore, blunted affect, alogia, and asociality
have been the most central domains in female patients with
schizophrenia, whereas alogia and avolition have been the
most central domains in their male counterparts [13].
Moreover, the latent structure of negative symptoms has
been estimated as an association of the five domains – anhe-
donia, avolition, asociality, blunted affect, and alogia [14].
Aim
To the best of our knowledge, network analyses on extrapyr-
amidal syndrome in patients with schizophrenia have rarely
been estimated. In this study, we used the data from
Research on Asian Psychotropic Prescription Patterns for
Antipsychotics (REAP-AP) [15], which is the largest inter-
national research collaboration within Asia, to estimate the
network structure of extrapyramidal symptom profiles in
Asian patients with schizophrenia.
Materials and methods
Study overview and participants
As described previously [15], based on a convenience sam-
pling method performed between March and June 2016,
3744 patients with schizophrenia were consecutively
recruited from 71 survey centers in Asian countries and spe-
cial administrative regions including Bangladesh, China,
Hong Kong, India, Indonesia, Japan, Korea, Malaysia,
Myanmar, Pakistan, Singapore, Sri Lanka, Taiwan, Thailand,
and Vietnam. The REAP-AP study protocol and informed con-
sent form were approved by the Institutional Review Boards
of Taipei City Hospital, Taipei, Taiwan (receipt number:
TCHIRB-10412128-E) and other survey centers. All study par-
ticipants provided written informed consent. To estimate a
network structure of extrapyramidal syndrome, we selected
participants fulfilling the following inclusion criteria: (i) a con-
firmed diagnosis of schizophrenia according to the 10th revi-
sion of the International Statistical Classification of Diseases
and Related Health Problems [16], (ii) pharmacotherapy with
antipsychotics and/or other psychotropic drugs, and (iii) data
from the Drug-Induced Extrapyramidal Symptom Scale
(DIEPSS) [17–19]. Participants with Tourette syndrome or tic
disorders, neurological disease including Parkinson’s disease
(PD) and epilepsy, or severe physical diseases including
malignancy were excluded. Finally, 1046 patients from India,
Indonesia, Japan, Malaysia, and Taiwan were included for an
estimation of the network structure of extrapyram-
idal syndrome.
Drug-induced extrapyramidal symptom scale
The DIEPSS was developed as a rating scale to evaluate
drug-induced extrapyramidal syndrome and consists of the
following nine items: gait (GAI), bradykinesia (BRA), sialorrhea
(SIA), muscle rigidity (RIG), tremor (TRE), akathisia (AKA), dys-
tonia (TON), dyskinesia (KIN), and overall severity (OVE). The
DIEPSS has fewer items than the Simpson-Angus Scale (SAS),
the Barnes Akathisia Rating Scale, and the Abnormal
Involuntary Movement Scale (AIMS). The DIEPSS consists of
only five parkinsonism-related items, whereas the SAS con-
sists of 10. Moreover, the DIEPSS consists of only one dyskin-
esia-related item, whereas the AIMS consists of seven
dyskinesia-related items. All the DIEPSS items use a 5-point
Likert scale scoring system (0 ¼ none-normal; 1 ¼ minimal-
questionable; 2 ¼ mild; 3 ¼ moderate; and 4 ¼ severe).
High levels of inter-rater reliability, test–retest reliability, and
con- current validity with other rating scales were reported
from the examined metric characteristics of the DIEPSS. For
this study, the DIEPSS was regarded as a reliable and valid
multi- dimensional rating scale to quantify extrapyramidal
syn- drome. Moreover, DIEPSS can identify low incidences
of olanzapine-induced extrapyramidal syndrome with more
sen- sitivity than those of haloperidol-induced syndrome
[17–19]. In addition, different frequencies have been reported
regard- ing the development of antipsychotic-induced
extrapyram- idal syndrome between Japanese patients with
schizophrenia and their Western counterparts [20–22]. The
DIEPSS has been efficiently used to evaluate extrapyramidal
syndrome in clin- ical studies for olanzapine, quetiapine,
and other antipsy- chotics in Japan [23,24]. Moreover, the
Korean, Serbian, and Norwegian versions of the DIEPSS have
shown favorable lev- els of inter-rater and test–retest
reliability [19,25,26].

Other assessment instruments
The Brief Psychiatric Rating Scale (BPRS) [27,28], and the
Anatomical and Therapeutic Chemical (ATC) classification sys-
tem [29] were used to evaluate overall psychiatric symptoms,
comorbid physical diseases, and psychotropic drug prescrip-
tion patterns of the study participants, respectively. The BPRS
psychometric characteristics confirmed favorable levels of
reliability, validity, and sensitivity [27,28]. Based on the ATC
classification system [29], psychotropic drugs were grouped
into the following five categories: antipsychotics
(N05A), mood stabilizers (antiepileptics and lithium; N03A
and N05AN), antidepressants (N06A), anxiolytics (N05B and
N05C), and antiparkinsonian drugs (N06A). The dichotomous
classifi- cation of first-generation and second-generation
antipsy- chotics was defined according to that proposed by
Tandon et al. [30]. According to the psychotropic dose
equivalence defined by Inada and Inagaki [31], equivalent
doses of chlor- promazine, imipramine, diazepam, and
levodopa were used to calculate the cumulative daily doses
of antipsychotics, antidepressants, anxiolytics,
antiparkinsonian drugs, respectively. High-dose antipsychotic
medication was defined as a daily cumulative dose of over
1000 mg of the chlorpro- mazine equivalent dose [32].
Statistical analysis
To evaluate the differences in baseline characteristics among
the five groups including Indians, Indonesians, Japanese,
Malaysians, and Taiwanese, analyses of covariance for con-
tinuous variables and the chi-squared test for discrete varia-
bles were used. Statistical significance was set at p <
0.05 (two-tailed) for all tests. All statistical analyses were
per- formed using the Statistical Package for the Social
Sciences (IBM SPSS Statistics version 21 for Windows;
SPSS Inc., Chicago, IL, USA).
The unidirectional network of the nine DIEPSS items, con-
sisting of both nodes (symptoms) and edges (interconnec-
tions among symptoms), was estimated using the R package
qgraph [33]. False-positive edges were controlled with the
least absolute shrinkage and selection operator (LASSO), and
very small edges were set to zero [34]. The GLASSO (or
graphical LASSO) procedure was used within an estimated
network, where the edges were partial correlation coeffi-
cients, and the mean edge was defined as the relationship
level between two symptoms controlling for all other rela-
tionships within the network. Shrinkage parameters were
also used to minimize the extended Bayesian information cri-
terion and accurate recovery for underlying network struc-
tures [35,36]. The Fruchterman–Reingold algorithm was used
to place stronger connected nodes closer together and rep-
resent the network geographically. All extrapyramidal symp-
toms were considered order-categorical variables. The
modularity-based community-detecting method was used to
investigate whether nodes were clustered together within
the network. The spin-glass algorithm was used to test
whether the number and weighted strength of edges within
a cluster exceeded those within another cluster in term of
NORDIC JOURNAL OF PSYCHIATRY 3
communities in the network. The spin-glass community func-
tion of the R package igraph was used over the GLASSO net-
work (weights ¼ null, vertex ¼ null, parupdate ¼ false,
gamma
¼ 0.5, start temperature ¼ 1, stop temperature ¼ 0.01, cool-
ing factor ¼ 0.99, spins ¼ 17) [37,38]. Additionally, node
strength, closeness, and betweenness centralities were esti-
mated. The most central symptoms within the network of
the extrapyramidal syndrome were estimated based on the
node strength, closeness, and betweenness centralities,
which substantially correlated with each other.
The correlation stability coefficient (CS-coefficient) repre-
sented the maximum proportion of cases that could be elim-
inated to obtain a 95% probability that the ranking
correlation between the original network and case-subset
network would amount to a very large effect (0.7). Centrality
stability was operationally defined with the CS-coefficient.
Thus, it was recommended that centrality indices be inter-
preted with a CS-coefficient >0.25, but preferably with a CS-
coefficient >0.5. Significant differences between centrality
and indices were estimated with 95% nonparametric bootstrap
confidence intervals (1000 bootstrap samples) of the differ-
ence between each pair of centrality indices [39,40].
Results
Baseline characteristics of the study participants
The baseline characteristics of the study participants are
shown in Table 1. The study participants included 354
Indians (33.3%), 217 Indonesians (20.4%), 79 Japanese (7.4%),
178 Taiwanese, and 236 Malaysians (22.2%). The average
age, body mass index, and total BPRS score of the partici-
pants was 38.7 years (standard deviation [SD] ¼ 12.2), 24.2 kg/
m2 (SD ¼ 4.9), and 34.7 (SD ¼13.1), respectively. More than
half the participants were males (n ¼ 640, 60.2%), enrolled as
outpatients (n ¼ 577, 54.2%) and with zero point score in the
CCI (n ¼ 565, 53.2%). One-third participants reported the dur-
ation of illness as over 1 year (n ¼ 354, 33.3%) and the dur-
ation of untreated psychosis as 3 months (n ¼ 394,
37.0%). Most participants used second-generation
antipsychotics (n ¼ 905, 85.1%), while one-third participants
used first-gen- eration antipsychotics (n ¼ 377, 35.3%).
Moreover, one-third participants used antipsychotic
polypharmacy (n ¼ 415,
39.0%), one-tenth used high-dose antipsychotic medications
(n ¼ 112, 10.5%), and one-third used anxiolytics (n ¼ 350,
32.9%) and antiparkinsonian drugs (n ¼ 419, 39.4%); less than
one-tenth participants used mood stabilizers (n ¼ 97, 9.1%)
and antidepressants (n ¼ 94, 8.8%). In terms of daily cumula-
tive doses, the mean chlorpromazine, imipramine, diazepam,
and levodopa doses were 497.0 mg (SD ¼ 391.6), 7.7 mg
(SD
¼ 32.4), 8.1 mg (SD ¼ 31.6), and 41.3 mg (SD ¼ 68.0),
respectively. As shown in Table 1, there were significant dif-
ferences in all the baseline characteristics among the five
groups (Indians, Indonesians, Japanese, Malaysians, and
Taiwanese). The response frequency distributions and abbre-
viations of the DIEPSS items are shown in Table 2. Because
the optimal cutoff score of each of the DIEPSS items was 2
[31,32], the incidences of GAI, BRA, SIA, RIG, TRE, AKA, TON,
and KIN were 7.6%, 12.1%, 8.0%, 2.8%, 17.8%, 7.2%, 5.0%,
4 S.-C. PARK ET AL.

Table 1. Baseline characteristics of the study participants (n ¼ 1064).

Total Indian Indonesian Japanese Malaysian Taiwanese Statistical
(n ¼ 1064) (n ¼ 354) (n ¼ 217) (n ¼ 79) (n ¼ 236) (n ¼ coefficients p Value
178)
Age, mean (SD) years 38.7 (12.2) 35.8 (11.3) 35.5 (10.4) 40.8 (13.2) 39.1 (12.5) 46.8 (11.4) F ¼ 31.942 <0.0001
2
Male, n (%) 640 (60.2) 238 (67.2) 138 (63.6) 47 (59.5) 122 (51.7) 95 (53.4) v ¼ 18.946 0.001
2
Outpatient, n (%) 577 (54.2) 229 (64.7) 78 (35.9) 46 (58.2) 160 (67.8) 64 (36.0) v ¼ 86.792 <0.0001
2
Duration of illness v ¼ 295.972 <0.0001
<3 months, n (%) 43 (4.0) 9 (2.5) 25 (11.5) 5 (6.3) 3 (1.3) 1 (0.6)
3–6 months, n (%) 31 (2.9) 12 (3.4) 12 (5.5) 2 (2.5) 5 (2.1) 0 (0.0)
6–12 months, n (%) 36 (3.4) 13 (3.7) 13 (6.0) 2 (2.5) 7 (3.0) 1 (0.6)
1–5 years, n (%) 244 (22.9) 92 (26.0) 68 (31.3) 14 (17.7) 62 (26.3) 8 (4.5)
5–10 years, n (%) 184 (17.3) 93 (26.3) 43 (19.8) 10 (12.7) 18 (7.6) 20 (11.2)
10–20 years, n (%) 307 (28.9) 102 (28.8) 42 (19.4) 21 (26.6) 91 (38.6) 51 (28.7)
>20 years, n (%) 219 (20.6) 33 (9.3) 14 (6.5) 25 (31.6) 50 (21.2) 97 (54.5)
2
Duration of untreated psychosis v ¼ 54.292 <0.0001
<3 months, n (%) 394 (37.0) 95 (26.8) 108 (49.8) 30 (38.0) 95 (40.3) 66 (37.1)
3–12 months, n (%) 363 (34.1) 140 (39.5) 73 (33.6) 21 (26.6) 75 (3.18) 54 (30.3)
1–5 years, n (%) 208 (19.5) 79 (22.3) 31 (14.3) 17 (21.5) 51 (21.6) 30 (16.9)
>5 years, n (%) 99 (9.3) 40 (11.3) 5 (2.3) 11 (13.9) 15 (6.4) 28 (15.7)
Brief Psychiatric Rating 34.9 (13.2) 33.5 (0.6) 39.2 (0.8) 43.2 (1.4) 26.8 (0.8) 38.6 (0.9) F ¼ 47.529 <0.0001
Scale, mean (SD) Body
mass index, mean 24.2 (4.9) 23.9 (4.7) 23.1 (4.8) 23.8 (4.5) 25.1 (5.1) 25.1 (5.2) F ¼ 6.189 <0.0001
(SD) kg/m2
2
Number of FGA v ¼ 65.096 <0.0001
0, n (%) 687 (64.6) 250 (70.6) 120 (55.3) 54 (68.4) 117 (49.6) 146 (82.0)
1, n (%) 298 (28.0) 86 (24.3) 72 (33.2) 22 (27.8) 93 (39.4) 25 (14.0)
2, n (%) 76 (7.1) 17 (4.8) 24 (11.1) 3 (3.8) 25 (10.6) 7 (9.2)
3, n (%) 3 (0.3) 1 (0.3) 1 (0.5) 0 (0.0) 1 (0.4) 0 (0.0)
Number of SGA v2 ¼ 72.975 <0.0001
0, n (%) 159 (14.9) 49 (13.8) 36 (16.6) 4 (5.1) 54 (22.9) 16 (9.0)
1, n (%) 745 (70.0 257 (72.6) 140 (64.5) 48 (60.8) 168 (71.2) 132 (74.2)
2, n (%) 155 (14.6) 47 (13.3) 41 (18.9) 24 (30.4) 14 (5.9) 29 (16.3)
3, n (%) 5 (0.5) 1 (0.3) 0 (0.0) 3 (3.8) 0 (0.0) 1 (0.6)
Number of antipsychotics v2 ¼ 69.341 <0.0001
1, n (%) 649 (61.0) 237 (66.9) 107 (49.3) 40 (49.5) 137 (58.1) 128 (71.9)
2, n (%) 332 (31.2) 84 (23.7) 86 (39.6) 25 (31.6) 92 (39.0) 45 (25.3)
3, n (%) 65 (6.1) 28 (7.9) 18 (8.3) 10 (12.7) 7 (3.0) 2 (1.1)
4, n (%) 16 (1.5) 5 (1.4) 5 (2.3) 3 (3.8) 0 (0.0) 3 (1.7)
5, n (%) 2 (0.2) 0 (0.0) 1 (0.5) 1 (1.3) 0 (0.0) 0 (0.0)
2
High-dose 112 (10.5) 39 (11.0) 14 (6.5) 20 (25.3) 21 (8.9) 18 (10.1) v ¼ 22.961 <0.0001
antipsychotics, n (%)
2
Long-acting injectable 237 (22.3) 60 (16.9) 26 (12.0) 13 (16.5) 112 (47.5) 26 (14.6) v ¼ 113.117 <0.0001
antipsychotics, n (%)
2
Mood stabilizer, n (%) 97 (9.1) 27 (7.6) 10 (4.6) 22 (27.8) 16 (6.8) 22 (12.4) v ¼ 43.541 <0.0001
2
Antidepressant, n (%) 94 (8.8) 42 (11.9) 17 (18.1) 2 (2.5) 17 (7.2) 24 (13.5) v ¼ 19.406 0.001
Anxiolytics, n (%) 350 (32.9) 122 (34.5) 34 (15.7) 47 (59.5) 37 (15.7) 110 (61.8) v2 ¼ 153.942 <0.0001
2
Antiparkinsonian drugs, 419 (39.4) 137 (38.7) 96 (44.2) 19 (24.1) 89 (37.7) 78 (43.8) v ¼ 11.737 0.019
n (%)
Chlorpromazine 497.0 (391.6) 525.1 (20.6) 431.1 (26.3) 667.9 (43.5) 434.9 (25.2) 527.7 (29.0) F ¼ 7.697 <0.0001
equivalent dose,
mean (SD)
Imipramine equivalent 7.7 (32.4) 11.5 (40.4) 2.0 (10.0) 3.2 (20.2) 6.2 (25.3) 10.9 (42.2) F ¼ 3.897 0.004
dose, mean (SD)
Diazapem equivalent 8.2 (31.6) 5.8 (12.3) 1.2 (3.6) 5.8 (12.3) 2.4 (7.1) 28.4 (69.7) F ¼ 25.612 <0.0001
dose, mean (SD)
Levodopa equivalent 41.3 (68.0) 35.2 (66.1) 43.9 (51.4) 37.3 (81.4) 28.4 (41.5) 68.7 (97.9) F ¼ 10.567 <0.0001
dose, mean (SD)
FGA: first-generation antipsychotics; SGA: second-generation antipsychotics.

Table 2. Response frequency distributions and abbreviations of the DIEPSS items (n ¼

1064).
% Score
DIEPSS items Abbreviation %0 %1 %2 %3 %4
Gait, n (%) GAI 814 (76.5) 170 (16.0) 56 (5.3) 21 (2.0) 3 (0.3)
Bradykinesia, n (%) BRA 763 (71.7) 172 (16.2) 101 (9.5) 25 (2.3) 3 (0.3)
Sialorrhea, n (%) SIA 840 (78.9) 139 (13.1) 61 (5.7) 20 (1.9) 4 (0.4)
Muscle rigidity, n (%) RIG 772 (72.6) 158 (14.8) 118 (1.3) 14 (1.3) 2 (0.2)
Tremor, n (%) TRE 689 (64.8) 186 (17.5) 167 (15.7) 21 (2.0) 1 (0.1)
Akathisia, n (%) AKA 862 (81.0) 125 (11.7) 68 (6.4) 9 (0.8) 0 (0.0)
Dystonia, n (%) TON 893 (83.9) 119 (11.2) 41 (3.9) 8 (0.8) 3 (0.3)
Dykinesia, n (%) KIN 895 (84.1) 116 (10.9) 41 (3.9) 10 (0.9) 2 (0.2)
Overall severity, n (%) OVE 641 (60.2) 235 (22.1) 164 (15.4) 23 (2.2) 1 (0.1)
DIEPSS: Drug-Induced Extrapyramidal Symptoms Scale.

and 5.0%, respectively. With respect to OVE, the incidences
of minimal, mild, moderate, and severe cases of extrapyram-
idal syndrome were 22.1%, 15.4%, 2.2%, and 0.1%,
respectively.
Network estimation and centrality comparison of
extrapyramidal symptoms
As shown in Figure 1, constructing a network from the
DIEPSS results revealed that 26 (72.2%) of all possible 35
edges were greater than zero. The estimated network
revealed strong inter-connections for GAI-BRA, TRE-OVE, RIG-
TON, RIG-OVE, AKA-TON, AKA-KIN, and AKA-OVE. A
NORDIC JOURNAL OF PSYCHIATRY 5
community-detection algorithm organized the nine items of
the DIEPSS into three clinically meaningful clusters – cluster
A included SIA, AKA, TON, and KIN; cluster B included GAI
and BRA; and cluster C included RIG, TRE, and OVE.
As shown in Figure 2, inspecting the node strength cen-
trality of the DIEPSS items revealed that KIN was the most
central domain within the estimated network of extrapyram-
idal syndrome, whereas SIA was the most poorly inter-con-
nected within the network. In addition to KIN, OVE, RIG, and
BRA were situated relatively centrally within the network.
Moreover, the closeness and betweenness centralities of the
DIEPSS items were visualized. In terms of centrality stability,
the node strength centrality and closeness centrality demon-
strated interpretable levels (CS-coefficients ¼ 0.350 and

Figure 1. Estimated network of extrapyramidal symptoms in Asian patients with schizophrenia (n ¼ 1064). Green lines represent positive associations, whereas red
lines represent negative associations. AKA: akathisia; BRA: bradykinesia; GAI: gait; KIN: dyskinesia; OVE: overall severity; RIG: muscle rigidity; SIA: sialorrhea; TON: dys-
tonia; TRE: tremor.

Figure 2. Node strength, betweenness, and closeness centralities of extrapyramidal symptoms in Asian patients with schizophrenia (n ¼ 1064). AKA: akathisia; BRA:
bradykinesia; GAI: gait; KIN: dyskinesia; OVE: overall severity; RIG: muscle rigidity; SIA: sialorrhea; TON: dystonia; TRE: tremor.
6 S.-C. PARK ET AL.
Figure 3. Extrapyramidal side effects induced by antipsychotics. Reproduced with permission from Inada [23].
0.350, respectively), although the betweenness centrality
demonstrated a low level (CS-coefficient ¼ 0.050).
Discussion
To summarize, with an interpretable level of node strength
centrality, our findings revealed that dyskinesia is the most
central domain within an estimated network of extrapyram-
idal syndrome in patients with schizophrenia. Furthermore,
earlier extrapyramidal syndrome symptoms can be classified
into three symptom clusters – extrapyramidal syndrome
without parkinsonism (SIA, AKA, TON, and KIN), postural
instability and gait difficulty-dominant parkinsonism (GAI and
BRA), and tremor-dominant parkinsonism (RIG, TRE, and
OVE). Moreover, GAI-BRA, TRE-OVE, RIG-TON, RIG-OVE, AKA-
TON, AKA-KIN, and AKA-OVE were strongly inter-connected
with the three symptom clusters of the estimated network.
Consistent with previous findings, this study found that
dyskinesia is the most central domain within an estimated
network of extrapyramidal syndrome with an interpretable
level of centrality stability. According to the meta-analysis
findings by Tenback et al. [41], acute antipsychotic-induced
dystonia, akathisia, and parkinsonism are considered non-
therapeutic risk factors for the onset of tardive dyskinesia.
Thus, an association between acute akathisia and parkinson-
ism could be a marker of individual variation in the dopa-
mine system sensitivity [42]. In addition, tardive dyskinesia
may be a manifestation of underlying psychosis-related vul-
nerabilities, including neurodevelopmentally induced neuro-
pathologic characteristics, sensitization of nigrostriatal
dopamine neurons, and glutamate-mediated neurotoxic
effects [43]. Moreover, a family history of primary movement
disorders has been proposed as an independent risk factor
for antipsychotic-induced extrapyramidal symptoms [44].
Additionally, the Clinical Antipsychotic Trials of Intervention
Effectiveness genome-wide association test has been ana-
lyzed to identify candidate genes for the severity of tardive
dyskinesia. The GL2 gene, which encodes a transcription fac-
tor involved in the development of the dopaminergic system
during embryogenesis, could contribute to tardive dyskinesia
susceptibility in patients with chronic schizophrenia [45].
Our findings demonstrate that earlier antipsychotic-
induced extrapyramidal symptoms can be divided into three
groups – extrapyramidal syndrome without parkinsonism,
postural instability and gait difficulty-dominant parkinsonism,
and tremor-dominant parkinsonism. This grouping may be
consistent with the conceptualization by Inada and Yagi [46],
which divided extrapyramidal side effects into dystonia, aka-
thisia, parkinsonism and rabbit syndrome, and tardive dyskin-
esia based on their acute and chronic aspects (Figure 3).
Since acute dystonia, akathisia, and parkinsonism have been
proposed as risk factors for tardive dyskinesia [41], the con-
ceptualization of extrapyramidal syndrome without parkin-
sonism (SIA, AKA, TON, and KIN) can be partly supported.
The division of parkinsonism into GAI-BRA and RIG-TRE-OVE
subgroups is partly consistent with the PD subtypes, includ-
ing tremor-dominant PD and postural instability and gait dif-
ficulty-dominant PD [47]. Thus, parkinsonism may need a
different approach as it may have different underlying mech-
anisms and markers depending on the case. Moreover, the
GAI-BRA, TRE-OVE, RIG-TON, RIG-OVE, AKA-TON, AKA-KIN, and
AKA-OVE inter-connections are partly consistent with the
three distinctive clusters of parkinsonism.
Limitations
Our study had several limitations. First, the study included
participants of diverse Asian ethnicities including Indians,
Indonesians, Japanese, Taiwanese, and Malaysians. Although
the study participants were recruited using the convenience
sampling method, they cannot be regarded as a representa-
tive sample of Asian patients with schizophrenia. Thus, the
network structure of extrapyramidal syndrome can be poten-
tially affected by the selection bias of sampling in our find-
ings. The associations between metabolic polymorphisms
(CYP2D6 3, 4, 5, and 10 and CYP1A2-C/A) and anti-
psychotic-induced tardive dyskinesia and movement disor-
ders have been repeatedly identified [48–50]. Therefore, to
the best of our knowledge, although the inter-ethnic

differences of metabolic polymorphisms have been poorly
reported within Asians, metabolic polymorphisms in Indians,
Indonesians, Japanese, Taiwanese, and Malaysians can influ-
ence the prevalence of extrapyramidal syndrome. Further
studies about network analyses of extrapyramidal syndrome
in an ethnic group that is more homogenous will be needed.
Second, the study participants were limited to Asian ethnic-
ities. According to a large mental health case register of
South London, UK, akathisia and parkinsonism are most fre-
quently presented in Asians, whereas dystonia and tardive
dyskinesia are most frequently presented in Africans [51].
However, there are no significant inter-ethnic differences in
the prevalence of tardive dyskinesia among Chinese,
Malaysians, and Westerners [52]. In our findings, tardive dys-
kinesia had a lower mean value and a higher SD than other
extrapyramidal syndromes. However, the Pearson correlation
coefficient (r) between SD and node strength centrality of
the DIEPSS items is considered negligible ( 0.14) [53]. Third,
since more than half of the study participants had duration
of illness >10 years, extrapyramidal syndrome could be pre-
sented more frequently. The variation in the prevalence of
tardive dyskinesia can be predominantly influenced by dur-
ation of exposure and dose levels of antipsychotic drugs
rather than inter-ethnic differences [54]. Thus, the duration
of illness of the study participants can influence the preva-
lence of extrapyramidal syndrome, including tardive dyskin-
esia. Fourth, as shown in Table 1, the baseline characteristics
of the five groups were significant different. However, to the
best of our knowledge, the potential influences of baseline
characteristics on the estimated network structure of extra-
pyramidal syndrome cannot be controlled. Further studies
conducted on a group that is more homogenous will be
needed to estimate a more precise network structure of
extrapyramidal syndrome. Fifth, because of the cross-sec-
tional aspects of our data, only a unidirectional network
could be estimated. Since longitudinal studies can differenti-
ate the ‘outdegree’ and ‘indegree’ centralities, but cross-sec-
tional studies cannot, a causal relationship within the
Sixth, an estimated network of extrapyramidal syndrome
may change with the clinical progression of schizophrenia.
Further studies that estimate networks of extrapyramidal syn-
drome limited to the clinical course of schizophrenia need to
be performed.
Conclusions
W reported a novel estimation of antipsychotic-induced
extrapyramidal symptoms in a network model. Moreover,
with reliable validity, the estimated network has identified
that dyskinesia is the most centrally situated symptom of
extrapyramidal syndrome. Additionally, the community-
detection algorithm has proposed three distinctive syndrome
clusters within the network – extrapyramidal syndrome with-
out parkinsonism, postural instability and gait difficulty-dom-
inant parkinsonism, and tremor-dominant parkinsonism.
NORDIC JOURNAL OF PSYCHIATRY 7
Author contributions
Conceived and designed the study: Seon-Cheol Park, Yong Chon Park,
Naotaka Shinfuku, Toshiya Inada; Analyzed the data: Seon-Cheol Park,
Yong Chon Park; Wrote the first draft of the manuscript: Seon-Cheol
Park; Revision of manuscript: Seon-Cheol Park, Gyung-Mee Kim, Kato A.
Takahiro, Mian-Yoon Chong, Shih-Ku Lin, Shu-Yu Yang, Ajit Avasthi,
Sandeep Grover, Roy Abraham Kallivayalil, Yu-Tao Xiang, Kok Yoon Chee,
Andi Jayalangkara Tanra, Chay Hoon Tan, Kang Sim, Norman Sartorius,
Naotaka Shinfuku, Yong Chon Park, Toshiya Inada; Agree with results
and conclusions and accept final manuscript: Seon-Cheol Park, Gyung-
Mee Kim, Kato A. Takahiro, Mian-Yoon Chong, Shih-Ku Lin, Shu-Yu Yang,
Ajit Avasthi, Sandeep Grover, Roy Abraham Kallivayalil, Yu-Tao Xiang,
Kok Yoon Chee, Andi Jayalangkara Tanra, Chay Hoon Tan, Kang Sim,
Norman Sartorius, Naotaka Shinfuku, Yong Chon Park, Toshiya Inada.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
This work was supported by the National Research Foundation of Korea
(NRF) grant funded by the Korea government (MSIT)
[2019R1A2C1090146].
Notes on contributor
Seon-Cheol Park is a psychiatric specialist (MD and PhD). He is an assist-
ant professor at Department of Psychiatry, Inje University College of
Medicine, Busan and director of Gijang Community Mental Health
Center, Busan, South Korea. His profession interests are in the field of
depression, psychopathology, and network analysis.
ORCID
Seon-Cheol Park http://orcid.org/0000-0003-3691-4624
Gyung-Mee Kim http://orcid.org/0000-0002-8010-1607
Naotaka Shinfuku http://orcid.org/0000-0002-7390-9077
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Received: 6 January 2020 Revised: 11 June 2020 Accepted: 24 June 2020

DOI: 10.1002/hup.2752

RESEARCH ARTICLE

Coprescription of mood stabilizers in schizophrenia, dosing,

and clinical correlates: An international study
1 1 2 3
Wai Kwong Lim | Qian Hui Chew | Yan‐Ling He | Tian‐Mei Si |
4 5 6 6
Fung‐Kum Helen Chiu | Yu‐Tao Xiang | Takahiro A. Kato | Shigenobu Kanba |
7 8 9 10
Naotaka Shinfuku | Min‐Soo Lee | Seon‐Cheol Park | Yong‐Chon Park | Mian‐
11 12 12 13
Yoon Chong | Shih‐Ku Lin | Shu‐Yu Yang | Adarsh Tripathi |
14 14 15
Ajit Avasthi | Sandeep Grover | Roy Abraham Kallivayalil |
16 17 18 19
Pichet Udomratn | Kok Yoon Chee | Andi J. Tanra | Md Golam Rabbani |
20 21 21 22
Afzal Javed | Samudra Kathiarachchi | Dulshika Waas | Wing Aung Myint |
23 24 24 25
Norman Sartorius | Van Cuong Tran | Kim Viet Nguyen | Chay‐Hoon Tan |
26 1
Ross J. Baldessarini | Kang Sim
1
Institute of Mental Health, Singapore, Singapore
2
Department of Psychiatric Epidemiology, Shanghai Mental Health Center, Shanghai, China
3
Institute of Mental Health, Peking University, Beijing, China
4
Department of Psychiatry, Chinese University of Hong Kong, Hong Kong, China
5
Faculty of Health Sciences, University of Macau, Macau, China
6
Department of Neuropsychiatry, Graduate School of Medicine, Kyushu University, Fukuoka, Japan
7
Department of Psychiatry, Kobe University, Kobe, Japan
8
Department of Psychiatry, College of Medicine, Korea University, Seoul, South Korea
9
Department of Psychiatry, Inje University Haeundae Paik Hospital, Busan, South Korea
10
Department of Psychiatry, Hanyang University, Seoul, South Korea
11
Department of Psychiatry, Kaoshiung Chang Gung Memorial Hospital and Chang Gung University School of Medicine, Kaohsiung, Taiwan
12
Psychiatric Center, Taipei City Hospital, Taipei, Taiwan
13
Department of Psychiatry, King George's Medical University, Lucknow, India
14
Department of Psychiatry, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
15
Pushpagiri Institute of Medical Sciences, Tiruvalla, India
16
Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
17
Department of Psychiatry & Mental Health, Tunku Abdul Rahman Institute of Neurosciences, Kuala Lumpur, Malaysia
18
Department of Psychiatry, Hasanuddin University Faculty of Medicine, Makassar, Indonesia
19
Bangladesh Association of Psychiatrists, Bangladesh, Bangladesh
20
Pakistan Psychiatric Research Center, Fountain House, Lahore, Pakistan
21
Department of Psychiatry, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
22
Mental Health Society, Myanmar Medical Association, Yangon, Myanmar
23
Association for the Improvement of Mental Health Programmes, Geneva, Switzerland
24
Vietnam Psychiatric Association (VPA), Hanoi, Vietnam
25
Department of Pharmacology, National University Hospital, Singapore, Singapore
26
International Consortium for Mood & Psychotic Disorder Research, McLean Hospital, Belmont, Massachusetts, USA
 - -
Hum Psychopharmacol Clin Exp. 2020;e2752.

https://doi.org/10.1002/hup.2752
wileyonlinelibrary.com/journal/hup © 2020 John Wiley & Sons Ltd.
1 of 7
2 of 7
- LIM ET AL.

Correspondence
Kang Sim, Institute of Mental Health, 10,
Buangkok View, Singapore 539747, Republic
of Singapore.
Email: kang_sim@imh.com.sg
Abstract
Objective: Studies examining coprescription and dosages of mood stabilizers (MSs)
with antipsychotics for psychotic disorders are infrequent. Based on sparse extant
data and clinical experience, we hypothesized that adjunctive MS use would be
associated with certain demographic (e.g., younger age), clinical factors (e.g., longer
illness duration), and characteristics of antipsychotic treatment (e.g., multiple or high
antipsychotic doses).
Methods: Within an Asian research consortium focusing on pharmaco‐epidemio-
logical factors in schizophrenia, we evaluated rates of MS coprescription, including
high doses (>1000 mg/day lithium‐equivalents) and clinical correlates.
Results: Among 3557 subjects diagnosed with schizophrenia in 14 Asian countries,
MSs were coprescribed with antipsychotics in 13.6% (n ¼ 485) of the sample, with
10.9% (n ¼ 53) on a high dose. Adjunctive MS treatment was associated (all p <
0.005) with demographic (female sex and younger age), setting (country and hos-
pitalization), illness (longer duration, more hospitalizations, non‐remission of illness,
behavioral disorganization, aggression, affective symptoms, and social–occupational
dysfunction), and treatment‐related factors (higher antipsychotic dose, multiple
antipsychotics, higher body mass index, and greater sedation). Patients given high
doses of MSs had a less favorable illness course, more behavioral disorganization,
poorer functioning, and higher antipsychotic doses.
Conclusions: Schizophrenia patients receiving adjunctive MS treatment in Asian
psychiatric centers are more severely ill and less responsive to simpler treatment
regimens.

KEYWORDS
adjunctive treatment, Asia, mood stabilizers, schizophrenia

1 | INTRODUCTION (Horowitz et al., 2014) and to supplement clozapine treatment

Schizophrenia is a severe mental illness associated with life‐long
disability, high social burden, excess mortality, and major costs and
has proven to be difficult to treat successfully (GBD, 2017; Owen,
Sawa, & Mortensen, 2016). Contemporary treatment of schizo-
phrenia involves antipsychotic drugs and rehabilitative methods
(Owen et al., 2016), as well as the use of adjunctive psychotropic
medications. Mood stabilizers (MSs) have been used to augment the
effects of antipsychotic drugs for schizophrenia, at rates ranging
from 7% to 28% especially in Europe and North America (Buchanan,
Kreyenbuhl, Zito, & Lehman, 2002; Haro & Salvador‐Carulla, 2006;
Sim et al., 2011; Szkultecka‐Debek et al., 2016; Xiang et al., 2012).
However, evidence that such adjunctive interventions are effective
and safe is limited and inconsistent. Sodium valproate has been
specifically studied, with some unfavorable observations regarding
its efficacy as an adjunctive treatment for schizophrenia (Casey
et al., 2009; Glick, Bosch, & Casey, 2009), but other findings were
more favorable, including in comparisons with placebo, especially
for patients with prominent aggression and impulsive behavior
(Siskind et al., 2018; Zheng, Xiang, Yang, Xiang, & de Leon, 2017).
Other adjunctive MSs, including lithium carbonate (Leucht, Kissling,
& McGrath, 2004) and carbamazepine (Leucht, Helfer, Dold, Kis-
sling, & McGrath, 2014), have been found to be ineffective in the
treatment of schizophrenia. Evidence for lamotrigine has been
mixed and includes both unfavorable findings (Goff et al., 2007),
but some evidence of efficacy in schizophrenia with obsessive‐
compulsive features (Poyurovsky, Glick, & Koran, 2010) and in
clozapine resistant schizophrenia (Tiihonen, Wahlbeck, & Kiviniemi,
2009).
Despite evidently widespread international use of MSs for the
treatment of patients with schizophrenia, there are cogent reasons to
further evaluate their clinical use and value, especially in Asia, where
such studies have been rare, geographically limited, and usually
without consideration of drug doses and related factors (Sim et al.,
2011; Xiang et al., 2012).
Given these circumstances, we aimed to examine the rate of
adjunctive use of MSs for patients with schizophrenia across Asia,
including drug doses and factors associated with such treatment.
LIM ET AL.
Studies of effects of doses of MSs can be facilitated by the availability
of methods for estimating lithium equivalents or doses equivalent to
typical clinical daily mg‐doses of lithium carbonate (Baldessarini,
2013; Rajaratnam et al., 2017). We hypothesized that adjunctive
treatment with MSs would be associated with indicators of illness
severity (such as hospitalization and nonremission), particular types
of psychopathology (such as aggression and affective features), and
use of multiple antipsychotic agents, and at relatively high total daily
chlorpromazine‐equivalent (CPZ‐eq) doses.
2 | METHODS
2.1 | Study subjects and locations
This study examined data collected in the Research on Asian Psy-
chotropic prescription patterns in Schizophrenia (REAP‐SZ) project, a
pharmaco‐epidemiological study started in 1999 (Chong et al., 2004)
and fourth round of the REAP‐AP survey was done in 2016. Data
collected include the nature of adjunctive use of MSs for schizo-
phrenia patients across 14 Asian countries and regions (Bangladesh,
Hong Kong, India, Indonesia, Japan, Malaysia, Myanmar, Pakistan, PR
China, RO Korea, Singapore, Sri Lanka, Taiwan, Thailand, and Viet-
nam). Data collection follows the same protocol at each site.
Consecutive subjects diagnosed with schizophrenia received anti-
psychotic drug on the day in various hospital and ambulatory, and
inpatient settings were recruited. Data recorded included subject
age, sex, diagnosis, setting of treatment (outpatient or inpatient),
clinical features, and all medications and doses prescribed by clini-
cians responsible for their care. Diagnoses were confirmed by at least
two research psychiatrists at each site, following ICD‐10 (World
Health Organization, 1992) or Diagnostic and Statistical Manual of
Mental Disorders (DSM‐5) criteria (American Psychiatric Associ-
ation (APA), 2013). The study protocol was approved by an institu-
tional Ethics Review Committee at each collaborating site. All
participants were fully informed of the aims of the study and pro-
vided written, informed consent for anonymous and aggregate
reporting of their findings. The study was conducted in accordance
with the Declaration of Helsinki. Based on the concomitant use of
lithium or an anticonvulsant with mood stabilizing properties, the
study sample was divided into those receiving MSs and those not
receiving MSs.
2.2 | Drug doses
We estimated lithium carbonate‐equivalent (Li‐eq) mg/day doses of
agents with mood stabilizing properties (carbamazepine, lamotrigine,
lithium carbonate, and sodium valproate; Rajaratnam et al., 2017).
Based on clinical impressions, high‐dose MS use was defined as
adjunctive MS prescription of >1000 Li‐eq mg/day. Doses of anti-
psychotic agents are reported as CPZ‐eq mg/day, as described pre-
viously (Baldessarini, 2013).
- 3 of 7
2.3 | Data analyses
Averages are reported as means þ standard deviation (SD), and
relative rates of factors among patients cotreated with MSs or not
are reported as odds ratios (OR) with their 95% confidence intervals
(CI). Statistical analyses were based on the Statistical Package for the
Social Sciences (IBM Corp, 2015). Normality of distributions of
continuous measures was tested with the Kolmogorov–Smirnov one‐
sample test before further analysis. Differences between groups
receiving versus not receiving MSs were tested by analysis of vari-
ance (ANOVA; t‐test) for normally distributed continuous data and
nonparametric Mann–Whitney U‐tests for non‐normally distributed
continuous data; contingency tables (χ2) were used for categorical
variables. Multivariate logistic regression modeling was used to
adjust for relevant covariates and to determine factors associated
significantly and independently with adjunctive MS treatment.
3 | RESULTS
3.1 | Subjects and treatments
The study sample included 3557 adult subjects, of whom 59.0% (n ¼
2099) were men; mean age (�SD) was 39.9 � 12.8 years (Table 1).
Adjunctive treatment with MSs at any dose was found in 485 (13.6%)
subjects: 457 (12.8%) received one, 27 (0.76%) received two, and 1
subject (0.03%) received three MSs. The use of MSs was most
prevalent in PR China, Japan, and Pakistan and was least in
Bangladesh, Malaysia, Indonesia, and India (Table 1). Among MSs
prescribed, usage ranked: sodium valproate (n ¼ 396; 11.1%) >
lithium (n ¼ 69; 1.94%) > carbamazepine (n ¼ 37; 1.04%) > lamo-
trigine (n ¼ 12; 0.34%). The overall mean � SD Li‐eq dose of MSs was
613 � 456 mg/day.
Treatment with second‐generation antipsychotics (SGAs) was
twice as prevalent as with older, first‐generation agents (FGAs): 80.0%
versus 39.8% (χ2 ¼ 1199, p < 0.0001). Use of more than one anti-
psychotic agent was noted in 40.1% of subjects, and such polytherapy
was somewhat more prevalent with MS cotreatment (46.2%) than
without (39.1; χ2 ¼ 8.36, p ¼ 0.004). The mean total daily CPZ‐eq
antipsychotic dose was 428 � 358 mg/day overall for the entire
sample, and antipsychotic dose was significantly greater when
MSs cotreatment was used (521 � 432 vs. 413 � 343 CPZ‐eq
mg/day;
t ¼ 6.20, p < 0.0001).
3.2 | Factors associated with MS use
Factors significantly associated with any use of adjunctive MSs
included female sex and current hospitalization, but not current age
(Table 2). MS‐cotreated subjects also had multiple psychiatric
hospitalizations, nonremission of illness, disorganized speech, verbal
or physical aggression, affective symptoms, social–occupational
dysfunction, as well as higher daily CPZ‐eq doses of antipsychotics,
4 of 7
- LIM ET AL.

TABLE 1 Characteristics of study sample (N ¼ 3557)

Subjects Age ± SD Men Hospitalized First‐admission In remission Adjunctive Relative MS use

Country (n) (years) (%) (%) (%) (%) MS use (%) (OR [CI])

PR China 152 40.9 � 16.0 65.1 90.8 36.2 48.7 36.2 27.8 [3.73–207]

Japan 219 46.6 � 14.3 62.1 58.4 14.1 35.2 28.8 19.5 [2.63–144]

Pakistan 287 37.2 � 11.9 55.1 47.7 20.4 36.9 26.1 17.3 [2.35–128]

Thailand 319 39.4 � 12/3 66.5 42.9 32.1 60.2 19.4 11.8 [1.60–87.3]

Hong Kong 31 38.8 � 13.9 58.1 100 9.70 71.0 19.4 11.8 [1.34–103]

Singapore 160 47.9 � 13.5 35.6 73.1 11.1 24.4 16.3 9.51 [1.26–72.0]

Vietnam 270 39.1 � 11.7 67.4 100 33.3 16.7 13.7 7.78 [1.04–58.1]

Taiwan 392 47.5 � 11.8 45.7 56.6 7.20 52.6 13.0 7.33 [0.99–54.2]

Myanmar 163 37.7 � 11.2 65.6 55.2 42.2 37.4 9.80 5.33 [0.69–41.3]

Sri Lanka 96 40.6 � 13.5 60.4 52.1 34.0 30.2 7.30 3.85 [0.46–32.2]

RO Korea 112 39.4 � 12.1 44.6 5.40 33.3 42.0 7.10 3.77 [0.46–31.0]

India 475 36.0 � 10.4 66.5 31.2 55.6 65.7 6.10 3.19 [0.43–23.9]

Indonesia 539 36.2 � 10.4 64.0 50.5 45.6 59.7 5.90 3.19 [0.43–23.8]

Malaysia 292 39.2 � 12.1 51.5 34.2 24.0 66.8 5.80 3.03 [0.39–233]

Bangladesh 50 33.4 � 10.1 58.0 0.00 ‐ 30.0 2.00 1.00 (index)

Totals 3557 39.9 � 12.8 59.0 51.9 29.8 49.0 13.6 ‐

Note: MS use ¼ adjunctive treatment with mood stabilizers. Data are in rank order of prevalence of MS use.
Abbreviations: CI, confidence interval; MS, mood stabilizer; OR, odds ratio.
use of more than one antipsychotic agent, and with higher body mass sites, ranging from 36.2% of subjects in PR China to 2.00% in
index, and more sedation (Table 2). Bangladesh—regional variance that remains unexplained. The over-
Logistic regression modeling designated any adjunctive use of all mean rate of MS use, at 13.6% accords well with reports from
MSs as the dependent variable and found several significantly and Europe and North America, ranging from 7% to 27% (Buchanan
independently associated factors. These included the country et al., 2002; Haro & Salvador‐Carulla, 2006; Szkultecka‐Debek et al.,
(greatest use in PR China and least in Taiwan), current hospitaliza- 2016), but is somewhat lower than rates of 20.4%–27.7% in pre-
tion, female sex, relatively young age, longer duration of illness, vious Asian surveys (Sim et al., 2011; Xiang et al., 2012). Accord-
disorganized speech, verbal or physical aggression, social– ingly, these findings add to the impression that use of MSs is quite
occupational dysfunction, and lack of hallucinations (Table 3). prevalent in the treatment of patients with schizophrenia
Subjects given high doses of MSs (>1000 mg/day Li‐eq) differed throughout the world. Off‐label or adjunctive use of MS has been
significantly from those given lower MS doses in several ways. described in other studies where there is incomplete response to
Between these MS‐cotreated subgroups, mean doses of MSs differed antipsychotic monotherapy, but efficacy studies of the individual
highly significantly and were 3.32 times greater if a high dose of MS MSs have been inconclusive (Buchanan et al., 2010). Pharmacoki-
was used: 1625 � 619 versus 489 � 215 Li‐eq mg/day. In addition, netic interactions between antipsychotics and MSs could lead to
subjects given high doses of MSs were more likely to be treated with increased effective dose of antipsychotics which should be borne in
an older FGA, to have social–occupational dysfunction, disorganized mind (Schoretsanitis et al., 2016). The potential significance of
speech, to be given a 1.33‐fold higher mean dose of antipsychotics preferential use of valproate among MSs is not clear, although the
(670 � 547 vs. 504 � 414 CPZ‐eq mg/day), and were less likely to be preference accords with previous reports of some success in its use
in remission currently. in schizophrenia, even when clozapine has proved to be unsatis-
factory (Horowitz et al., 2014; Siskind et al., 2018; Zheng et al.,
2017). Clinicians could consider the use of MS in those with
4 | DISCUSSION aggression and affective symptoms, but should review response to
MS and individualize therapy.
In this large, descriptive, pharmaco‐epidemiological study of 3557 Adjunctive treatment with an MS was significantly associated
adult patients diagnosed with schizophrenia in 14 Asian countries or with indications of more severe illness and less successful treatment
regions, there were several notable findings. Use of cotreatment by antipsychotic drugs alone. These included multiple
with lithium or an anticonvulsant MS varied markedly among study hospitalizations, current hospitalization, more dysfunction,
LIM ET AL.
- 5 of 7

TABLE 2 Comparison of patients given adjunctive mood stabilizers or not

Mood stabilizers t‐score (df) or OR

Factors Present (n ¼ 485) Absent (n ¼ 3072) (95% CI) p‐value
Antipsychotic dose (CPZ‐eq mg/day [SD]) 521 (432) 413 (343) 5.17 (3556) <0.001

Hospitalized (n [%]) 344 (70.9) 1502 (48.9) 2.55 (2.07–3.14) <0.001

Affective symptoms (n [%]) 80 (16.5) 317 (10.3) 1.72 (1.32–2.24) <0.001

Disorganized speech (n [%]) 200 (41.2) 838 (27.3) 1.87 (1.54–2.28) <0.001

Social–occupational dysfunction (n [%]) 284 (58.6) 1326 (43.2) 1.86 (1.53‐–0.26) <0.001

Verbal aggression (n [%]) 161 (33.2) 726 (23.6) 1.61 (1.31–1.97) <0.001

Physical aggression (n [%]) 135 (27.8) 596 (19.4) 1.60 (1.29‐–0.99) <0.001

First admission (n [%]) 62 (18.0) 489 (32.5) 0.460 (0.340–0.610) <0.001

2
BMI (kg/m [SD]) 24.6 (4.85) 23.9 (4.66) 3.09 (3055) 0.002

Multiple antipsychotics (n [%]) 224 (46.2) 1204 (39.2) 1.33 (1.10–1.61) 0.004

In remission (n [%]) 209 (43.1) 1533 (49.9) 0.760 (0.630–0.92) 0.005

Sedated (n [%]) 63 (13.7) 296 (10.1) 1.42 (1.06–1.90) 0.018

Male sex (n [%]) 263 (54.2) 1834 (59.7) 0.800 (0.660–0.97) 0.023

Second‐generation antipsychotics (n [%]) 405 (83.5) 2442 (79.5) 1.31 (1.01–1.69) 0.040

Weight gain (n [%]) 74 (16.6) 366 (13.2) 1.31 (1.00–1.72) 0.052

Negative symptoms (n [%]) 190 (39.2) 1081 (35.2) 1.19 (0.970–1.44) 0.089

Delusions (n [%]) 222 (45.8) 1284 (41.8) 1.18 (0.970–1.43) 0.100

Disorganized/catatonic behavior (n [%]) 95 (19.6) 528 (17.2) 1.17 (0.920–1.50) 0.197

Hallucinations (n [%]) 219 (45.2) 1426 (46.4) 0.950 (0.780–1.15) 0.604

Age (years [SD]) 40.2 (12.8) 39.8 (12.8) 0.470 (3556) 0.638

First‐generation antipsychotics (n [%]) 191 (39.4) 1225 (39.9) 0.980 (0.80–1.19) 0.836

Note: Statistics are based on ANOVA for continuous factors (t score with df); or contingency analysis for categorical factors (OR with [95% CI]). Data are
listed in order of p‐value (with significant differences indicated in bold).
Abbreviations: ANOVA, analysis of variance; BMI, body mass index; CI, confidence interval; CPZ‐eq, chlorpromazine‐equivalent; df, degrees of freedom;
OR, odds ratio.

and nonremission with unresolved psychotic symptoms that included
aggressive behaviors and disorganized speech and behavior. MS‐
treated subjects also were receiving higher CPZ‐eq doses of anti-
psychotic drugs, including preferential use of modern SGAs, as well as
treatment with multiple different antipsychotics. In addition to un-
satisfactory responses to more conservative treatments, it may be
that clinical features related to mood or affect, including aggressive
behaviors that may have encouraged addition of a MS. These
included affective features and aggressive behaviors (Tables 2 and 3).
Of note, affective features in schizophrenia patients were previously
reported to be associated with MS cotreatment (Horowitz et al.,
2014; Wang, Xia, Helfer, Li, & Leucht, 2016). The MS cotreatment
was also helpful in the reduction of patient hostility (Citrome et al.,
2004). In addition, relatively high doses of MSs were used in asso-
ciation with the use of older antipsychotic drugs, greater social–
occupational dysfunction, disorganized speech, and lack of illness
remission, as well as with relatively high doses of antipsychotics—all
suggesting relatively challenging or treatment‐resistant illness.
These clinical findings identify a subgroup of patients who are in
need of closer attention and more intensive management and
rationalization of pharmacotherapy management, including antipsy-
chotic polytherapy and high daily antipsychotic dose. Clinicians
should monitor for response before and after MS augmentation and
individualize treatment for their patients. Further follow‐up studies
on the efficacy of MSs as adjunctive treatments in schizophrenia are
proposed to shed more light on this matter.
4.1 | Limitations
This study has several important limitations. Although the sample
size is relatively large and involved a broad cross section of Asian
nations, the numbers of subjects in some sites was small (Table 2) and
the data collected are cross sectional without longitudinal follow‐up
or details or previous and future illness course. Efforts were made to
standardize methods of diagnosis, clinical assessment, and data
 6 of 7
- LIM ET AL.

T A B L E 3 Factors significantly associated with adjunctive use pharmacotherapies as well as continued efforts to advance novel
of mood stabilizers
pharmacological and nonpharmacological strategies to improve
Wald p‐ symptomatic and functional outcomes in patients with chronic psy-
Factor OR 95% CI test value chotic disorders.

Country (vs. Malaysia) ‐ ‐ 174 <0.001

AC KNOW L E DGE ME N T
PR China 7.48 3.97–14.1 38.8 <0.001
We thank all patients who participated in the study.
Japan 6.72 3.63–12.4 36.9 <0.001

Thailand 5.82 3.20–10.6 33.4 <0.001 CO N FLI CT OF INT ERE S T

Pakistan 3.46 1.87–6.40 15.7 <0.001 The authors declare no conflict of interest.

Singapore 2.74 1.39–5.40 8.44 0.004

ORCI D
Taiwan 2.01 1.10–3.64 5.22 0.022
Tian‐Mei Si https://orcid.org/0000-0001-9823-2720
Months ill (vs. >20 years) 27.6 <0.001 Yu‐Tao Xiang https://orcid.org/0000-0002-2906-0029
3–6 0.214 0.081–0.570 9.52 0.002 Kang Sim https://orcid.org/0000-0003-3209-9626

7–12 0.356 0.181–0.700 8.96 0.003

RE FE RE NC E S
13–60 0.427 0.284–0.644 16.5 <0.001
American Psychiatric Association (APA). (2013). Diagnostic and statistical
61–120 0.676 0.467–0.978 4.31 0.038 manual of mental disorders, DSM‐5 task force (5th ed.). Arlington, VA:
Hospitalized 1.80 1.38–2.36 18.4 <0.001 American Psychiatric Association.
Baldessarini, R. J. (2013). Chemotherapy in psychiatry (3rd ed.). New York,
Younger age 0.978 0.967–0.988 17.4 <0.001 NY: Springer Press.
Social–Occupational 1.49 1.17–1.89 10.6 0.001 Buchanan, R. W., Kreyenbuhl, J., Kelly, D. L., Noel, J. M., Boggs, D. L.,
Fischer, B. A., … Schizophrenia Patient Outcomes Research Team
dysfunction
(PORT) (2010). The 2009 schizophrenia PORT psychopharmaco-
Affective symptoms 1.98 1.47–2.67 20.2 <0.001 logical treatment recommendations and summary statements.
Verbal aggression 1.49 1.10–2.00 6.76 0.009 Schizophrenia Bulletin, 36(1), 71–93.
Buchanan, R. W., Kreyenbuhl, J., Zito, J. M., & Lehman, A. (2002). The
Disorganized speech 1.36 1.06–1.75 5.81 0.016 schizophrenia PORT pharmacological treatment recommendations:
Conformance and implications for symptoms and functional
Less hallucinations 0.764 0.602–0.969 4.91 0.027
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Fewer men 0.806 0.652–0.997 3.95 0.047 Casey,Wozniak, P., &D.Saltarelli,
D. E., Daniel, G., Tamminga,M. (2009). Divalproex
C., Kane, J. M., TranER combined
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recording across sites, but some heterogeneity of findings across Chong, M. Y., Tan, C. H., Fujii, S., Yang, S. Y., Ungvari, G. S., Si, T., &
Shinfuku, N. (2004). Antipsychotic drug prescription for schizo-
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phrenia in East Asia: Rationale for change. Psychiatry and Clinical
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 Global Journal of Health Science; Vol. 11, No. 2; 2019
ISSN 1916-9736 E-ISSN 1916-9744
Published by Canadian Center of Science and Education

The Side Effect of Haloperidol in Schizophrenic Patients: Analysis of

Red Blood Cell Distribution Width (RDW) and Mean Platelet
Volume (MPV) Values
Andi Jayalangkara Tanra1, Hawaidah1, Yazzit Mahri1, Saidah Syamsuddin1,
Andi Nilawati Usman 2,3 & Sonny Teddy Lisal1
1
Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Indonesia
2
Halal Center, Hasanuddin University, Indonesia
3
Public Health, Mandala Waluya College, Indonesia
Correspondence: Yazzit Mahri, Department of Psychiatry Postgraduate, Hasanuddin University, Makassar
90245, Indonesia. Tel: 62-821-952-79678. E-mail: zitechdr7@gmail.com

Received: November 26, 2018 Accepted: January 7, 2019 Online Published: January 15, 2019
doi:10.5539/gjhs.v11n2p55 URL: https://doi.org/10.5539/gjhs.v11n2p55

Abstract
Introduction: Like the increase of pro-inflammatory cytokines and oxidative stress as schizophrenia
pathophysiology, haloperidol also increases RDW and MPV values. Both of these values have been clinicians
concern because they are a risk factor for the various type of vascular disease.
Objective: This study aims to determine the side effect of haloperidol on RDW and MPV values in
schizophrenic patients.
Methods: This research method uses observational analytic design with a prospective cohort approach with pre
and posts analysis conducted at the Regional Special Hospital of South Sulawesi Province during May - July
2018 in 30 schizophrenic subjects. The subjects were diagnosed as first episode schizophrenia based on ICD 10,
blood samples were taken, for RDW and MPV values before and after haloperidol was given at the 4th and 8th
weeks.
Results: The results showed that the mean RDW value at the 4th week was higher in 15 mg/day haloperidol
group (15.8) compared to 7.5 mg/day haloperidol group (15.3) with p<0.05. Mean RDW value taken at 8th week
was higher in 15 mg/day haloperidol group (16.4) compared to 7.5 mg/day haloperidol group (15.6) with
p<0.001. Mean MPV value taken at 8th week was higher in 15 mg/day haloperidol group (13.3) compared to 7.5
mg/day haloperidol group (11.6) with p<0.001.
Conclusion: This study showed an increase in the RDW value in schizophrenia subjects prior to the haloperidol
administration. RDW and MPV values were higher after haloperidol treatment compares to before haloperidol
treatment. The increase of RDW and MPV values tend to be influenced by haloperidol dosage and administration
duration.
Keywords: Haloperidol, RDW value, MPV value, schizophrenia
1. Introduction
Schizophrenia is the most common psychotic disorder, where symptoms usually appear in late adolescence or
young adults between ages 15-45 years. The lifetime prevalence of schizophrenia is between 0.3% and 0.7%
(Amir,
2010; Kaplan, 2015). Numerous studies reported that schizophrenic patients had a higher level of inflammatory
cytokine concentrations in blood than controls. The high-level concentration of inflammatory cytokines is closely
related to the mental status of the patient. When the concentration of inflammatory cytokines was high, it
associated with recurrence of symptoms of schizophrenia. When patients are stable, there is no difference in the
concentration of inflammatory cytokines with controls (Kirkpatrick & Miller, 2013; Meyer, Schwarz, & Muller,
2011).
Objective evidence of schizophrenia had been carried out by examining levels of cytokines and other pro-
inflammatory agents, but these examinations required sophisticated equipment and also costly, another promising
examination that can by measuring the RDW and the MPV values, which has become a routine procedure in
most laboratories with lower cost compared to cytokines and other pro-inflammatory agents. Changes in the
RDW and
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MPV values had proved by several studies and related to inflammation, increased pro-inflammatory cytokines
from schizophrenia, and as the effects of antipsychotic use (Asoglu et al., 2016; Semiz et al., 2013; Steiner et al.,
2008; Suvisaari & Mantere, 2013).
The RDW is a mathematical description of erythrocyte size variations, which is a description of the variation in
the size and shape of erythrocytes. RDW is a reflection of the coefficient of variation in the distribution of red
blood cell volume obtained by the formula: (SD/ MCV) x 100%, the normal value of RDW ranges between 11.5-
14.5%. The higher the RDW value, the greater the variation of cell size. The hematological analysis also gives
the MPV value which is obtained by the formula: (PCT/ PLT) x 100 fL, with a normal range of 6.5-11.5 fL
(Farah & Khamisy-Farah, 2015).
Examination of CBC became the focus of attention in this study, specifically the RDW and MPV values whereas
several studies had found an association between changes in their value with the inflammatory process,
subclinical side effects of antipsychotic use, especially haloperidol, and its role as a risk factor for various
vascular diseases. In a study conducted by Asoglu et al. (2016), it found that an increase in cytokines as an
inflammatory factor strongly associated with inhibition of erythrocyte maturation by erythropoietin as reflected
by an increase in the RDW value. In vitro studies, showed platelet aggregation was higher in schizophrenic
patients than in healthy individuals. The findings of this study support the previous literature, which showed that
patients with schizophrenia showed an increased platelet activation associated with an increase of MPV values.
Previous research by Keser et al. (2016), found an association between RDW values and severity of coronary
artery disorders and the left ventricular function. Another study conducted by Danese et al. (2015), suggested an
increase in RDW value with an acute coronary syndrome. Sahin et al. (2014), illustrate the strong relationship
between RDW values and the severity of coronary artery disease in patients with non-ST elevation myocardial
infarction. Becker et al. (2009) also found that MPV is a predictor of cardiovascular risk (Chu et al., 2010;
Danese, Lippi, & Montagnana, 2015; Keser et al., 2016; Sahin et al., 2015).
The use of haloperidol as one of the management of schizophrenia is an oxidative stress state, in which
antioxidant enzymes and electron transport chain in mitochondria inhibited and as a result, oxidative cell damage
occurs which in turn causing an imbalance between antioxidants and pro-oxidants, and increased the RDW and
MPV values. Haloperidol affects the structure of blood platelets by increasing its volume. These findings explain
the relationship between haloperidol and platelet activity. In the schizophrenia group, it is shown that the use of
haloperidol is a free predictor of increased of the RDW and MPV values. Antipsychotics, haloperidol, for
example, have an affinity for dopamine and serotonin receptors, which ultimately triggers the change in the
activity of erythrocytes and platelets. Some studies have been carried out on the blood and brains of
schizophrenic patients with haloperidol treatment showing a negative impact on the iron level that caused anemia
which is one of the factors that can trigger of an increase in the RDW value (Wasti et al., 2013; Patel, 2015;
Semiz et al., 2013).
Based on this review, the researchers are interested in conducting a study which aims to determine the side effect
of haloperidol on RDW and MPV values in schizophrenic patients.
2. Methods and Materials
2.1 Subject
The study sample was schizophrenic patients based on ICD 10, both inpatients and outpatients at the Regional
Special Hospital of South Sulawesi Province which met the inclusion criteria during May to July 2018.
2.2 Design and Procedures
This study used observational analytic design with a prospective cohort approach with pre and post analysis.
Each subject who met the inclusion criteria and was willing to take part in the study was taken his identity
including name, address, gender, age, latest education level, occupation, and history of physical illness. Written
informed consent also obtained from all subjects.
Other measurements including blood pressure, pulse, respiration, temperature, height, weight, and physical
examination, type of schizophrenia and dosage of medication were recorded. A blood sample was taken before
and after haloperidol treatment in the 4th and eighth weeks. Then measurements of complete blood counts and
data collection of RDW and MPV values were carried out.
2.3 Data Analysis Techniques
Statistical analysis was performed using Chi-Square, Independent-t, and Paired-t-tests.

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3. Results
Observational analytic research with a prospective cohort approach with pre and post analysis was conducted to
determine the side effect of haloperidol on RDW and MPV values in schizophrenic patients. The study was
conducted at the Special Hospital of the South Sulawesi Province from May to July 2018.
During the study period, there were 36 subjects who met the inclusion criteria. 6 subjects were excluded because
they could not be observed in the 4th and 8th weeks so that the total amount samples until the end of the study
was
30 subjects. Most subjects were male (18 subjects or 60.0%), and 12 subjects were female (40%). Most subjects
were 30-39 years old (56.7%), and subjects aged 20-29 years were 5 subjects (16.7%), and over 40 years were 8
subjects (26.7%). Most subject were entrepreneur (9 subjects or 30.0%), farmers (8 subjects or 26,7%),
housewife (5 subjects or 16.7%), and 8 subjects (26.7%) were unemployed. The education level of subjects
consisted of 2 subjects were an elementary school (6.7%), 14 subjects were a junior high school (46.7%), and 14
subjects were a senior high school (46.7%). 14 subjects were paranoid schizophrenia (46.7%), and 16 subjects
were schizophrenia NOS (53.6%). Dosage of haloperidol consisted of 6 subjects (20.0%) were given 7.5
mg/day, and
24 subjects (80.0%) were given 15 mg/day (See Table 1).

Table 1. Characteristics of samples in the study (n = 30)

Characteristic Frequency (n) Percentage (%)
Male 18 60.0
Sex
Female 12 40.0
20-29 5 16.7
*Age (Year) 30-39 17 56.7
≥ 40 8 26.7
Farmer 8 26.7
Housewife 5 16.7
Occupation
Entrepreneur 9 30.0
Unemployed 8 26.7
Elementary 2 6.7
Education Junior high school 14 46.7
Senior high school 14 46.7
Paranoid schizophrenia 14 46.7
Diagnosis
Schizophrenia NOS 16 53.3
7.5 mg/day 6 20.0
Haloperidol dosage
15 mg/day 24 80.0
*Age range: 25-45 years, source: primary data, 2018.

Independent t-test showed that the mean initial RDW value did not differ significantly between the two dosage
group (p>0.05). However, a normal range of RDW is 11.5-14.5%, so both of dosage group had a high RDW.
The mean RDW in the 4th week was significantly higher in 15 mg/day dosage group compared to 7.5 mg/day
dosage group (p<0.05). The mean RDW value in the 8th week was significantly higher in 15 mg/day dosage
group compared to 7.5 mg/day dosage group (p<0.05). Clinically, both dosage groups had a high RDW either in
the 4th week or in the 8th week (See Table 2 and Figure 1).

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Table 2. Comparison of RDW value based on haloperidol dosage

Variable 7.5 mg/day dosage
Haloperidol 6n 15.0
Mean± ±0.1
SD P
Initial RDW value 15 mg/day 24 14.9 ± 0.3 0.072
7.5 mg/day 6 15.3 ± 0.3
RDW value in the 4th week 0.012
15 mg/day 24 15.8 ± 0.8
7.5 mg/day 6 15.6 ± 0.3
RDW value in the 8th week 0.001
15 mg/day 24 16.4 ± 0.7
Independent t-test. n: samples amount, SD: Standard deviation, p: significance.

17

16

15
M E A N

14 7.5 mg/day dosage group

16.4 15 mg/day dosage group
15.8 15.6
15.3
13 15 14.9

12

11 Initial RDW value RDW value

RDWInitial
valueRDW RDW
in the 4thvalue n 4 RDW
in the Weeink 8
8thvalue
Weeki
Figure 1. Comparison of RDW value based on haloperidol dosage

Paired-t-test showed that in 7.5 mg/day dosage group: the mean RDW value in the 4th week was not significantly
different from the initial RDW value (p>0.05), the mean RDW value in the 8th week was significantly higher than
the initial RDW value (p<0.05), the mean RDW value in the 8th week was significantly higher than in the 4th
week (p<0.05). In 15 mg/day dosage group: the mean RDW value either in the 4th week or in the 8th week
was significantly higher than the initial RDW value (p<0.001), the mean RDW value in the 8th week was
significantly higher than RDW in the 4th week (p<0.001) (See Table 3).

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Table 3. Comparison of RDW values according to a measurement time

Haloperidol dosage n Mean ± SD P
Pair 1 0.064
Initial RDW 6 15.0 ± 0.1

7.5 mg/day Pair 2 RDW value in the 4th week 6 15.3 ± 0.3 0.006
Initial RDW 6 15.0 ± 0.1
Pair 3 0.015
RDW value in the 8th week 6 15.6 ± 0.3
Pair 1 RDW value in the 4th week 6 15.3 ± 0.3 0.000
th
RDW value in the 8 week 6 15.6 ± 0.3
15 mg/day Pair 2 0.000
Initial RDW 24 14.9 ± 0.3
Pair 3 RDW value in the 4th week 24 15.8 ± 0.8 0.000
Initial RDW 24 14.9 ± 0.3
Paired t-test. n: Samples amount, SD: Standard deviation, p: Significance.
RDW value in the 8th week 24 16.4 ± 0.7
th
RDW value in the 4 week 24 15.8 ± 0.8
Independent t-test showed that the mean MPV value did not differ significantly between the two groups (p>0.05)
RDW
either in the initial week or in the the 8th weekfinding showed
value inLaboratory
4th week. 24 that 16.4
both±had
0.7 a normal MPV. The mean
th
MPV value in the 8 week was significantly higher in the 15 mg/day dosage group compared to 7.5 mg/day
dosage group (p<0.001). Laboratory finding showed that both groups had a high MPV (See table 4 and figure 2).

Table 4. Comparison of MPV values based on haloperidol dosage

Variable Haloperidol dosage n Mean ± SD p
7.5 mg/day 6 7.6 ± 0.5
Initial MPV value 0.975
15 mg/day 24 7.6 ± 0.7
7.5 mg/day 6 8.8 ± 0.6
MPV value in the 4th week 0.057
15 mg/day 24 9.7 ± 1.8
7.5 mg/day 6 11.6 ± 0.8
MPV value in the 8th week 0.000
15 mg/day 24 13.3 ± 0.8
Independent t-test. n: Samples amount, SD: Standard deviation, p: Significance.

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14

12

10
M E A N

8
13.3 7.5 mg/day dosage group
6 11.6 15 mg/day dosage group
9.7
8.8
4 7.7 7.6

2
0 Initial MPV value MPV value
Initialvalue
MPV MPV Value MPV Value in the 4th MPV Value in the 8th
i n the 4th in the 8th Week
week week
Week

Figure 2. Comparison of MPV values based on haloperidol dosage

Paired-t-test showed that in 7.5 mg/day dosage group, the mean MPV value in the 4th week was significantly
higher than the initial MPV value (p<0.05), the mean MPV value in the 8th week was significantly higher than
the initial MPV value (p<0.001), the mean MPV value in the 8th week was significantly higher than in the 4th
week (p<0.001). In 15 mg/day dosage group, the mean MPV value either in the 4th week or in the 8th week was
significantly higher than the initial MPV value (p<0.001), the mean MPV value in the 8th week was significantly
higher than in the 4th week (p<0.001) (See Table 5).

Table 5. Comparison of MPV values according to measurement time

Haloperidol dosage n Mean ± SD p
Pair 1 0.026
Initial MPV value 6 7.6 ± 0.5

7.5 mg/day Pair 2 MPV value in the 4th week 6 8.8 ± 0.6 0.000
Initial MPV value 6 7.6 ± 0.5
Pair 3 0.000
MPV value in the 8th week 6 11.6 ± 0.8
Pair 1 MPV value in the 4th week 6 8.8 ± 0.6 0.000
th
MPV value in the 8 week 6 11.6 ± 0.8
15 mg/day Pair 2 0.000
Initial MPV value 24 7.6 ± 0.7
Pair 3 MPV value in the 4th week 24 9.7 ± 1.8 0.000
Initial MPV value 24 7.6 ± 0.7
Paired t-test. n: Samples amount, SD: Standard deviation, p: Significance
MPV value in the 8th week 24 13.3 ± 0.8
th
MPV value in the 4 week 24 9.7 ± 1.8
4. Discussion
th
MPV value in the 8 week 24 13.3±0.8
This study showed that the increase in RDW and MPV values in schizophrenic patients were influenced by the

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dosage amount and duration of haloperidol administration. The longer haloperidol was administered and the
greater the dosage of haloperidol given, the greater the increase of the RDW and MPV values.
The samples analyzed consisted of 30 subjects aged between 30-45 years (mean 35 years). Based on the
characteristics of the sample data, most of the subjects were male. Although the prevalence was the same
between men and women, there was a difference in the onset and course of the disease. Men had an earlier onset
of schizophrenia than women. More than half of all hospitalized schizophrenic patients were male and only one-
third of schizophrenic patients were female. Several studies had suggested that men are more likely to show
early symptoms of schizophrenia in the form of negative symptoms as an onset, and a high prevalence of
aggression. Women were more likely to have better social functioning than men. This is a major cause of men
being hospitalized when suffering from schizophrenia than women (Kaplan, 2015).
Results of the Independent t-test from the ratio of RDW value to haloperidol 7.5 mg/day and haloperidol 15
mg/day, showed that the mean initial RDW value did not differ significantly between the two groups (p>0.05).
Meanwhile, the mean RDW value in the 4th week was significantly higher in the group of 15 mg haloperidol per
day compared to 7.5 mg per day, which was 15.8 to 15.3 (p<0.05). The mean RDW value in the 8th week was
significantly higher in the group of 15 mg haloperidol per day compared to 7.5 mg per day, which was 16.4 to
15.6 (p<0.001). Noticeably that the group with 15 mg per day haloperidol gave a significant increase in the RDW
value since the
4th week compared to the group with 7.5 mg haloperidol per day.
Based on the result of the analysis, it was concluded that the increase in the initial RDW value was probably not
influenced by haloperidol dosing, but from other factors. This was consistent with the research conducted by
Asoglu et al. (2016), who found that an increase in cytokines as an inflammatory factor was strongly associated
with inhibition of erythrocyte maturation by erythropoietin, which was reflected by an increase in the RDW
value. Another study conducted by Zhang et al. (2009); Boskovic and Vovk (2008); and Gonzalez et al. (2014),
about RDW had shown a direct relationship between damage of blood cells in the circulation due to high
oxidative stress and the increase of RDW values. Whereas Miller and Kirkpatrick (2013) found that pro-
inflammatory cytokines, as well as oxidative stress, contribute to an increase in the RDW value in
schizophrenia. The inflammatory response and oxidative stress from the pathogenesis of schizophrenia itself can
increase the value of the RDW even before exposure to treatment. This discovery can be a diagnostic value for
the development of schizophrenic pathophysiology.
Paired t-test of RDW values from 7.5 mg/day haloperidol group did not show a significant difference in the 4th
week to initial study (p>0.05), and in the 8th week was significantly higher than in the initial study (p<0.001).
The mean RDW value in the 8th week was significantly higher than RDW in the 4th week (p<0.001). Whereas
in the
15 mg haloperidol group, the mean RDW value in the 4th week was significantly higher than the initial week,
which was 15.8 to 14.9 (p<0.001). The mean RDW value in the 8th week was significantly higher than the initial
week, which was 16.4 to 14.9 (p<0.001). In addition, the mean value of RDW in the 8th week was significantly
higher than RDW in the 4th week, which was 16.4 to 15.8 (p<0.001).
Increased or larger dosages contribute to the increase of the RDW value. This result is consistent with the initial
hypothesis that the administration of haloperidol had an effect on increasing the RDW value of schizophrenic
patients. These results are consistent with research conducted by Wasti et al. (2013), which states that haloperidol
contributes to an increase in RDW values and MPV values that can represent treatment side effects in
schizophrenic patients and can be used to support monitoring strategies to reduce blood disorders from drug
treatment antipsychotics. This finding could be a treatment value and prognostic value of antipsychotic drug
treatment in schizophrenic patients.
Independent t-test results from the comparison of MPV values based on haloperidol 7.5 mg/day and 15 mg/day,
found that the mean initial MPV value did not differ significantly between the two groups (p>0.05). Meanwhile,
the mean MPV value in the 4th week did not differ significantly between the two groups (p>0.05). The mean
MPV value in the 8th week was significantly higher in the 15 mg haloperidol group compared to 7.5 mg
haloperidol group (p<0.001). Clinically, both had a high MPV value. Results of the paired t-test of MPV values
based on the time of measurement of haloperidol 7.5 mg/day and 15 mg/day, showed that the administration of
7.5 mg/day haloperidol in the 4th week was significantly higher than the initial MPV value (p<0.001). While the
mean MPV value at the 8th week was significantly higher than the initial MPV value (p<0.001). In addition, the
mean of MPV value in the 8th week was significantly higher than in the 4th week (p<0.001).
In the group of 15 mg haloperidol, was found that the mean of MPV value in the 4th week was significantly
higher than the initial MPV value (p<0.001). Whereas the mean of MPV value in the 8th week was significantly
higher than the initial MPV value (p<0.001). In addition, the mean of MPV value in the 8th week was
significantly higher
61
gjhs.ccsenet.org Global Journal of Health Science Vol. 11, No. 2; 2019

than in the 4th week (p<0.001). It could be concluded that the increase of the MPV value occurred at the 8th
week of haloperidol administration, and both groups contributed to the increase in MPV value, whereas the
administration of 15 mg was more significant to increase the MPV value compared with the administration of 7.5
mg.
The dosages amount greatly affected the rate of increased MPV values. These results were consistent with the
initial hypothesis that the administration of haloperidol had an effect on increasing the MPV value of
schizophrenic patients. These results were consistent with the research conducted by Semiz et al. (2013), stating
that antipsychotics can affect the structure of blood platelets, which increases their volume. This finding
contributes an explanation about the relationship between antipsychotics and platelet activity which was reflected
in an increase in MPV values. Meanwhile, according to research conducted by Patel (2015), antipsychotics that
have dopamine and serotonin receptor affinity can eventually trigger changes in platelet activity.
5. Conclusion
Researchers concluded that RDW and MPV values in schizophrenic patients were higher after haloperidol
treatment than before haloperidol treatment. An increase in the RDW and MPV values in schizophrenic patients
tend to be influenced by the duration of administration and the amount of haloperidol. The longer haloperidol
was administered and the greater the dosage of haloperidol given, the greater the increase in the RDW and MPV
values.
There was an increase in the RDW value before haloperidol administration. Researchers suggest that an initial
screening check for RDW and MPV values for schizophrenic patients should be performed at the first admission
to the hospital as a basis for consideration of selection and administration of antipsychotic. A study is needed
compares the use of typical antipsychotics and atypical antipsychotics to see the side effect on RDW and MPV
values of schizophrenic patients. Regular monitoring of RDW and MPV values is needed to support management
strategies to reduce blood disorders from the treatment of antipsychotic drugs that can trigger various vascular
diseases in schizophrenic patients.
Acknowledgments
The authors declare no potential conflict of interest in writing this original article. The authors would like to
support the contributions of Tenri Esa, M. D. (Clinical Pathologist), and Arifin Seweng, M. D. (Research
Methodology Advisor).
Competing Interests Statement
The authors declare that there are no competing or potential conflicts of interest.
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 Journal of Affective Disorders 257 (2019) 331–339

Contents lists available at ScienceDirect

Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research paper

Electroconvulsive shock restores the decreased coverage of brain blood

vessels by astrocytic endfeet and ameliorates depressive-like behavior
⁎
Ilhamuddin A. Azisa,b,c, Sadayuki Hashiokaa, , Keiko Tsuchiea, Tsuyoshi Miyaokaa,
Rostia A. Abdullaha, Erlyn Limoab, Ryosuke Arauchia, Ken Inoued, Shoko Miuraa,
Muneto Izuharaa, Misako Kanayamaa, Koji Otsukia, Michiharu Nagahamaa, Kiminori Kawanoa,
Tomoko Arakia, Maiko Hayashidaa, Rei Wakea, Arata Oh-Nishia, Andi J. Tanrab, Jun Horiguchia,
Masatoshi Inagakia
a
Department of Psychiatry, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
b
Department of Psychiatry, Hasanuddin University, Jl. Perintis Kemerdekaan Km. 10, Makassar 90245, South Sulawesi, Indonesia
c
Department of Biochemistry, Hasanuddin University, Jl. Perintis Kemerdekaan Km. 10, Makassar 90245, South Sulawesi, Indonesia
d
Health Service Center, Kochi University, Akebono-cho, Kochi 780-8520, Japan

A BS T RA CT

Background: Although growing evidence indicates that ECT affects astrocytes, the exact mechanisms of the therapeutic effect of ECT are still unknown. Astrocytic
endfeet express the water channel aquaporin (AQP) 4 abundantly and ensheath brain blood vessels to form gliovascular units. It has been shown that the coverage of
blood vessels by AQP4-immunostained endfeet is decreased in the prefrontal cortex (PFC) of patients with major depression. This study was made to determine
whether ECT restores the astrocytic coverage of blood vessels with amelioration of depressive symptoms.
Methods: After electroconvulsive shock (ECS) administration to rats, the forced swimming test (FST) and Y-maze test were performed. Subsequently, immuno-
fluorescence analysis was conducted to measure the coverage of blood vessels by astrocytic endfeet in the PFC and hippocampus by using the endothelial cell marker
lectin and anti-AQP4 antibody. We also performed Western blot to examine the effects of ECS on the hippocampal expression of AQP4 and the tight junction molecule
claudin-5.
Results: Gunn rats showed learned helplessness and impaired spatial working memory, compared to normal control Wistar rats. ECS significantly improved the
depressive-like behavior. Gunn rats showed a decrease in astrocytic coverage of blood vessels, that was significantly increased by ECS. ECS significantly increased
expression of AQP4 and claudin-5 in Gunn rats.
Conclusions: ECS increased the reduced coverage of blood vessels by astrocytic endfeet in the mPFC and hippocampus with amelioration of depressive-like behavior.
Therefore, therapeutic mechanism of ECT may involve restoration of the impaired gliovascular units by increasing the astrocytic-endfoot coverage of blood vessels.

1. Introduction
Application of electroconvulsive therapy (ECT) is still considered to
be superior for some cases of psychiatric disorders in spite of much
advances in drug development. ECT modified by general anesthesia and
muscular relaxation has been recognized as a safe and effective treat-
ment for drug-resistant major depression, schizophrenia, mania and
catatonia (Weiner and Reti, 2017). Growing evidence indicates that
glial cells are involved in response to ECT (Jinno and Kosaka, 2008)
(Limoa et al., 2016). However, the exact mechanisms of therapeutic
effect of ECT have yet to be clarified. Glial cells have attracted attention
as new promising targets for antidepressant action (Hashioka et al.,
2013). In fact, an in vitro study has demonstrated that production of
brain-derived neurotrophic factor (BDNF) and lactate for neurons is
increased in rodent astrocytes treated with the selective serotonin re-
uptake inhibitor fluoxetine (Allaman et al., 2011), indicating that as-
trocyte is an important source of neurotrophic factor (Quesseveur et al.,
2013) and a main mediator of glucose metabolism. Another in vitro
study has shown that the tricyclic antidepressant imipramine induces
human astrocytes differentiate into neuronal phenotype, suggesting

⁎
Corresponding author.
E-mail addresses: hashioka@f2.dion.ne.jp (S. Hashioka), keits@med.shimane-u.ac.jp (K. Tsuchie), miyanyan@med.shimane-u.ac.jp (T. Miyaoka),
arauchi@med.shimane-u.ac.jp (R. Arauchi), ke-inoue@kochi-u.ac.jp (K. Inoue), mo114928@med.shimane-u.ac.jp (S. Miura),
misakoka@med.shimane-u.ac.jp (M. Kanayama), kotsuki@med.shimane-u.ac.jp (K. Otsuki), michi@med.shimane-u.ac.jp (M. Nagahama),
kkawano@med.shimane-u.ac.jp (K. Kawano), tomokoa@med.shimane-u.ac.jp (T. Araki), maiko-s@med.shimane-u.ac.jp (M. Hayashida),
rei@med.shimane-u.ac.jp (R. Wake), arata@resvo-inc.com (A. Oh-Nishi), jhorigu@med.shimane-u.ac.jp (J. Horiguchi),
minagaki@med.shimane-u.ac.jp (M. Inagaki).

https://doi.org/10.1016/j.jad.2019.07.008
Received 21 February 2019; Received in revised form 30 June 2019; Accepted 3 July 2019
Available online 04 July 2019
0165-0327/ © 2019 Elsevier B.V. All rights reserved.
I.A. Azis, et al.
involvement of this phenomenon in antidepressant-induced neurogen-
esis (Cabras et al., 2010). These findings prompt us to investigate the
mechanisms involving astrocytes in the therapeutic effect of ECT.
Aquaporin (AQP) 4 is a water channel and plays pivotal roles in the
brain functions (Nicchia et al., 2004). Astrocytic endfoot processes, on
which AQP4 is expressed abundantly, ensheath entire network of blood
vessels in the brain and form gliovascular units with endothelial cells
and pericytes (Simard et al., 2003; Wolburg et al., 2009). It has been
shown that AQP4 is required for the anti-depressive action via reg-
ulating adult hippocampal neurogenesis (Kong et al., 2009). A recent
postmortem study on patients with major depression, that is clinically
well known to be associated with cerebrovascular disease, has revealed
a decrease in the coverage of blood vessels by AQP4-immunostained
endfeet of astrocytes in the prefrontal cortex (Rajkowska et al., 2013). It
is, therefore, tempting to elucidate the effect of ECT on the decreased
coverage of blood vessels by AQP4-immunopositive endfeet, that ap-
pears to be involved in the pathogenesis of the major depression.
Our previous study has revealed that Gunn rats with glial activation
in the hippocampus present depressive-like behavior as shown by
prolonged immobility time in the forced swimming test (FST) and the
tail suspension test (Arauchi et al., 2018). The Gunn rat is a mutant of
the Wistar strain and has a genetic deficiency in glucuronyltransferase
(Gunn, 1944). This deficiency leads to high levels of unconjugated bi-
lirubin in their blood and the brain. Therefore, Gunn rats have been
used as an experimental model of kernicterus (bilirubin encephalo-
pathy), which can be considered as an organic brain disorder. Since
patients with organic brain disorder often present symptoms of schi-
zophrenia and affective disorder (Hamilton et al., 1983), it appears to
be rational that Gunn rats show depression-like behavior. In the present
study, we first confirmed that electroconvulsive shock (ECS), an animal
counterpart of ECT, ameliorated the depressive-like behavior of Gunn
rats, such as learned helplessness and impaired working memory, using
the FST and Y-maze test. We next investigated the morphology of
gliovascular units with regard to the coverage of blood vessels by as-
trocytic endfeet in the diseased brain of Gunn rat. Because it has been
shown that there is no significant difference in GFAP-immunostained
coverage of blood vessels between the postmortem brains of major
depression patients and those of normal controls (Rajkowska et al.,
2013), we labelled astrocytic endfeet with AQP4, not with GFAP. We
finally determined the effect of ECS on the astrocytic coverage of blood
vessels in the brain of Gunn rats whose depressive-like behavior was
ameliorated by ECS, to examine whether the change in morphology of
gliovascular units is related to the therapeutic efficacy of ECS.
2. Materials and methods
2.1. Animals
Eight-week-old male homozygous (j/j) Gunn rats and male Wistar
rats (SLC, Inc., Shizuoka, Japan) were used in this study (12 rats for
each strain). The rats were housed in plastic cages (39 × 27 × 18 cm)
under standard conditions with a room temperature (RT) of 23 ± 2 °C,
humidity of 55 ± 5%, and 12-h light/12-h dark cycle (light phase 7:00
to 19:00). The rats were allowed free access to food and water. One
week before commencing the experiment, the rats underwent a hand-
ling procedure once daily to reduce experimental stress. The handling
procedure consisted of picking rats up with a gloved hand, stroking, and
massaging them for 10 min. All procedures were conducted with the
approval of the Shimane University Animal Ethics Committee, in ac-
cordance with the guidelines of the National Health and Medical
Research Council of Japan.
2.2. ECS procedure
The animals were assigned into four groups, i.e., Wistar Sham (WS),
Wistar ECS (WE), Gunn Sham (GS) and Gunn ECS (GE) group. To avoid
332
Journal of Affective Disorders 257 (2019) 331–339
stress or pain induced by the ECS procedure, each rat was first an-
esthetized in an isoflurane inhalation chamber (4% for initial induc-
tion) with an oxygen flow rate of 2–4 L/min. After the rat fell asleep, it
was taken out from the chamber and anesthesia was continued by
putting an isoflurane inhalation mask (2% for maintenance) with an
oxygen flow rate of 2–4 L/min. In every ECS procedure, electric shock
was given under such anesthesia. ECS was administered transcranially
via bilateral ear clip electrodes by using an E.C. Stimulator MK-810
(Muromachi Kikai, Tokyo, Japan). The stimulus was a sine wave pulse,
100 V, 60 Hz, 50 mA, 1.5 s. Each stimulation resulted in a typical tonic-
clonic seizure lasting for less than 10 s. The ECS group received an ECS
treatment once daily for 6 consecutive days. The sham-treated groups
were handled identically to the ECS groups including anesthesia except
that no current was delivered. Each individual in all the groups was
given the FST and Y-maze test. After the behavior tests, the brain were
taken out to conduct immunofluorescent studies.
2.3. FST
The FST was performed according to protocol reported previously
with modification (Arauchi et al., 2018). A plastic cylinder, whose
diameter is 19 cm, filled with 10 L of water (25 °C ± 1 °C), 40 cm in
depth. On the first day, rats were gently placed individually in the water
for 15 min to be habituated. The rat left in the cylinder was either
unable to touch the bottom or escape. The animals were dried with a
towel and put in a warmer chamber for 10 min to avoid hypothermia,
and then returned to their home cages. After each trial, the cylinder was
washed, rinsed, and refilled with fresh water to avoid influence on the
next animal. On the next day, the rats were placed in the water for
6 min and their behavior was recorded with a video camera. Immobility
time occurring during the test was manually counted from the recorded
video by a trained observer in a blinded manner. The rats were con-
sidered immobile when they remained floated without struggling,
motionless and when they moved only to maintain their heads above
the water.
2.4. Y-maze test
Spatial working memory of rats was assessed by the Y-maze test on a
day after the last ECS administration based on previously described
procedures with some modifications (Shi et al., 2017). The maze ap-
paratus is made of gray opaque polyvinyl chloride with three arms
(500 × 250 × 100 mm3 and 120° apart) (Muromachi Kikai). The ap-
paratus was cleaned with a 10% ethanol solution and then dried with a
paper towel after each trial to make it odorless. Each rat was placed at
the terminus of one arm and allowed to move freely through the maze
for 8 min. When the rat's tail was entirely within the arm, entry was
considered to be complete. Alternation behavior was defined as suc-
cessive entries into all three arms on consecutive occasions. The per-
centage of spontaneous alternation behavior (SAB) was calculated ac-
cording to the following formula:
The number of alternation
% SAB = × 100 %
The total number of arm entries 2
2.5. Brain section preparation
After the behavior tests, the animals were sacrificed under deep
intraperitoneal anesthesia with an anesthetic mixture of three drugs:
medetomidine (Domitor, Nippon Zenyaku Kogyo, Tokyo, Japan), mid-
azolam (Dormicum, Astellas Pharma, Tokyo, Japan), and butorphanol
(Vetorphale, Meiji Seika Pharma, Tokyo, Japan). We mixed medeto-
midine 0.15 mg/kg b.w./rat, midazolam 2 mg/kg b.w./rat and butor-
phanol 2.5 mg/kg b.w./rat and added saline (Otsuka Pharmaceutical
Factory, Tokushima, Japan) to adjust the mixture to a volume of
0.5 ml/100 g b.w./rat. The rats were perfused transcardially with
I.A. Azis, et al.
500 mL of physiological saline, followed by 500 mL of 4% paraf-
ormaldehyde (PFA) in 0.1 M phosphate buffer (PB; pH 7.3). After per-
fusion, the brain was quickly removed from the skull, and fixed in a
solution of 4% PFA at RT for 4 h. The brains were immersed in 10%
sucrose at 4 °C overnight and subsequently were immersed in 20% su-
crose at 4 °C for 24 h. The brains were cut at 40-μm thickness in the
coronal plane by using a freezing microtome (Microm HM 430, Thermo
Scientific, Waltham, MA).
2.6. Immunofluorescent staining
We modified and followed the protocol for double immuno-
fluorescent staining described in previous studies (Arauchi et al., 2018;
Liaury et al., 2014; Limoa et al., 2016). The free floating brain sections
were pre-incubated for blocking with 0.1 M PB containing 3% bovine
serum albumin, 0.2% Triton X and 1.5% normal horse serum for 1 h at
RT. The sections were then incubated overnight at RT in a solution of
0.1 M PB, 0.2% Triton X, 1.5% normal horse serum, and the mouse
monoclonal anti-AQP4 antibody (1:500, Santa Cruz Biotechnology, CA)
mixed with Texas Red labeled Lycopersicon esculentum (tomato) lectin
(1:500, Vector Laboratories, CA) to detect endothelial cells. The sec-
tions incubated with the anti-AQP4 antibody were incubated with
Alexa 488-conjugated anti-mouse IgG (Invitrogen, Carlsbad, CA) di-
luted at 1:1000 for 3 h at RT. Afterwards, the slices were mounted onto
gelatin-coated slides (Matsunami Glass, Osaka, Japan) and then were
sunk in 0.1 M PB. Coverslips were applied onto the slides with anti-
fading mounting medium and subsequently were kept in darkness be-
fore inspection. Negative controls for immunostaining were performed
with omitting the primary antibody or lectin.
Journal of Affective Disorders 257 (2019) 331–339
specific rabbit antibody for AQP4 (1:1000, Santa Cruz Biotechnology,
INC, H-80: sc-20812), claudin-5 (1:500, Sigma-Aldrich, SAB4502981:
310145), or mouse anti-β-actin antibody (1:5000, Abcam, AC-15:
ab6276) at 4 °C overnight. Subsequently, the membranes were in-
cubated with horseradish peroxidase-conjugated anti-rabbit IgG anti-
body (1:5000, GE Healthcare Life Sciences: NA934, Tokyo, Japan) or
anti-mouse IgG antibody (1:5000, GE Healthcare Life Sciences: NA931,
Tokyo, Japan) for 1 h at RT. Blots were developed using the chemilu-
minescent system (Amersham, GE Healthcare UK). The band intensity
was quantified by densitometry and the NIH Image analysis software
version 1.63 (NIH, Bethesda, MD). Individual expression levels of AQP4
or Claudin-5 were normalized to the expression levels of β-actin and
presented as percentages of the control group (i.e., Wistar sham) ex-
pression, that was defined as 100%.
2.9. Statistical analyses
All the data were expressed as the mean ± standard error of the
mean (S.E.M). The statistical analyses were carried out using the SPSS
software (Dr. SPSS II for Windows, IBM Japan, Tokyo, Japan).
Statistical comparisons among the groups were made with a one-way
analysis of variance (ANOVA) followed by the post hoc Fischer's least
significant difference test. We also used two-way ANOVA to determine
the effects of genotype or ECS treatment on immobility time, SAB and
AQP4 coverage, and interactive effect between genotype and ECS
treatment. Pearson correlation was conducted to establish relationship
between immobility time in the FST and AQP4 coverage of blood
vessels. A p-value less than 0.05 was considered statistically significant.

2.7. Image analysis for coverage of brain blood vessels 3. Results

Fluorescent images were captured by a BZ-X700 all-in one micro- 3.1. Effect of ECS on immobility time in the FST
scope (Keyence, Osaka, Japan) with a 40x objective lens and analyzed
by the BZ-X analyzer software. Regions of interest consist of two areas The FST was performed to evaluate the effect of ECS on depressive-
within the prefrontal cortex [i.e., the prelimbic (PrL) area and the in- like behavior of Gunn rats by counting the immobility time. As shown
fralimbic (IL) area] and three areas within the hippocampal formation in Fig. 1, the immobility time in the FST was 17.44 ± 4.05 s in the WS
[i.e., the dentate gyrus (DG), the cornu ammonis (CA)1 and the CA3]. group, 20.86 ± 5.61 s in the WE group, 73.19 ± 9.36 s in the GS
The images were taken from both hemispheres of 12–14 slices in the group, and 35.71 ± 8.08 s in the GE group. Immobility time of the GS
PrL region (two images from each slice), 8–11 slices in the IL region, group was significantly longer than that of WS. The ECS administration
and 12–15 slices in the hippocampal formation. Overall, 64–80 images to Gunn rats significantly shortened the duration of immobility com-
per animal (n = 5) were examined. The fluorescence colors in captured pared to that in the GS group. ECS did not affect immobility time sig-
images were split equally into red, green and blue colors by the BZ-X nificantly on Wistar rats. Both genotype and ECS treatment had
analyzer software. The “hybrid cell count” operating procedure with
“single extraction” was used to specify the target area by selecting the
outer margin of the stained areas. First, the lectin-positive area was
extracted from the merged fluorescent image of the lectin-positive area
(red) and the AQP4-positive area (green) and was displayed red. Next,
colocalization area, namely, the AQP4-positive area on the lectin-po-
sitive area was extracted and displayed yellow. These extraction pro-
cedures were performed based on the consistent threshold of fluores-
cence intensity, which was manually predefined. The pixels of the
yellow areas were calculated to determine the percentage of “cov-
erage”, which was defined as area of co-localization/total area of brain
blood vessels.

2.8. Western blot analysis

Hippocampal tissues were isolated and homogenized in ice-cold cell

lysis buffer (Cell Signaling, #9803, Danvers, NA) supplemented with
protease inhibitor (Roche, 11873580001, Mannheim, Germany). The
tissues were extracted at ratio of 1 mg of tissue to 10 μL of buffer. The
tissues were sonicated and subsequently centrifuged at 13,000 g for
10 min at 4 °C. The supernatants were collected and studied. Twenty-
five to fifty μg of protein were separated by 10% SDS-PAGE and
transferred to PVDF membranes. The membranes were incubated with
Fig. 1. Effect of ECS on immobility time of normal rats and Gunn rats in the
FST.
Immobility time of Gunn rats was significantly longer than that of Wistar rats.
The prolonged immobility time of Gunn rats was significantly shortened by
ECS. Each value is the mean ± S.E.M. (n = 6), *p < 0.05, #p < 0.001.
ECS, electroconvulsive shock.

333
I.A. Azis, et al.
Fig. 2. Effect of ECS on spontaneous alternation behavior of normal rats and
Gunn rats in the Y-maze test.
The percentage of spontaneous alternation behavior (SAB) of Gunn rats was
significantly decreased compared to Wistar rats. The decreased % SAB of Gunn
rats was significantly increased by ECS. Each value is the mean ± S.E.M.
(n = 6), *p < 0.05. SAB, spontaneous alternation behavior; ECS, electro-
convulsive shock.
significant effects on immobility time in the FST with a significant in-
teractive effect between genotype and treatment.
3.2. Effect of ECS on spontaneous alternation behavior (SAB) in the Y-maze
test
Spatial working memory was determined by SAB in the Y-maze test
(Fig. 2). The percentage of SAB was 76.62 ± 1.12% in the WS group,
69.51 ± 5.44% in the WE group, 62.44 ± 2.36% in the GS group, and
78.56 ± 3.05% in the GE group. A significant decline in the % SAB was
observed in the GS group compared to the WS group. The ECS-ad-
ministered Gunn rats showed a significant increase of the % SAB
compared to the GS group. This finding suggests that ECS improved the
spatial memory impairment of Gunn rats. On the other hand, there was
no significant difference between the WS group and the WE group.
Neither genotype nor ECS treatment showed a significant effect on SAB
in the Y-maze test, even though there was a significant interactive effect
between them.
3.3. Effect of ECS on the coverage of brain blood vessels by astrocytic
endfeet
The coverage of brain blood vessels by astrocytic endfeet in both the
PrL area and the IL area of the medial prefrontal cortex (mPFC) was
investigated. Representative merged fluorescence images show brain
blood vessels labelled by lectin (red) and astrocytic endfeet stained with
anti-AQP4 antibody (green) in the prelimbic area of the Wistar sham
(Fig. 3B), Gunn sham (Fig. 3C) and Gunn ECS groups (Fig. 3D). Overlap
area (yellow) of AQP4 immunoreactivity and lectin staining indicates
astrocytic coverage of brain blood vessels. A decrease in the overlap
area was discerned in the PrL area of the GS group compared with the
other groups. We performed quantitative analysis of astrocytic coverage
of brain blood vessels. In the PrL area, the % of AQP4 coverage area was
76.44 ± 1.73% in the WS group, 74.58 ± 1.39% in the WE group,
68.66 ± 2.23% in the GS group, and 75.39 ± 1.13% in the GE group
(Fig. 3E). The % of AQP4 coverage of the GS was significantly decreased
compared to that of the WS (Fig. 3E). The % of AQP4 coverage in the
GE was significantly increased compared to that in the GS (Fig. 3E). In
the IL area, the % of AQP4 coverage was 77.72 ± 1.40% in the WS
group, 75.66 ± 1.94% in the WE group, 69.43 ± 2.65% in the GS
group, and 74.80 ± 1.60% in the GE group (Fig. 3F). The % of AQP4
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Journal of Affective Disorders 257 (2019) 331–339
coverage in the IL area of the GS was significantly less than that of the
WS (Fig. 3F). Although the GE group showed a high average of AQP4
coverage compared to the GS group, the difference did not reach sta-
tistical significance (p = 0.07) (Fig. 3F). Neither genotype nor
ECS treatment showed a significant effect on AQP4 coverage in the PrL
area, while there was a significant interactive effect between
genotype and treatment. There was a significant effect of genotype,
but not of ECS treatment, on AQP4 coverage in the IL area, without a
significant in- teractive effect between genotype and ECS treatment. In
addition, there was a negative correlation between immobility time
in the FST and AQP4 coverage of blood vessels in the PrL area
(r = −0.476, p = 0.034) and IL area (r = −0.508, p = 0.022).
The AQP4 coverage of blood vessels in the hippocampal formation
was also evaluated. Representative merged fluorescence images show
brain blood vessels labelled by lectin (red) and astrocytic endfeet
stained with anti-AQP4 antibody (green) in the CA1 of the Wistar sham
(Fig. 4B), Gunn sham (Fig. 4C) and Gunn ECS groups (Fig. 4D). Similar
to the PrL area, a decrease in the overlap area was observed in the CA1
of the GS group compared with the other groups. Quantitative analysis
revealed that the % of AQP4 coverage in the DG was 76.68 ± 0.94% in
the WS group, 75.40 ± 2.61% in the WE group, 72.29 ± 1.83% in the
GS group, 77.28 ± 1.49% in the GE group (Fig. 4E). The % of AQP4
coverage in the CA1 was 75.29 ± 2.70% in the WS group,
75.59 ± 0.97% in the WE group, 68.60 ± 1.76% in the GS group,
75.51 ± 1.45% in the GE group (Fig. 4F). In the CA3,% of AQP4
coverage was 77.70 ± 2.17% in the WS group, 75.66 ± 1.10% in the
WE group, 69.96 ± 1.37% in the GS group, 76.91 ± 1.88% in the GE
group (Fig. 4G). A similar trend was found in the DG (Fig. 4E), the CA1
(Fig. 4F), and the CA3 (Fig. 4G) in comparing the AQP4 coverage
among the WS, GS, and GE groups. The scattered plot indicates a sig-
nificant reduction in the coverage of blood vessels by AQP4-positive
endfeet in the CA1 (Fig. 4F) and CA3 (Fig. 4G) of the GS group in
comparison with the WS group. However, it did not reach statistical
significance in the DG (Fig. 4E). A significant increase in AQP4 cov-
erage was observed in the GE group compared to the GS group in the
CA1 (Fig. 4F) and CA3 (Fig. 4G). Although the ECS administration to
Gunn rats showed a tendency to increase the AQP4 coverage in the DG,
there was no significant difference compared to that of the GS
(p = 0.07) (Fig. 4E). Like in the medial prefrontal cortex, the % of
AQP4 coverage in the WE group did not significantly differ from that in
the WS group in all the hippocampal formation regions. Neither gen-
otype nor ECS treatment showed a significant effect on AQP4 coverage
in the hippocampal DG, CA1 and CA3. There was no significant inter-
active effect between genotype and treatment in the DG and CA1, while
that in the CA3 reached significance. In addition, there was a negative
correlation between the immobility time and the AQP4 coverage in the
CA1 (r = −0.488, p = 0.029). However, a correlation between
the
immobility time and the AQP4 coverage was not significant in the DG
and CA3.
3.4. Effect of ECS on the hippocampal expression of AQP4 and claudin-5
To examine the effect of ECS on the hippocampal expression of
AQP4 and the tight junction molecule claudin-5, we also performed
quantitative analysis using Western blot. The representative results are
shown in Fig. 5A. AQP4 expression levels in the GS group were sig-
nificantly lower than those in the WS group (Fig. 5B). However, AQP4
expression in the GE group was significantly increased compared to that
in the GS group (Fig. 5B). Claudin-5 expression in the GE group was
significantly increased compared to that in the GS group, whereas there
was no significant difference in claudin-5 expression between the GS
group and the WS group (Fig. 5C).
4. Discussion
There were four major findings in the present study. First, the
I.A. Azis, et al. Journal of Affective Disorders 257 (2019) 331–339

Fig. 3. Effect of ECS on the astrocytic-endfoot coverage of blood vessels in the medial prefrontal cortex of normal rats and Gunn rats. The regions of interest consist of
the prelimbic (PrL) area and the infralimbic (IL) area (A). Representative merged fluorescence images show brain blood vessels labelled by lectin (red) and astrocytic
endfeet stained with anti-AQP4 antibody (green) in the prelimbic area of the normal rat sham (Wistar sham) (B), Gunn sham (C) and Gunn ECS groups (D). The Gunn
sham group shows vessel areas uncovered with astrocytic endfeet, that look red (indicated by arrows, C). On the other hand, the Wistar sham and Gunn ECS groups
show colocalization of astrocytic endfeet and blood vessels (indicated by arrowheads, B, D), that looks yellowish, suggesting increased vessel areas covered with
astrocytic endfeet. Scale bars indicate 50 µm. The percentage of the coverage of lectin-positive brain blood vessels by AQP4-positive astrocytic endfeet in the
prelimbic area (E) and the infralimbic area (F). Each value is the mean ± S.E.M. (n = 5), *p ≤ 0.05; n.s., not significant; AQP4, aquaporin 4. (For interpretation
of the references to color in this figure legend, the reader is referred to the web version of this article.)
coverage of blood vessels by AQP4-immunoreactive endfeet of astro- by ECS. While an antidepressant effect of ECS was observed in diseased
cytes in the mPFC and the hippocampal formation was significantly Gunn rats, ECS did not affect the normal Wistar rats in the present
reduced in Gunn rats compared to that of Wistar rats, a normal rat study. This finding is inconsistent with previous studies which showed
strain. Second, ECS significantly reduced immobility time in the FST, that ECS significantly decreased the immobility time of Wistar rats in
suggesting that ECS ameliorated depressive-like behavior of Gunn rats. the FST (Li et al., 2007; Theilmann et al., 2014). The difference in ECS
Third, ECS significantly improved deficits of working memory of Gunn conditions (e.g., amplitude, voltage, shock duration, the number of
rats as shown by normalized percentage of SAB in the Y-maze test. The shock times and body parts put with electrodes) and anesthetic proce-
last, ECS significantly increased the reduced coverage of brain blood dures may attribute to such a discrepancy.
vessels by astrocytic endfeet in Gunn rat. To our knowledge, this is the The well-known clinical observation is that major depression sig-
first study that determines the effect of ECS on the coverage of blood nificantly impairs working memory (Pelosi et al., 2000), while ECT has
vessels by astrocytic endfeet in the pathological brain. adverse effects such as cognitive deficit and amnesia in the acute phase
Immobility time in the FST can be regarded as behavioral despair (Semkovska and McLoughlin, 2010). This fact has led to a debate as to
which is supposed to reflect depressed moods (Porsolt et al., 1977). The whether amnesia associated with ECT is an intrinsic pathological
FST on rodents has been extensively used as a simple animal model for component of major depression. Under our experimental conditions,
investigating the neurobiology of depression because of its procedural ECS administration on normal Wistar rats showed a trend to decrease
simplicity and its high reproducibility (Porsolt et al., 1977). Our finding the % SAB. To our knowledge, there has been only one study that
that repeated ECS administration improved the depressive-like beha- evaluated the effect of ECS on spatial working memory in rodents under
vior of Gunn rats as shown by shortened immobility time in the FST is pathological conditions associated with major depression
consistent with previous studies using the FST, which demonstrated (Henningsen et al., 2013). Our result that repeated ECS treatment sig-
that ECS significantly reduced the duration of immobility in several nificantly ameliorated the impaired spatial working memory of Gunn
genetic rat models of depression, such as Flinders sensitive line rats rats as shown by increased % SAB in the Y-maze test is congruent with
(Hesselberg et al., 2016), Wistar Kyoto rats (Kyeremanteng et al., 2014) the aforementioned study which showed the significant efficacy of ECS
and BDNF knock down rats (Taliaz et al., 2013). Since depressive-like in normalizing a deficit in % SAB in rats exposed to chronic mild stress
behavior of Gunn rats is ECS-treatable, as in genetic rat models of de- (Henningsen et al., 2013).
pression, their depressive-like behavior may be associated with Our observation that the coverage of brain blood vessels by AQP4-
common pathophysiological microenvironments which can be modified immunoreactive astrocytic endfeet was significantly diminished in

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I.A. Azis, et al. Journal of Affective Disorders 257 (2019) 331–339

Fig. 4. Effect of ECS on the astrocytic-endfoot coverage of blood vessels in the hippocampal formation of normal rats and Gunn rats. The regions of interest consist of
the dentate gyrus (DG), cornu ammonis (CA)1 and CA3 (A). Representative merged fluorescence images show brain blood vessels labelled by lectin (red) and
astrocytic endfeet stained with anti-AQP4 antibody (green) in the CA1 of the normal rat sham (Wistar sham) (B), Gunn sham (C) and Gunn ECS groups (D). The Gunn
sham group shows vessel areas uncovered with astrocytic endfeet, that look red (indicated by arrows, C). On the other hand, the Wistar sham and Gunn ECS groups
show colocalization of astrocytic endfeet and blood vessels, that looks yellowish, suggesting increased vessel areas covered with astrocytic endfeet, (indicated by
arrowheads, B, D). Scale bars indicate 50 µm. The percentage of the coverage of lectin-positive brain blood vessels by AQP4-positive astrocytic endfeet in the DG (E),
CA1 (F) and CA3 (G). Each value is the mean ± S.E.M. (n = 5), *p ≤ 0.05; n.s., not significant; AQP4, aquaporin 4. (For interpretation of the references to color
in this figure legend, the reader is referred to the web version of this article.)
Gunn rats presenting depressive-like behavior is consistent with a Therefore, it could establish a causative role for the decreased endfoot
postmortem study that showed that the coverage of vessels by AQP4 coverage in manifestation of depressive symptoms to examine whether
was significantly reduced in the orbitofrontal cortex of patients with ECS administration to AQP4-knockout mice improves their cognitive
major depression compared to normal controls (Rajkowska et al., deficits. The reduced coverage of brain blood vessels by astrocytic
2013). Our result is also in line with an animal study in which rats endfeet may be related to reduction in glucose metabolism in the brain,
selectively bred for high anxiety-like behavior, an animal model of that is mainly mediated by astrocytes (Kreft et al., 2012). In fact, sev-
depression, showed significantly attenuated coverage of blood vessels eral neuroimaging studies have demonstrated the decreased glucose
in the PFC by AQP4-immunoreactive astrocyte processes compared to metabolism in the prefrontal cortex of depressed patients (Baxter et al.,
non-selected Wistar rats (Di Benedetto et al., 2016). To our knowledge, 1989; Martinot et al., 1990).
this is the first study showing that antidepressant treatment, namely Our previous studies have demonstrated that Gunn rats possess as-
ECS administration in our study, restores the decreased coverage of trocytic activation in the hippocampus as shown by increased im-
brain blood vessels by astrocytic endfeet in the pathological brain. munoreactivity for GFAP and S100B (Arauchi et al., 2018; Limoa et al.,
Based on these findings, the astrocytic-endfoot coverage of blood ves- 2016). In addition, it has been demonstrated that ECS significantly at-
sels may be negatively correlated with manifesting depressive symp- tenuate the increased hippocampal expression of GFAP in Gunn rats,
toms. To verify this hypothesis, further studies to determine the effects indicating ECS has inhibitory effects on activated astrocytes
of antidepressant treatment, especially neuropharmacological medica- (Limoa et al., 2016). Interestingly, it has been shown that an increase in
tion, on the astrocytic-endfoot coverage of brain blood vessels are the number of GFAP-positive astrocytes, that can be referred to as as-
clearly warranted. trogliosis or astrocytic activation, was accompanied by a decrease in
It has been shown that ECT increases serum levels of BDNF and glial amount of AQP4-immunopositive endfeet colocalized with brain blood
cell line-derived neurotrophic factor (GDNF) in patients with major vessels in a mouse model of a cerebral small vessel disease with features
depression (Rocha et al., 2016; Zhang et al., 2009). A recent in vitro of gliovascular disruption and cognitive deficits (Holland et al., 2015).
study demonstrated that GDNF had a protective effect on astrocytes to Activated astrocytes may, therefore, contribute toward impaired glio-
prevent apoptosis (Wang et al., 2018). Therefore, the ECT-induced vascular units with a decrease in the endfoot coverage of brain blood
production of neurotrophic factors, especially GDNF, may increase the vessels. Considering our previous observation of the efficacy of ECS in
astrocytic-endfoot coverage of blood vessels. inhibiting activated astrocytes in the hippocampus of Gunn rats, re-
Animal studies using AQP4-knockout mice have demonstrated that generating the impaired gliovascular units associated with activated
AQP4-knockout mice present cognitive deficits similar to those im- astrocytes may be involved in the therapeutic mechanisms of ECT. In
plicated in major depression (Skucas et al., 2011) and that AQP4 other words, the therapeutic effect of ECS may be exerted, at least in
knockout disrupts fluoxetine treatment-induced improvement of de- part, by increasing the decreased endfoot coverage of blood vessels,
pressive-like behavior caused by chronic mild stress (Kong et al., 2009). that is presumably related to activated astrocytes.

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I.A. Azis, et al. Journal of Affective Disorders 257 (2019) 331–339

Fig. 5. Effect of ECS on the expression of AQP4 and claudin-5 in the hippocampus of normal rats and Gunn rats. The hippocampal homogenates were separated by
10% SDS-PAGE and immunoblotted for AQP4 or claudin-5 (A). Individual expression levels of AQP4 (B) or claudin-5 (C) were normalized to the expression levels of
β-actin and presented as percentages of the control group (i.e., Wistar sham) expression, that was defined as 100%. Each value is the mean ± S.E.M., (n = 5),
*p ≤ 0.05; #p ≤ 0.001, n.s., not significant; AQP4, aquaporin 4; ECS, electroconvulsive shock.
In this study, the mPFC was intensively analyzed as the region of and major depression (Cross-Disorder Group of the Psychiatric
interest, since the rat mPFC is supposed to correspond to the human Genomics, 2013). Animal studies are also in line with these findings.
dorsolateral PFC that plays an important role in executive functions, Dominant-negative Disrupted-In-Schizophrenia-1 transgenic mice, a
including working memory (Barbey et al., 2013). The mPFC subregions model for schizophrenia, have been demonstrated to present depres-
PrL and IL correspond to human Brodmann areas 32 and 25, respec- sive-like behavior as well as schizophrenia-like behavior (Hikida et al.,
tively (Varea et al., 2005). Dysfunctions of the dorsolateral PFC are 2007). Our previous studies have revealed that Gunn rats with genetic
involved in various psychiatric disorders, including schizophrenia and unconjugated hyperbilirubinemia show impaired sensory-motor gate
major depression (Ferguson and Gao, 2018). We also intensively ana- and recognition memory deficits, which are signs similar to schizo-
lyzed the hippocampal formation based on the evidence that hippo- phrenia (Liaury et al., 2014; Limoa et al., 2016), and also present de-
campal dysfunction along with a small volume is strictly associated pressive-like behavior (Arauchi et al., 2018). Moreover, it has been
with major depression, stress and memory deficits (MacQueen and implied that neonatal hyperbilirubinemia is a vulnerability factor for
Frodl, 2011). In addition, alterations in hippocampal anatomy, perfu- subsequent development of mental disorders, including schizophrenia,
sion, and activation have consistently been demonstrated in schizo- substance abuse, personality disorder and neurosis (Dalman and
phrenia (Tamminga et al., 2010). Cullberg, 1999). Accordingly, Gunn rats seem to be a suitable animal
Although the immobility time in the FST represents desperate be- model for studies of a wide range of psychiatric disorders in respect to
havior associated with major depression, it can also be considered as a both pathophysiology and symptomatology.
form of apathy or avolition, which is a negative symptom of schizo-
phrenia (Arauchi et al., 2018). Likewise, impaired spatial working
memory, as shown by decreased% SAB in the Y-maze test, can be in- 5. Conclusions
terpreted as both a cognitive deficit symptom in major depression
(Henningsen et al., 2013) and a part of cognitive impairment in schi- Our findings indicate that repeated ECS administration to Gunn rats
zophrenia (Knox et al., 2017). ameliorates depressive-like behavior and increases the decreased cov-
Patients with schizophrenia are at an increased risk for the devel- erage of brain blood vessels by astrocytic endfeet in the PrL area of the
opment of depression (Samsom and Wong, 2015). Overlap in the mPFC, the CA1 and CA3 areas of the hippocampal formation.
symptoms and genetic risk factors between schizophrenia and depres- Therefore, the therapeutic mechanisms of ECT may involve restoration
sion implies that a common etiological mechanism may underlie the of the impaired gliovascular units by increasing the decreased astro-
presentation of comorbid depression in schizophrenia (Samsom and cytic-endfoot coverage of blood vessels. These findings may provide
Wong, 2015). In fact, genome-wide genotype data from the Psychiatric crucial information to elucidate roles of impaired gliovascular units
Genomics Consortium show that genetic correlation is high between with decreased astrocytic coverage of blood vessels in the pathogenesis
schizophrenia and bipolar disorder, moderate between schizophrenia of neuropsychiatric disorders and to develop future therapeutic inter-
ventions via modulating astrocytic functions.

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I.A. Azis, et al.
CRediT authorship contribution statement
Ilhamuddin A. Azis: Data curation, Formal analysis, Writing -
original draft, Validation. Sadayuki Hashioka: Writing - original draft,
Validation. Keiko Tsuchie: Data curation, Validation. Tsuyoshi
Miyaoka: Validation. Rostia A. Abdullah: Data curation, Validation.
Erlyn Limoa: Data curation, Validation. Ryosuke Arauchi: Data
curation, Validation. Ken Inoue: Writing - review & editing, Validation.
Shoko Miura: Writing - review & editing, Validation. Muneto Izuhara:
Writing - review & editing, Validation. Misako Kanayama: Writing -
review & editing, Validation. Koji Otsuki: Writing - review & editing,
Validation. Michiharu Nagahama: Writing - review & editing,
Validation. Kiminori Kawano: Writing - review & editing, Validation.
Tomoko Araki: Writing - review & editing, Validation. Maiko
Hayashida: Writing - review & editing, Validation. Rei Wake: Writing -
review & editing, Validation. Arata Oh-Nishi: Writing - review &
editing, Validation. Andi J. Tanra: Writing - review & editing,
Validation. Jun Horiguchi: Writing - review & editing, Validation.
Masatoshi Inagaki: Writing - review & editing, Validation.
Acknowledgments
This study was supported by JSPS KAKENHI Grant numbers
15550689 (SH and TM) and 19K08018 (SH). We thank Dr. Edith G.
McGeer (Kinsmen Laboratory of Neurological Research, The University
of British Columbia) for her kind support.
Conflict of interest
All authors declare that they have no conflicts of interest.
Author statement
This animal study was approved by the Shimane University Animal
Ethics Committee, under the guidelines of the National Health and
Medical Research Council of Japan. This manuscript has not been
published and is not under consideration for publication elsewhere. All
authors have read the manuscript and have approved this submission.
There has been no significant financial support for this work that could
have influenced its outcome.
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doi:10.1111/psyg.12416 PSYCHOGERIATRICS 2019

ORIGINAL ARTICLE

Concurrent antipsychotic use in older adults treated with

antidepressants in Asia
1* 2* 3* 4,5 6
Min DONG, Liang-Nan ZENG, Qinge ZHANG, Gabor S. UNGVARI, Chee H. NG,
7 8 9 10 10 11
Helen F. K. CHIU, Tian-Mei SI, Kang SIM, Ajit AVASTHI, Sandeep GROVER, Mian-Yoon CHONG,
12 13 14 15 16
Kok-Yoon CHEE, Shigenobu KANBA, Min-Soo LEE, Shu-Yu YANG, Pichet UDOMRATN,
17 18 19 20
Roy A. KALLIVAYALIL, Andi J. TANRA, Margarita M. MARAMIS, Winston W. SHEN,
21 22 23 24
Norman SARTORIUS, Rathi MAHENDRAN, Chay-Hoon TAN, Naotaka SHINFUKU and
1
Yu-Tao XIANG

1
Unit of Psychiatry, Faculty of Health Sciences, Abstract
University of Macau, Macao SAR, 2Department of
Neurosurgery, The Affiliated Hospital of Southwest Aim: Depressive disorders are common in old age. Antipsychotics (APs) are
3
Medical University, Luzhou, The National Clinical often used as an adjunctive treatment with antidepressants (ADs) in this
Research Center for Mental Disorders, China & population but its patterns of use in Asia are not known. This study
Center of Depression, Beijing Institute for Brain
explored the rate of combination of APs and ADs in older adult psychiatric
Disorders & Mood Disorders Center, Beijing And-
ing Hospital, Capital Medical University and patients in Asia.
8
Peking University Institute of Mental Health (the Methods: This is a secondary analysis of the database of a multicentre
sixth Hospital) & National Clinical Research Center study which recorded participants’ basic demographical and clinical data in
for Mental Disorders & the key Laboratory of Men- standardised format in 10 Asian countries and territories. The data were
tal Health, Ministry of Health (Peking University),
7 analysed using univariate and multivariate logistic regression analyses.
Beijing and Department of Psychiatry, Chinese
University of Hong Kong, Hong Kong, China, Results: A total of 955 older adult psychiatric in- and outpatients were
4
University of Notre Dame Australia, Fremantle, included in this study. The proportion of concurrent AP and AD use was
5
Division of Psychiatry, School Medicine, Univer- 32.0%, ranging from 23.3% in Korea to 44.0% in Taiwan. Multivariate logis-
sity of Western Australia, Perth, 6Department of tic regression analysis found that younger age, inpatient status and diagno-
Psychiatry, University of Melbourne, Melbourne,
9 sis of schizophrenia, anxiety and other mental disorders were significantly
Victoria, Australia, Institute of Mental Health and
22 related to a higher proportion of concurrent use of APs and ADs.
Department of Psychological Medicine and
23
Pharmacology, National University of Singapore, Conclusion: Around a third of older adult psychiatric patients had concurrent
Singapore, Singapore, 10Department of Psychiatry, AP and AD use in the Asian countries/regions surveyed. Considering the
Post Graduate Institute of Medical Education and uncer- tain effectiveness and questionable safety of the AP and AD
Research (PGIMER), Chandigarh and 17Depart- combination in this patient population, such should be cautiously used.
ment of Psychiatry, Pushpagiri Institute of Medical
Sciences, Thiruvalla, India, 11Department of Psychi-
atry, Chang Gung Memorial Hospital, Chiayi &
Chang Gung University, Taoyuan and
15
Department
of Pharmacy, Songde Branch, Taipei City
Hospital,
& College of Medicine, Fu Jen Catholic University
and 20Departments of Psychiatry, TMU-Wan Fang
Medical Center and School of Medicine, Taipei
12
Medical University, Taipei, Taiwan, Department
of Psychiatry & Mental Health, Tunku Abdul
Rahman Institute of Neurosciences, Kuala Lumpur
13
Hospital, Kuala Lumpur, Malaysia, Department
of Neuro- psychiatry, Kyushu University, Fukuoka
and 24Inter- national Center for Medical Research,
Kobe University School of Medicine, Kobe,
Japan,
14
Department of Psychiatry, College of Medicine,
16
Korea University, Seoul, Korea, Department of
Psychiatry, Faculty of Medicine, Prince of Songkla
University, Songkhla, Thailand, 18Department of
Psychiatry, Hasanuddin University Faculty of

© 2019 Japanese Psychogeriatric Society 1

M. Dong et al.

Medicine, Makassar, 19Dr. Soetomo Hospital – Fac-

ulty of Medicine, Airlangga University, Surabaya,
21
Jawa Timur, Indonesia and Association for the
Improvement of Mental Health Programmes,
Geneva, Switzerland
Correspondence: Dr Yu-Tao Xiang MD PhD, Faculty
of Health Sciences, University of Macau, Avenida da
Universidade, 3/F, Building E12, Taipa, Macau
SAR
999078, China. Email: xyutly@gmail.com
These authors contributed equally to this work.
Disclosure: We declare that the authors have no
competing interests related to this study.
University of Macau MYRG2015-00230-FHS;
MYRG2016-00005-FHS
Taiwan and the University of Macau
MYRG2015-00230-FHS; MYRG2016-00005-FHS
Taipei City Hospital 10201-62-077
Received 22 July 2018; revision received 15 October 2018;
accepted 24 December 2018.
Key words: adjunctive treatment, antidepressants,
antipsychotics, Asia, older adults.

older adults are more likely to experience medication-

INTRODUCTION
Depressive disorders are frequent in older adults. For
example, one survey found that the prevalence of
major depression was up to 16% in old people living
1
in private households or institutions. Another study
reported that the prevalence of major depressive
disorder, minor depression and clinically relevant
depressive symptoms in old people living in the com-
munity were 1.8%, 9.8% and 13.5%, respectively.
2 are unknown in older adult psychiatric patients in
Compared to younger adults, older adults suffering
from depression have an increased risk of physical
and psychological comorbidities, more disability and
social isolation,
3–6
greater economic cost,
7,8
and
higher mortality.
1,9
Psychotropic medications are prescribed for older
adults up to 7–18 times more frequently than
10
for middle-aged adults. Of the psychotropic
medica- tions, antidepressants (ADs) are one of
11,12
those most widely prescribed. For example, one
study found that 51.8% of nursing home residents
suffered from depression, of whom 82.8% received
13
ADs. Antipsy- chotics (APs), such as aripiprazole,
quetiapine and olanzapine, are often used for
14
augmenting ADs for depression. Over half of older
adults who received ADs are also prescribed other
psychotropic drugs, particularly benzodiazepines
15
(BZDs) and APs. Com- pared to younger adults,
due to their poorer general health status and age-
related physiological changes,
16,17
induced adverse events. Therefore, polypharmacy
using psychotropic medications in older adults, if indi-
cated at all, should be cautiously prescribed.
Regular surveys of prescription patterns are useful
to examine the appropriateness of pharmacother-
18
apy. Although AP and AD combinations are often
used, the frequency of such co-prescription patterns
Asia. This study set out to examine the concurrent
use of APs and ADs in older adult psychiatric
patients in several Asian countries and territories,
and explore its independent demographic and clinical
correlates.
METHODS
Study design and sample
The Research on Asian Psychotropic Prescription
Patterns for Antidepressants (REAP-AD) project is an
international, multicentre survey on the use of ADs,
19
which was conducted between March and June
2013 in 42 centres and hospitals in 10 Asian terri-
tories and countries, including China, Malaysia, Hong
Kong, India, Indonesia, Japan, Thailand, Korea, Sin-
gapore and Taiwan. Patients with any mental disor-
der treated with ADs on the day of data collection
were consecutively screened and enrolled in the

2 © 2019 Japanese Psychogeriatric Society

 Antipsychotics in older adults

survey. The data were collected with a standardised

32.0
10.4

62.1
16.2
17.1
13.3
44.3
2.8

6.6

AP, antipsychotic; BZD, benzodiazepine; MS, mood stabilizer; NaSSA, noradrenergic and specific serotonergic antidepressant; SNRI, serotonin/norepinephrine reuptake inhibitor; SSRI, selective serotonin
%
(N = 955)
Overall
protocol in all participating hospitals. Patients who
were eligible for the study were aged 50 years or

306
99
27
593
155
163
127
423
63
n
above and were either in- or outpatients. In many
Asian countries, patients aged 50 years or older are

9.5

5.4
43.2

90.5

51.4
Indonesia

%
(N = 74)

0
0
0
defined as ‘older adult’. This cut-off is in line with
20–22
some other studies. The study protocol was

32
7
0
67
0
0
0
38
4
n
approved by the Institutional Review Boards at each
participating centre and hospital. When the survey

23.4
25.8
14.8
55.5

17.2
39.1
6.3
6.3

9.4
(N = 128)

%
Thailand
involved retrospective anonymous medical chart
review, informed consent was waived. However,

30
33
19
71
8
8
22
50
12
n
when patients were interviewed, they provided writ-
ten informed consent.

29.9

70.1

19.4

46.3
1.5
1.5

0.0
Malaysia

%
(N = 67)

3
Assessment

20
1
1
47
4
13
2
31
0
n
Patients’ demographical and clinical data were
retrieved by reviewing medical records, or during a

25.4
11.1

69.8
15.9

28.6
9.5
3.2

9.5
%
(N = 63)

0
India
clinical interview supplemented by a review of medi-
cal records. Diagnoses were established according

16
7
0
44
10
6
2
18
6
n
to International Classification of Diseases, 10th revi-
23
sion or Diagnostic and Statistical Manual of Mental

7.3
44.0

52.3
20.2
10.1
21.1
69.7
10.1
(N = 109)

%
Table 1 Prescription of psychotropic medications for older adult psychiatric patients by country/territory

Taiwan

0
24
Disorders, 4th edition. For the sake of comparison
in the statistical analysis, doses of ADs were trans-

48
8
0
57
22
11
23
76
11
n
25
formed into imipramine equivalent (IMI-eq) doses.
35.4

62.5

10.4
33.3
2.1

6.3

8.3
Singapore

%
(N = 48)

25
Statistics
Data analyses were performed with the SPSS statisti-
17
1
0
30
3
12
5
16
4
n

cal package, Version 20 (SPSS Inc., Chicago, IL,

23.3

67.3
23.3

26.7
3.3
USA). The demographical and clinical data were
%
(N = 150)

12
0

24
26
Korea

compared between patients treated with APs plus

RO

ADs and on ADs only with Mann–Whitney U-test,

101
35
18
0

35
36
39
40
5
n

2
independent samples t-test or χ test, if applicable.
Independent associations between demographical
33.6
12.6

43.7
20.2
33.6
13.4
59.7
12.6
5.9
(N = 119)

%
Japan

and clinical characteristics (independent variables)

and the combination of APs and ADs (dependent var-
40
15

52
24
40
16
71
15
7
n

iable) were explored with binary logistic regression

analysis. The variables that significantly differed in
43.6

53.8
17.9
15.4
15.4
48.7
7.7

2.6
%
(N = 39)

0
Hong
Kong

reuptake inhibitor; TCA, tricyclic antidepressant.

univariate analysis were entered as independent vari-

ables, and the combination of APs and ADs was the
17
3
0
21
7
6
6
19
1
n

dependent variable. Statistical significance was set at

32.3

65.2
26.6
19.6

40.5
3.8

7.6

3.2

0.05 (two-sided).
%
(N = 158)

0
China

103
51
6
0

42
31
12
64
5
n

RESULTS
A total of 955 older adult patients who received anti-
Country/territory

depressants were enrolled in the study. The rate of

Tetracyclics

Other drugs
APs TCAs

combination of APs and ADs in the whole sample

NaSSAs
SNRIs

was 32.0% ranging from 23.3% in Korea to 44.0% in

SSRIs

BZDs
MS

Taiwan (Table 1). Table 2 shows the demographic

© 2019 Japanese Psychogeriatric Society 3

M. Dong et al.

Table 2 Basic demographic and clinical characteristics of the study sample

Whole sample No APs On APs
(N = 955) (n = 649) (n = 306) Statistics

Mean SD Mean SD Mean SD t /z df P

Age (years) 62.6 9.5 63.3 9.7 60.9 8.7 3.7 953 <0.001
AD dose, IMIeq (mg/day) 131.2 112.5 126.5 109.1 141.1 118.8 −1.9 --- 0.051
Number of ADs 1.2 0.5 1.27 0.51 1.21 0.53 −2.1 --- 0.029
Number of depressive symptoms 3.4 2.0 3.4 2.0 3.5 2.1 −0.8 --- 0.38

n % n % n % χ2 df P
Age (years) 9.1 1 0.002
50–64 615 64.4 397 61.2 218 71.2
65 and older 340 35.6 252 38.8 88 28.8
Male 375 39.3 238 36.7 137 44.8 5.7 1 0.017
Psychiatric hospital 351 36.8 201 31.0 150 49.0 29.1 1 <0.001
Outpatients 722 75.6 544 83.8 178 58.2 74.1 1 <0.001
General hospital psychiatric unit 687 71.9 448 69.0 239 78.1 8.4 1 0.004
Country/territory 25.2 9 0.003
Income 3.1 2 0.21
High income 465 48.7 308 47.5 157 51.3
Upper middle income 353 37.0 252 38.8 101 33.0
Lower middle income 137 14.3 89 13.7 48 15.7
Major medical conditions 421 44.1 281 43.3 140 45.8 0.5 1 0.47
Use of antidepressants
TCAs 99 10.4 75 11.6 24 7.8 3.0 1 0.07
Tetracyclics 27 2.8 21 3.2 6 2.0 1.2 1 0.26
SSRIs 593 62.1 407 62.7 186 60.8 0.3 1 0.56
SNRIs 155 16.2 104 16.0 51 16.7 0.06 1 0.80
NaSSAs 163 17.1 109 16.8 54 17.6 0.1 1 0.74
Other ADs 127 13.3 85 13.1 42 13.7 0.07 1 0.79
Use of MS 63 6.6 31 4.8 32 10.5 10.8 1 0.001
Use of BZDs 423 44.3 268 41.3 155 50.7 7.3 1 0.007
Principal psychiatric diagnosis 93.5 3 <0.001
Mood disorders 671 70.3 479 73.8 192 62.7
Anxiety disorders 130 13.6 109 16.8 21 6.9
Schizophrenia 79 8.3 19 2.9 60 19.6
Other diagnoses 75 7.9 42 6.5 33 10.8

Bolded values: <0.05. AD, antidepressant; AP, antipsychotic; BZD, benzodiazepine; IMI-eq, imipramine-equivalent; MS, mood stabilizer; NaSSA, noradrenergic
and specific serotonergic antidepressant; SNRI, serotonin/norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic
antidepressants.

and clinical data for the whole sample and separately
for the ADs and the combination groups. In the whole
sample, the mean age was 62.6 years and
375 patients (39.3%) were men; the proportion of
mood disorders, anxiety disorders, schizophrenia
and other diagnoses was 70.3%, 13.6%, 8.3% and
7.9%, respectively. The mean dose of ADs in IMI-eq
was 131.2 mg/day.
Concurrent APs and ADs use was significantly
associated with younger age, male gender, lower
numbers of ADs, inpatient treatment, in psychiatric or
public hospitals, more frequent use of mood stabili-
sers (MS) and BZDs, and psychiatric diagnoses
(Table 2). Binary logistic regression analyses found
that concurrent APs abd ADs prescriptions were
independently related to younger age, inpatient treat-
ment and diagnosis of schizophrenia, anxiety and
other mental disorders (Table 3).
DISCUSSION
This was the first survey of concurrent use of APs
and ADs in older adult psychiatric patients in Asia.
The proportion of concurrent prescriptions was
32.0% in the whole sample but it varied markedly
across countries/territories, with the highest in Tai-
wan (44.0%) and lowest in Korea (23.3%). These fig-
ures are much higher than the corresponding ones
26
in the USA (13.9%) and Europe (12.3%). The dis-
crepancy across study sites could be related to the

4 © 2019 Japanese Psychogeriatric Society

 Antipsychotics in older adults
Table 3 Independent demographic and clinical correlates of con- 30,31 32–34
current antipsychotic and antidepressant use receiving ADs and adjunctive ADs. This
may be related to the effect of ADs in modifying
Odds
serotoner-
gic (5-HT) dysfunction that is thought to be involved in
Variables P-value ratio 95% CI 14,35,36
the pathophysiology of psychotic symptoms.
Age (years) 0.026 0.98 0.963–0.998 Although AD monotherapy has been recom-
Number of ADs 0.97 1.006 0.727–1.392 37
Male 0.301 0.181 0.861–1.619 mended in treating depressive disorders, adjunctive
Psychiatric hospital 0.424 1.183 0.783–1.787 APs are often used as an augmentation strategy for
Outpatients <0.001 0.305 0.213–0.438 38
treatment-resistant depression. Second generation
General hospital 0.307 1.309 0.781–2.192
psychiatric unit antipsychotics (SGAs) are frequently co-prescribed
Use of MS 0.253 1.41 0.783–2.539 with ADs39,40 given that SGAs improve depressive
Use of BZDs 0.519 1.112 0.806–1.533 41
Principal psychiatric symptoms by enhancing monoaminergic transmis-
14,42
diagnosis sion. A meta-analysis demonstrated that adjunc-
Mood disorders — 1 — tive SGAs have significant effects on the severity of
Anxiety disorders 0.01 0.493 0.289–0.842
Schizophrenia <0.001 6.284 3.432–11 505
major depression, resulting in improved quality of life
43
Other diagnoses 0.004 2.265 1.296–3.957 and less functional deficit.
Country/territory In this survey, inpatients were more likely to be
China 0.395 1 0
Hong Kong 0.271 1.586 0.698–3.606
treated with APs and ADs combinations, probably
44
Japan 0.276 1.408 0.761–2.609 due to the more severe psychiatric symptoms. Pre-
South Korea 0.554 1.238 0.611–2.509 vious studies in the USA and Europe found that
Singapore 0.951 1.028 0.429–2.463
Taiwan 0.367 1.360 0.698–2.651
depressed patients prescribed with APs present with
26
India 0.325 1.456 0.689–3.075 more severe comorbid psychotic symptoms. The
Malaysia 0.541 1.265 0.596–2.688 finding that younger age was associated with concur-
Thailand 0.391 0.765 0.415–1.411
Indonesia 0.039 2.004 1.035–3.878 rent APs and ADs use is perhaps due to the better
tolerance of polypharmacy in younger ages. Con-
Bold values: <0.05; participating country/territory has been controlled for as
a covariate. AD, antidepressants; BZD, benzodiazepine; MS, mood stabilizer versely, the higher risk of medication-induced
adverse events in older patients may discourage psy-
diversity of socio-cultural factors, local clinical prac- chiatrists to prescribe combinations of psychotropic
tices, healthcare polices, medication cost, and medications.
27 Several limitations of the study should be
insurance coverage. For example, there is a widely
acknowledged. First, the sample size in several coun-
held view in Asia that combination of medications of
tries/territories was small, therefore analyses could
different pharmacological activities has better effi-
28 not be performed separately in each study site. Sec-
cacy in clinical practice. In addition, the co-
ond, as only 10 Asian countries/territories were
existence of psychotic and depressive symptoms
included in the study, the findings are not representa-
occurring in various psychiatric disorders are fre-
tive of the whole Asian patient population. Third, due
quent in elderly patients, increasing the likelihood of
to the cross-sectional study the causality between
concurrent use of APs and ADs. As the risk of side
variables could not be explored. Fourth, due to logis-
effects of psychotropic drugs may increase due to
tical reasons the severity of depressive and psychotic
the age-related changes in pharmacokinetic and
17 symptoms was not measured, hence their associa-
pharmacodynamic responses in older patients, the
tions with prescription patterns could not be ana-
safety of APs and ADs combinations should be
lyzed. Fifth, the study mainly focused on prescription
taken into consideration in clinical practice.
of ADs in psychiatric hospitals or psychiatric units in
Concurrent use of APs and ADs was
general hospitals. Patients with other psychiatric and
associated with psychiatric diagnoses (particularly
medical diagnoses treated with ADs, such as demen-
schizophrenia), younger age and inpatient treatment in
tia or other neuropsychiatric disorders, are rarely
this study. ADs were often prescribed for negative and
depressive symptoms and cognitive impairment in treated in psychiatric hospitals/units in most Asian
29 countries, thus they were not covered in this study.
schizophre- nia. Negative and depressive
Finally, several relevant factors of prescription pat-
symptoms could be improved in around a third of
terns, such as cost of treatment, were not recorded.
schizophrenia patients

© 2019 Japanese Psychogeriatric Society 5

M. Dong et al.
In conclusion, around a third of older adult psychi-
atric patients in 10 Asian countries and territories
received concurrent ADs and APs. Given the
increased age-related risks of psychotropic
medication-induced side effects, the combination of
ADs and APs should be used with caution in this
population.
ACKNOWLEDGMENTS
This work was supported by the Taipei City Hospital
(10201-62-077), Taipei, Taiwan and the University of
Macau (MYRG2015-00230-FHS; MYRG2016-00005-
FHS). The authors would like to thank all clinicians
involved in the REAP-AD project.
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7
 Nordic Journal of Psychiatry

ISSN: 0803-9488 (Print) 1502-4725 (Online) Journal homepage: https://www.tandfonline.com/loi/ipsc20

Cannabis use correlates with aggressive behavior

and long-acting injectable antipsychotic treatment
in Asian patients with schizophrenia

Seon-Cheol Park, Hong Seok Oh, Adarsh Tripathi, Roy Abraham Kallivayalil,
Ajit Avasthi, Sandeep Grover, Andi Jayalangkara Tanra, Shigenobu Kanba,
Takahiro A. Kato, Toshiya Inada, Kok Yoon Chee, Mian-Yoon Chong, Shih-Ku
Lin, Kang Sim, Yu-Tao Xiang, Chay Hoon Tan, Afzal Javed, Norman Sartorius,
Naotaka Shinfuku & Yong Chon Park

To cite this article: Seon-Cheol Park, Hong Seok Oh, Adarsh Tripathi, Roy Abraham Kallivayalil,
Ajit Avasthi, Sandeep Grover, Andi Jayalangkara Tanra, Shigenobu Kanba, Takahiro A. Kato,
Toshiya Inada, Kok Yoon Chee, Mian-Yoon Chong, Shih-Ku Lin, Kang Sim, Yu-Tao Xiang,
Chay Hoon Tan, Afzal Javed, Norman Sartorius, Naotaka Shinfuku & Yong Chon Park (2019)
Cannabis use correlates with aggressive behavior and long-acting injectable antipsychotic
treatment in Asian patients with schizophrenia, Nordic Journal of Psychiatry, 73:6, 323-330, DOI:
10.1080/08039488.2019.1632381
To link to this article: https://doi.org/10.1080/08039488.2019.1632381

Published online: 26 Jun 2019.

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NORDIC JOURNAL OF PSYCHIATRY
2019, VOL. 73, NO. 6, 323–330
https://doi.org/10.1080/08039488.2019.1632381

ARTICLE

Cannabis use correlates with aggressive behavior and long-acting injectable

antipsychotic treatment in Asian patients with schizophrenia
Seon-Cheol Parka , Hong Seok Ohb , Adarsh Tripathic , Roy Abraham Kallivayalild, Ajit Avasthie,
Sandeep Grovere, Andi Jayalangkara Tanraf, Shigenobu Kanbag, Takahiro A. Katog, Toshiya Inadah,
Kok Yoon Cheei, Mian-Yoon Chongj,k, Shih-Ku Linl , Kang Simm, Yu-Tao Xiangn, Chay Hoon Tano ,
Afzal Javedp, Norman Sartoriusq, Naotaka Shinfukur and Yong Chon Parks
a
Department of Psychiatry, Inje Universtiy Haeundae Paik Hospital, Busan, Republic of Korea; bDepartment of Psychiatry, Konyang University
Hospital, Daejeon, Republic of Korea; cDepartment of Psychiatry, King George’s Medical University, Chowk, India; dPushpagiri Institute of
Medical Sciences, Tiruvalla, India; eDepartment of Psychiatry, Post Graduate Institute of Medical Education and Research (PGIMER),
Chandigarh, India; fFaculty of Medicine, Department of Psychiatry, Hasanuddin University, Makassar, Indonesia; gDepartment of
Neuropsychiatry, Graduate School of Medicine, Kyushu University, Fukuoka, Japan; hDepartment of Psychiatry and Psychobiology, Nagoya
University, Graduate School of Medicine, Nagoya, Japan; iTunku Abdul Rahman Institute of Neuroscience, Kuala Lumpur Hospital, Kuala
Lumpur, Malaysia; jChang Gung Memorial Hospital, Chiayi, Taiwan; kChang Gung University School of Medicine, Taoyuan City, Taiwan;
l
Psychiatric Center, Taipei City Hospital, Taipei, Taiwan; mWest Region, Institute of Mental Health and Yong Loo Lin School of Medicine,
National University of Singapore, Singapore, Singapore; nFaculty of Health Sciences, Unit of Psychiatry, Institute of Translational Medicine,
University of Macau, Macau SAR, China; oDepartment of Pharmacology, National University Hospital, Singapore, Singapore; pPakistan
Psychiatric Research Centre, Fountain House, Lahore, Pakistan; qAssociation for the Improvement of Mental Health Programmes, Geneva,
Switzerland; rDepartment of Social Welfare, School of Human Sciences, Seinan Gakuin University, Fukuoka, Japan; sDepartment of
Neuropsychiatry, Hanyang University Guri Hospital, Guri, Republic of Korea

ABSTRACT ARTICLE HISTORY

Background: Although cannabis use has been linked with schizophrenia in a dose–response Received 11 March 2019
pattern, to our knowledge, the relationship between cannabis and schizophrenia has rarely been Revised 28 May 2019
reported in Asian population. Accepted 12 June 2019
Aim: We compared the clinical characteristics and psychotropic prescription patterns between
canna- bis users and non-users among Asian patients with schizophrenia. Moreover, we aimed to KEYWORDS
Aggressive behavior; Asian;
identify the cannabis; long-acting
independent correlates of cannabis use in these subjects. injectable antipsychotics;
Methods: We performed the analysis of the data from the Research on Asian Psychotropic schizophrenia
Prescription Patterns for Antipsychotics (REAP-AP), a collaborative consortium survey used to collate
the prescription patterns for antipsychotic and other psychotropic medications in patients with schizo-
phrenia in Asia. We included 132 schizophrenia patients in the group of lifetime cannabis use and
1756 in the group that had never used cannabis. A binary logistic model was fitted to detect the
clin- ical correlates of lifetime cannabis use.
Results: Adjusting for the effects of age, sex, geographical region, income group, duration of
untreated psychosis, and Charlson comordity index level, a binary logistic regression model
revealed that lifetime cannabis use was independently associated with aggressive behavior [adjusted
odds ratio
(aOR) ¼ 1.582, 95% confidence interval (CI) ¼ 1.006–2.490, p ¼ .047] and with long-acting
injectable antipsychotic treatment (aOR ¼ 1.796, 95% CI ¼ 1.444–2.820, p ¼ .001).
Conclusion: Our findings indicate a close link between lifetime cannabis use and aggressive behavior.
The use of long-acting, injectable antipsychotics preferentially treats the aggressive behavior cannabis
users among patients with schizophrenia in Asia, especially, the South or Southeast Asia.

Background
exposure to cannabis is associated with schizophrenia in a
Cannabis use has a paradoxical and debated link with schizo- dose–response pattern. By a two-sample Mendelian random-
phrenia. Antipsychotics have the potential effectiveness ization study using summary-level genome-wide data
to reduce cannabis use in schizophrenia whereas from the International Cannabis Consortium and the
cannabinoids can have the potential effectiveness to reduce Psychiatric Genomics Consortium [4], it has been shown that,
the symptoms in schizophrenia [1]. Most of all, a dose– despite the small size of the estimate, the cannabis use
response relationship between cannabis use and psychosis causally increases the risk of schizophrenia. Also, lifetime
was evident in several studies [2]. Andreasson and cannabis use is associ- ated with an earlier onset of
colleagues [3] have presented, from a cohort of 45,570 psychosis in a 10-year observa- tion study for 229 patients
Swedish men, that the level of with schizophrenia spectrum

CONTACT Seon-Cheol Park cogito-ergo-sum@hanmail.net Department of Psychiatry, Inje University Haeundae Paik Hospital, 48108 Busan, Republic
of Korea
2019 The Nordic Psychiatric Association
324 S.-C. PARK ET AL.
disorder [5]. More specifically, in a naturalistic study on
1,119 patients with schizophrenia spectrum disorder, there was
a 3- year earlier onset of psychosis associated with cannabis
use [6]. Thus, the relationship between cannabis use and a
risk of psychosis has been explained as a complex interplay
between gene, environment, and stress. An interaction
between canna- bis use and stress can trigger the risk of
schizophrenia or psychosis. On the contrary, because of
its potential anti- psychotic properties, cannabis has been
proposed as a poten- tial drug for schizophrenia. Cannabidiol
is a compound of cannabis that has moderate inhibitory
effects on the degrad- ation of endocannabinoid
anandamide without the activation of cannabinoid receptors
[7]. Based on the inverse relationship between psychotic
symptoms and the elevation of ananda- mide levels in the
cerebrospinal fluid, cannabidiol has been proposed as an
antipsychotic drug [8]. Moreover, cannabidiol has been
regarded as a new adjunctive therapy for schizo- phrenia
by a randomized controlled trial since its effects are not
associated with dopamine receptor antagonism [9].
The complex relationship between cannabis use and
schizophrenia may be explained by the pharmacological
effects of delta-9-tetrahydrocannabinol (D9-THC) and canna-
bidiol, which are known as the two most common cannabi-
9
noids. The relative proportions of D -THC and cannabidiol
vary with the different forms of cannabis. In association with
D9-THC, the core psychotic and cognitive symptoms are tran-
siently exacerbated in patients with schizophrenia [10]. Also,
9
schizophrenia-like negative symptoms are elicited by D -THC
[11]. On the contrary, cannabis preparations with a relatively
high cannabidiol have been associated with the reduction in
the risk of psychotic symptoms and cognitive impairments
after the cannabis use [12]. The psychotic symptoms and
cognitive deficits, which are induced by D9-THC, are attenu-
ated by a pretreatment with cannabidiol [13].
Aim
Despite the potential effects of cannabis on schizophrenia, to
our knowledge, the relationship between cannabis use and
schizophrenia has been rarely studied in Asian patients with
schizophrenia in real clinical practice. In addition, a possibility
has been suggested that cannabis-using and non-using
patients are different groups in schizophrenia spectrum dis-
order [14]. The Research on Asian Psychotropic Prescription
Patterns for Antipsychotics (REAP-AP) has been the largest
international collaborative survey of any psychiatric aspect in
Asia [15,16]. Thus, using the data from the REAP-AP, we
aimed to (i) compare the baseline characteristics, psychiatric
symptoms, psychotropic drug use patterns, and adverse
effects between schizophrenia patients with and without life-
time cannabis use and (ii) detect the clinical correlates of the
lifetime cannabis use in Asian patients with schizophrenia.
Materials and methods
Study overview
As described previously [15,16], with the convenience sam-
pling method, a total of 3,744 patients were consecutively
recruited from 71 survey centers in 15 Asian countries/areas
including Bangladesh, China, Hong Kong, India, Indonesia,
Japan, Korea, Malaysia, Myanmar, Pakistan, Singapore, Sri
Lanka, Taiwan, Thailand, and Vietnam, during the period
from March to June 2016 in the fourth REAP-AP. The study
protocol and informed consent forms for the REAP-AP were
approved by the institutional review boards of Taipei City
Hospital, Taipei, Taiwan (receipt number: TCHIRB-10412128-E)
and other survey centers. The informed consent forms were
signed by all the study subjects prior to their participation in
the study. Also, the information for history of cannabis use,
Brief Psychiatric Rating Scale (BPRS) [17], Drug-induced
Extrapyramidal Symptoms Scale (DIEPSS) [18], Charlson
Comorbidity Index (CCI) [19], and psychotropic drug prescrip-
tion patterns according to Anatomical Therapeutic Chemical
(ATC) classification system [20] were collected from the sur-
vey centers only in India, Indonesia, Japan, Malaysia, and
Taiwan. Since our subjects were recruited from 15 different
countries/areas with different languages, the English versions
of the case report forms and several assessment scales were
commonly used by the clinical psychiatrists and study coor-
dinators at the survey centers. Also, a coordination meeting
to improve the consistency of data collection, assessment
scale evaluation, and diagnosis of schizophrenia was held
before the initiation of the study.
In our study, to perform the analysis of data from the
REAP-AP [15,16], we selected subjects who met the following
inclusion criteria: (i) a diagnosis of schizophrenia with the
Diagnostic and Statistical Manual of Mental Disorders, 5th
edition (DSM-5) [21], (ii) treatment with antipsychotics and/or
other psychotropic drugs and (iii) availability of the medical
record for lifetime cannabis use. In our study, lifetime canna-
bis use was recorded only in India, Indonesia, Japan,
Malaysia, and Taiwan, therefore 1,888 patients in these coun-
tries/territories were included for analyses. Based on the
United Nations classification, the five countries/areas were
geographically classified under East Asia (Japan and Taiwan),
South Asia (India) and Southeast Asia (Indonesia and
Malaysia). Also, based on the World Bank list of economies,
the countries/areas were classified under high income (Japan
and Taiwan), upper middle income (Malaysia) and lower mid-
dle income (India and Indonesia) countries.
Cannabis use
According to the previous study designs [22,23], the lifetime
cannabis use was evaluated based on the subjects’ self-
reports and defined as cannabis consumption (smoking mari-
juana) at least once previously. Lifetime cannabis use was
defined as consuming cannabis more than once previously.
The subjects were dichotomized into those who have ever
and never used cannabis.
BPRS
The 18-item BPRS was used to evaluate the overall psychi-
atric symptoms of the subjects. The BPRS consisted of som-
atic concern, anxiety, emotional withdrawal, conceptual

disorganization, feelings of guilt, tension, mannerism and
posturing, grandiosity, depressed mood, hostility, suspicious-
ness, hallucinatory behavior, motor retardation, uncoopera-
tiveness, unusual thought content, blunted affect,
excitement, and disorientation. All the BPRS items used a
seven-point scoring system from 1 (not present) to 7 (very
severe) with the Likert scale [17]. The BPRS psychometric
properties including reliability, validity, and sensitivity were
confirmed [24].
DIEPSS
The DIEPSS was used to evaluate the drug-induced extrapyr-
amidal symptoms among the subjects. The DIEPSS consisted
of gait, bradykinesia, sialorrhea, muscle rigidity, tremor, aka-
thisia, dystonia, dyskinesia, and overall severity items. All the
DIEPSS items used a five-point scoring system from 0 (none
or normal) to 4 (severe) with the Likert scale. Its metric char-
acteristics including inter-rater reliability, test–retest reliabil-
ity, and concurrent validity were confirmed [18,25].
ATC classification
According to the ATC classification system [20] psychotropic
drugs were classified into 5 categories including the antipsy-
chotics (N05A), mood stabilizers (antiepileptics and lithium;
N03A and N05AN), antidepressants (N06A), anxiolytics (N05B
and N05C), and antiparkinsonian drugs (N04). Based on the
classification by Tandon and colleagues [26], antipsychotics
were dichotomously classified as first- and second-generation
medications. To evaluate the total amount of the first- and
second-generation antipsychotics that each of the subjects
used, the chlorpromazine-equivalent (mg) was used [27].
High-dose antipsychotic use was defined as the concept of
either a cumulative dose 1,000 mg/day of chlorpromazine-
equivalent [28] or a ratio of the prescribed daily dose (PDD)
to the defined daily dose (DDD) 1.5 [29]. Also, to evaluate
the total amount of benzodiazepine, the diazepam-equiva-
lent (mg) was used [30]. High-dose benzodiazepine use was
defined as a cumulative dose 30 mg/day of diazepam-
equivalent [31].
CCI
In a cohort study of 559 medical patients by Charlson and
colleagues [19], CCI was developed to classify the comorbid
physical diseases based on the 1-year mortality rate. The CCI
evaluated the comorbid physical diseases based on their
weight and was regarded as a predictive factor for long-term
outcome. Also, in our study, the CCI level was classified into
five groups including 0–1, 2–3, 4–5, 6–7 and >8. The long-
term course predictability of the CCI level was reliably and
validly confirmed [32].
Statistical analyses
The demographic, clinical and treatment-related characteris-
tics of schizophrenia patients with and without lifetime
NORDIC JOURNAL OF PSYCHIATRY 325
cannabis use were compared using independent t-tests for
continuous variables and X2 tests for discrete variables. Also,
the potential effects of confounding factors were adjusted
using the analyses of covariance for continuous variables and
the binary logistic analyses for discrete variables. Finally, a
binary logistic analysis model with a forward selection
method to avoid multicollinearity was fit to identify the fac-
tors independently associated with lifetime cannabis use.
Statistical significance was set at p < .05 (two-tailed). All stat-
istical analyses were conducted using IBM SPSS 24 (IBM Co.,
Armonk, NY).
Results
Baseline characteristics of schizophrenia patients with
and without lifetime cannabis use
As shown in Table 1, the lifetime rate of cannabis use was
7.0% (n ¼ 132), respectively. The average age (mean ± SD) of
the subjects, with and without lifetime cannabis use, were
36.3 ± 11.1 and 39.6 ± 13.1 years, respectively (t ¼ 3.232,
p ¼ .001). Subjects with lifetime cannabis use had a signifi-
cantly higher proportion of males (X2 ¼ 55.706, p < .0001)
than those without lifetime cannabis use. Subjects with life-
time cannabis use significantly differed from those without
lifetime cannabis use with respect to their distribution
2
among the five countries/areas (X ¼ 45.111, p < .0001), clas-
2
sified geographical regions (X ¼ 30.098, p < .0001), income
groups (X2 ¼ 30.600, p < .0001), and duration of untreated
psychosis (DUP) (X2 ¼ 8.033, p ¼ .045). Although the propor-
tional differences in the CCI levels were not significant, those
with lifetime cannabis use tended to be different from those
without lifetime cannabis use (X2 ¼ 9.427, p ¼ .051).
Psychiatric symptoms of schizophrenia patients with
and without lifetime cannabis use
As shown in Table 2, after adjusting for the potential effects
of age, sex, regional classification, income group, DUP, and
CCI level, those with lifetime cannabis use showed signifi-
cantly more prevalent delusion [adjusted odds ratio (aOR) ¼
2,342, p < .0001], aggressive speech (aOR ¼ 1.609, p ¼
.027), and aggressive behavior (aOR ¼ 1.709, p ¼ .019) than
those without lifetime cannabis use. On the contrary, there
were no differences by hallucination (aOR ¼ 1.088, p ¼ .663),
disor- ganized speech (aOR ¼ 1.456, p ¼ .089), catatonic
behavior (aOR ¼ 0.734, p ¼ .261), and negative symptoms
(aOR ¼
1.140, p ¼ .547) between the subjects with and without life-
time cannabis use.
Psychotropic drug prescription patterns of
schizophrenia patients with and without lifetime
cannabis use
As shown in Table 3, after adjusting for the potential effects
of age, sex, regional classification, income group, DUP, and
CCI level, those with lifetime cannabis use were characterized
by significantly more prescriptions with the long-acting
326 S.-C. PARK ET AL.
Table 1. Baseline characteristics of schizophrenia patients with and without lifetime cannabis use.
Cannabis use (lifetime)
Total sample Statistical Unadjusted Adjusted
(n ¼ 1888) Present (n ¼ 132) Absent (n ¼ coefficient p-value p-value†
1756)
Age, mean (SD) years 39.4 (13.0) 36.3 (11.1) 39.6 (13.1) t ¼ 3.232 .001 –
2
Male, n (%) 1105 (58.5) 118 (89.4) 987 (56.2) v ¼ 55.706 <.0001 –
2
Country/territory v ¼ 45.111 <.0001 –
India, n (%) 475 (25.2) 53 (40.2) 422 (24.0)
Indonesia, n (%) 564 (29.9) 29 (22.0) 535 (30.5)
Japan, n (%) 162 (8.6) 3 (2.3) 159 (9.1)
Malaysia, n (%) 295 (15.6) 36 (27.3) 259 (14.7)
Taiwan, n (%) 392 (20.8) 11 (8.3) 381 (21.7)
a
Regional classification v2 ¼ 30.098 <.0001 –
East Asian, n (%) 554 (29.3) 14 (10.6) 540 (30.8)
Southeast Asian, n (%) 859 (45.5) 65 (49.2) 794 (45.2)
South Asian, n (%) 475 (25.2) 53 (40.2) 422 (24.0)
b 2
Income group v ¼ 30.600 <.0001 –
High income, n (%) 554 (29.3) 14 (10.6) 540 (30.8)
Upper middle income, n (%) 295 (15.6) 36 (27.3) 259 (14.7)
Lower middle income, n (%) 1039 (55.0) 82 (62.1) 957 (54.5)
2
Inpatient, n (%) 824 (43.6) 56 (42.4) 768 (43.7) v ¼ 0.086 .770 .453
Duration of illness, n (%) v2 ¼ 5.187 .520 .130
<3 months, n (%) 133 (7.0) 12 (9.1) 121 (6.9)
3–6 months, n (%) 80 (4.2) 7 (5.3) 73 (4.2)
6–12 months, n (%) 82 (4.3) 6 (4.5) 76 (4.3)
1–5 years, n (%) 358 (19.0) 31 (23.5) 327 (18.6)
5–10 years, n (%) 306 (16.2) 16 (12.1) 290 (16.5)
10–20 years, n (%) 513 (27.2) 36 (27.3) 477 (27.2)
>20 years, n (%) 416 (22.0) 24 (18.2) 392 (22.3)
DUP v2 ¼ 8.033 .045 –
<3 months, n (%) 739 (41.4) 38 (30.9) 701 (42.1)
3–12 months, n (%) 599 (33.5) 52 (42.3) 547 (32.9)
1–5 years, n (%) 345 (19.3) 38 (22.8) 317 (19.1)
>5 years, n (%) 104 (5.8) 5 (4.1) 99 (5.9)
2
Employment, n (%) 335 (17.7) 30 (22.7) 305 (17.4) v ¼ 2.415 .120 .746
BMI, mean (SD) kg/m2 24.1 (4.9) 24.3 (5.2) 24.1 (4.8) t ¼ 0.254 .800 .911
CCI level v2 ¼ 9.427 .051 –
0–1, n (%) 1,444 (76.5) 115 (87.1) 1,329 (75.7)
2–3, n (%) 386 (86.9) 16 (94.1) 370 (86.7)
4–5, n (%) 50 (11.3) 1 (5.9) 49 (11.5)
6–7, n (%) 6 (1.4) 0 (0.0) 6 (1.4)
>8, n (%) 2 (0.5) 0 (0.0) 2 (0.5)
BMI: body mass index; CCI: Charlson comorbidity index; DUP: duration of untreated psychosis; SD: standard deviation.
a
Defined by United Nations classification: East Asia (Japan and Taiwan), South Asia (India) and Southeast Asia (Indonesia and Malaysia).
b
Defined by the World Bank list of economies: high income (Japan and Taiwan), upper middle income (Malaysia) and lower middle income (India
and Indonesia).
†Adjusted for the effects of age, sex, region classification, income group, DUP, and CCI level.
injectable antipsychotics (aOR ¼ 1.874, p ¼ .006) and high- long-acting injectable antipsychotic treatment, and high-dose
dose benzodiazepine (aOR ¼ 4.238, p < .0001) than those benzodiazepine were defined as initial covariates. The model
without lifetime cannabis use. was adjusted for the potential effects of age, sex, regional
classification, income group, DUP, and CCI levels in order to
Psychotropic drug-induced adverse effects in avoid multi-collinearity. Also, the Hosmer–Lemeshow good-
2
schizophrenia patients with and without lifetime ness-of-fit test (v ¼ 14.399, df ¼ 8, p ¼ .072) was used to
cannabis use validate the binary logistic model. The final model explained
2
14.6% (Nagelkerke R ) of the variability of lifetime cannabis
As shown in Table 4, after adjusting for the potential effects use and identified aggressive behavior [aOR ¼ 1.582, 95%
of age, sex, regional classification, income group, DUP, and
confidence interval (CI) ¼ 1.006–2.490, p ¼ .047] and long-
CCI level, there were no significant differences between life- acting injectable antipsychotic treatment (aOR ¼ 1.796, 95%
time cannabis users and non-users in terms of all the adverse
CI ¼ 1.144–2.820, p ¼ .011) as the independent clinical corre-
effect profiles and DIEPSS items. lates of lifetime cannabis use.

A binary logistic regression model fit to identify the

Discussion
independent clinical correlates of lifetime cannabis use
In summary, adjusting for the potential effects of age, sex,
As shown in Table 5, a binary logistic regression model was
regional classification, income group, DUP, and CCI levels,
fit to identify the independent clinical correlates of lifetime
schizophrenia patients with lifetime cannabis use have been
cannabis use in the subjects with schizophrenia. In the fitted
characterized by significantly more prevalent delusion,
model, delusion, aggressive speech, aggressive behavior,
aggressive speech/behavior, and frequent use of long-acting
 NORDIC JOURNAL OF PSYCHIATRY 327

Table 2. Psychiatric symptoms of schizophrenia patients with and without lifetime cannabis use.
Cannabis use (lifetime)
Total sample Statistical Unadjusted Adjusted
(n ¼ 1,888) Present (n ¼ 132) Absent (n ¼ 1,756) coefficient p-value p-value†
Psychotic symptom profiles
2
Delusion, n (%) 709 (37.6) 68 (51.5) 641 (36.5) v ¼ 11.798 .001 <.0001
2
Hallucination, n (%) 918 (48.6) 63 (47.7) 855 (48.7) v ¼ 0.046 .831 .663
Disorganized speech, n (%) 416 (22.0) 37 (28.0) 379 (21.6) v2 ¼ 2.971 .085 .089
2
Catatonic behavior, n (%) 269 (14.2) 19 (14.4) 250 (14.2) v ¼ 0.002 .960 .261
2
Negative symptom, n (%) 653 (34.6) 45 (34.1) 608 (34.6) v ¼ 0.015 .901 .547
2
Aggressive speech, n (%) 418 (22.1) 48 (36.4) 370 (21.1) v ¼ 16.657 <.0001 .027
Aggressive behavior, n (%) 284 (15.0) 38 (28.8) 246 (14.0) v2 ¼ 20.982 <.0001 .019
BPRS
a
Somatic concern, mean (SD) 1.8 (1.2) 1.7 (1.1) 1.8 (1.2) t ¼ 0.677 .498 .360
a
Anxiety, mean (SD) 2.1 (1.2) 1.8 (1.1) 2.2 (1.2) t ¼ 2.954 .003 .089
Emotional withdrawal,a mean (SD) 2.5 (1.5) 2.3 (1.5) 2.5 (1.5) t ¼ 1.183 .237 .150
a
Conceptual disorganization, mean (SD) 2.4 (1.5) 2.4 (1.6) 2.4 (1.5) t ¼ 0.606 .545 .269
a
Guilty feelings, mean (SD) 1.5 (0.9) 1.4 (0.8) 1.5 (0.9) t ¼ 0.351 .726 .552
a
Tension, mean (SD) 2.0 (1.1) 1.9 (1.2) 2.0 (1.1) t ¼ 0.627 .531 .942
Mannerism and posturing,a mean (SD) 1.5 (1.0) 1.5 (1.0) 1.5 (1.0) t ¼ 0.210 .834 .765
a
Grandiosity, mean (SD) 1.5 (1.0) 1.5 (1.0) 1.5 (1.0) t ¼ 0.072 .942 .521
a
Depressive mood, mean (SD) 1.8 (1.1) 1.8 (1.1) 1.8 (1.1) t ¼ 0.068 .946 .317
a
Hostility, mean (SD) 1.9 (1.2) 2.3 (1.5) 1.9 (1.3) t ¼ 2.695 .008 .146
Suspiciousness,a mean (SD) 2.4 (1.5) 2.7 (1.9) 2.4 (1.5) t ¼ 1.924 .056 .277
a
Hallucinatory behaviors, mean (SD) 2.6 (1.6) 2.8 (1.9) 2.6 (1.6) t ¼ 1.076 .284 .115
a
Motor retardation, mean (SD) 1.7 (1.2) 1.7 (1.2) 1.7 (1.2) t ¼ 0.283 .777 .726
a
Uncooperativeness, mean (SD) 1.9 (1.3) 2.1 (1.5) 1.8 (1.2) t ¼ 1.656 .100 .143
Usual thought content, a mean (SD) 2.5 (1.6) 2.5 (1.7) 2.5 (1.6) t ¼ 0.025 .980 .861
a
Blunted affect, mean (SD) 2.3 (1.4) 2.3 (1.4) 2.4 (1.4) t ¼ 0.129 .897 .940
a
Excitement, mean (SD) 1.6 (1.1) 1.7 (1.3) 1.6 (1.1) t ¼ 0.546 .586 .673
Disorientation,a mean (SD) 1.3 (0.8) 1.4 (1.1) 1.3 (0.8) t ¼ 0.924 .357 .099
BPRS: Brief Psychiatric Rating Scale; CCI: Charlson comorbidity index; DUP: duration of untreated psychosis; SD: standard deviation.
a
n ¼ 1407.
†Adjusted for the effects of age, sex, region classification, income group, DUP, and CCI level.

Table 3. Psychotropic drug prescription patterns of schizophrenia patients with and without lifetime cannabis use.
Cannabis use (lifetime)
Total sample Statistical Unadjusted Adjusted
(n ¼ 1,888) Present (n ¼ 132) Absent (n ¼ 1,756) coefficient p-value p-value†
Antipsychotics
2
First-generation antipsychotics, n (%) 630 (33.4) 58 (43.9) 572 (32.6) v ¼ 7.133 .008 .170
2
Chlorpromazine, n (%) 136 (7.2) 7 (5.3) 129 (7.3) v ¼ 0.767 .381 .403
Haloperidol, n (%) 213 (11.3) 13 (9.8) 200 (11.4) v2 ¼ 0.291 .589 .826
2
Second-generation antipsychotics, n (%) 1,605 (85.0) 104 (78.8) 1,501 (85.5) v ¼ 4.313 .038 .395
2
Amisulpride, n (%) 94 (5.0) 12 (9.1) 82 (4.7) v ¼ 5.073 .024 .168
2
Clozapine, n (%) 377 (20.0) 20 (15.2) 357 (20.3) v ¼ 0.060 .151 .384
Olanzapine, n (%) 339 (18.0) 23 (17.4) 316 (18.0) v2 ¼ 0.027 .869 .365
2
Risperidone, n (%) 662 (35.1) 45 (34.1) 617 (35.1) v ¼ 0.058 .808 .911
2
Long-acting injectable antipsychotics, n (%) 327 (17.3) 46 (34.8) 281 (16.0) v ¼ 30.451 <.0001 .006
2
Flupentixol decanoate, n (%) 70 (3.7) 8 (6.1) 62 (3.6) v ¼ 2.201 .138 .754
Fluphenazine decanoate, n (%) 88 (4.7) 9 (6.8) 79 (89.8) v2 ¼ 1.486 .223 .811
2
Haloperidol decanoate, n (%) 63 (3.3) 16 (12.1) 47 (2.7) v ¼ 33.952 <.0001 <.0001
2
Zuclopenthixol decanoate, n (%) 31 (1.6) 10 (7.6) 21 (1.2) v ¼ 30.942 <.0001 .002
2
Risperidone consta, n (%) 24 (1.3) 1 (0.8) 23 (1.3) v ¼ 0.298 .585 .826
Polypharmacy, n (%) 682 (36.1) 57 (43.2) 625 (35.6) v2 ¼ 3.065 .080 .404
2
High-dose antipsychotics, n (%) 186 (9.9) 19 (14.4) 167 (9.5) v ¼ 3.297 .069 .228
2
Mood stabilizers, n (%) 186 (9.9) 9 (6.8) 177 (10.1) v ¼ 1.471 .225 .183
2
Antidepressants, n (%) 166 (8.8) 11 (8.3) 155 (8.8) v ¼ 0.037 .847 .760
Anxiolytics, n (%) 602 (31.9) 44 (33.3) 558 (31.8) v2 ¼ 0.137 .711 .392
2
High-dose benzodiazepine, n (%) 98 (5.2) 17 (12.9) 81 (4.6) v ¼ 17.046 <.0001 <.0001
2
Antiparkinsonian drugs, n (%) 706 (37.4) 55 (41.7) 651 (37.1) v ¼ 1.107 .293 .953
ECT v2 ¼ 0.073 .964 .262
No, n (%) 1,660 (87.9) 117 (88.6) 1,543 (87.9)
Yes in the past, n (%) 150 (7.9) 10 (7.6) 140 (8.0)
Yes concurrently, n (%) 78 (4.1) 5 (3.8) 73 (4.2)
CCI: Charlson comorbidity index; DUP: duration of untreated psychosis; ECT: electroconvulsive therapy; SD: standard deviation.
†Adjusted for the effects of age, sex, region classification, income group, DUP, and CCI level.

injectable antipsychotics (especially, haloperidol decanoate confounding variables, aggressive behavior and long-acting
and zuclopenthixol decanoate) and high-dose benzodiazep- injectable antipsychotic treatment have been regarded as
ine compared to those without lifetime cannabis use. the independent correlates for lifetime cannabis use in Asian
Moreover, adjusting for the potential effects of these patients with schizophrenia.
328 S.-C. PARK ET AL.

Table 4. Psychotropic drug-induced adverse effects of schizophrenia patients with and without lifetime cannabis use.
Cannabis use (lifetime)
Total sample Statistical Unadjusted Adjusted
(n ¼ 1888) Present (n ¼ 132) Absent (n ¼ coefficient p-value p-value†
Adverse effect profiles 1756)
Rigidity, n (%) 226 (12.2) 18 (13.7) 208 (12.1) v2 ¼ 0.308 .579 .875
2
Akinesia, n (%) 80 (4.3) 5 (6.3) 75 (4.4) v ¼ 0.089 .766 .674
Tremor, n (%) 358 (19.3) 26 (19.8) 332 (19.3) v2 ¼ 0.026 .872 .708
2
Akathisia, n (%) 99 (5.4) 9 (6.9) 90 (5.2) v ¼ 0.642 .423 .360
2
Dystonia, n (%) 50 (2.7) 2 (1.5) 48 (2.8) v ¼ 0.746 .388 .279
2
Constipation, n (%) 372 (20.2) 24 (18.6) 348 (20.3) v ¼ 0.206 .650 .527
Excessive salivation, n (%) 217 (11.7) 16 (12.3) 201 (11.7) v2 ¼ 0.045 .832 .718
2
Dry mouth, n (%) 252 (13.6) 17 (13.1) 235 (13.7) v ¼ 0.037 .847 .602
2
Postural hypotension, n (%) 78 (4.2) 9 (6.9) 69 (4.0) v ¼ 2.432 .119 .209
2
Urination difficulty, n (%) 30 (1.6) 4 (3.1) 26 (1.5) v ¼ 1.873 .171 .132
Blurred vision, n (%) 67 (3.7) 7 (5.4) 60 (3.5) v2 ¼ 1.243 .265 .547
2
Sexual dysfunction, n (%) 102 (6.1) 8 (6.8) 94 (6.1) v ¼ 0.093 .760 .957
2
Galactorrhea, n (%) 64 (3.6) 1 (0.8) 63 (3.8) v ¼ 2.977 .084 .530
2
Impaired glucose tolerance, n (%) 95 (6.1) 3 (2.6) 92 (6.4) v ¼ 2.712 .100 .630
Hypercholesterolemia, n (%) 110 (7.4) 8 (7.1) 102 (7.4) v2 ¼ 0.011 .915 .619
2
Weight gain, n (%) 222 (12.5) 19 (15.3) 203 (12.3) v ¼ 0.955 .328 .889
2
Oversedation, n (%) 189 (10.4) 21 (16.7) 168 (10.0) v ¼ 5.663 .017 .216
DIEPSS
Gait,a mean (SD) 0.3 (0.7) 0.4 (0.8) 0.3 (0.7) t ¼ 0.363 .717 .760
a
Bradykinesia, mean (SD) 0.4 (0.8) 0.4 (0.8) 0.4 (0.8) t ¼ 0.055 .956 .869
a
Sialorrhea, mean (SD) 0.3 (0.7) 0.3 (0.7) 0.3 (0.7) t ¼ 0.717 .474 .489
a
Muscle rigidity, mean (SD) 0.4 (0.8) 0.4 (0.8) 0.4 (0.7) t ¼ 0.428 .669 .493
a
Tremor, mean (SD) 0.5 (0.8) 0.5 (0.8) 0.6 (0.8) t ¼ 0.202 .840 .736
a
Akathisia, mean (SD) 0.3 (0.6) 0.2 (0.5) 0.3 (0.6) t ¼ 1.806 .073 .056
a
Dystonia, mean (SD) 0.2 (0.6) 0.2 (0.5) 0.2 (0.6) t ¼ 0.954 .340 .296
a
Dyskinesia, mean (SD) 0.2 (0.6) 0.2 (0.5) 0.2 (0.6) t ¼ 0.229 .819 .795
a
Overall severity, mean (SD) 0.6 (0.8) 0.5 (0.8) 0.6 (0.8) t ¼ 0.731 .465 .361
CCI: Charlson comorbidity index; DIEPSS: Drug-induced Extrapyramidal Symptom Scale; DUP: duration of untreated psychosis; SD: standard deviation.
a
n ¼ 1420.
†Adjusted for the effects of age, sex, region classification, income group, DUP, and CCI level.

Table 5. A binary logistic regression model fit to identify the independent clinical correlates of lifetime cannabis use.
B Standard error Wald Adjusted p-value† Adjusted odds ratio† 95% Confidence interval
Aggressive behavior 0.459 0.231 3.937 .047 1.582 1.006–2.490
Long-acting injectable antipsychotic 0.586 0.230 6.468 .011 1.796 1.144–2.820
CCI: Charlson comorbidity index; DUP: duration of untreated psychosis.
†Adjusted for the effects of age, sex, region classification, income group, DUP, and CCI level.

Cannabis use has been proposed as a potent risk factor
for aggression in schizophrenia [33]. Partly consistent with
our findings, a study on a cohort of 70 acutely relapsed male
patients with schizophrenia has presented that delusions of
control and combined use of cannabis and alcohol are the
predictors for violent behavior [34]. The neuroimaging find-
ings of frontal and temporal abnormalities have been con-
sistently presented in aggressive schizophrenia patients [35].
The neuroanatomical correlates of schizophrenia patients
with cannabis use have shown similar patterns to those of
aggressive schizophrenia patients. In a tensor-based morpho-
metric study on individuals at an elevated genetic risk of
schizophrenia, cannabis users were characterized by a
greater loss of gray matter from the right anterior hippocam-
pus and left superior frontal lobe compared to cannabis non-
users [36]. A 5-year follow-up study on the first-episode of
schizophrenia has shown that cannabis users are character-
ized by more pronounced thinning of the left dorsal pre-
frontal cortex, left anterior cingulate cortex, and left occipital
lobe compared to cannabis non-users [37]. Schizophrenia
patients with cannabis use are characterized by a smaller
volume of anterior cingulate gyrus than those without can-
nabis use and the healthy volunteers [38]. Thus, despite
partly inconsistent findings, it is speculated that the abnor-
malities in frontal and temporal lobes could be the shared
common neurobiological underpinning of cannabis use,
aggressive behavior, and schizophrenia. Furthermore, as ear-
lier mentioned in the introduction, a dose-response pattern
can be fit into the relationship between cannabis use and
psychosis risk [2,14]. It is speculated that more prevalent
delusion of schizophrenia patients with lifetime cannabis use
is partly consistent with a shared vulnerability for schizophre-
nia and cannabis use through genetics or stress [39]. A mice
model has suggested that pro-hallucinogenic signaling of 5-
HT2A receptors through Akt/mTOR is promoted by chronic
cannabis use. Hence, the relationship between cannabis
exposure and risk of developing psychosis may be explained
by the model [40]. Also, the risk of aggressive behavior is
consistently increased by positive psychotic symptoms of
schizophrenia [33]. The relationship between aggressive
behavior and psychosis-like experiences can be in an associ-
ation with childhood abuse or cognitive abnormalities [41].

Thus, in our findings, delusion may be an intervening vari-
able for aggressive behavior in schizophrenia patients with
lifetime cannabis use.
In our findings, long-acting antipsychotics have been
more frequently used in schizophrenia patients with lifetime
cannabis use. More frequent uses of haloperidol decanoate
and zuclopenthixol decanoate in schizophrenia patients with
lifetime cannabis use may be explained by the fact that
most of the cannabis users are Southern Asians or Southeast
Asians in our study. These findings are partly consistent with
an increase in the risk of relapse, duration of hospital stay
and hospital admissions in cannabis-using patients with
schizophrenia spectrum disorder compared to non-using
patients with the disorder [42,43]. The relationship between
long-acting injectable antipsychotics and cannabis use in
patients with schizophrenia may be explained by the poorer
treatment response presented by cannabis-using patients
with schizophrenia spectrum disorder. An experimental study
has shown that the D9-THC-induced psychotic symptoms are
inadequately prevented by D2 receptor antagonists [10].
Despite their better efficacy, long-acting injectable antipsy-
chotics are characterized by higher rates of D2 antagonism-
related symptoms (extrapyramidal and prolactin-related
symptoms) compared to oral antipsychotics [44]. Thus, the
possibility cannot be excluded that the use of high-dose
benzodiazepine may be related with that of long-acting
injectable antipsychotics in schizophrenia patients with life-
time cannabis use. Since benzodiazepines have the potential
side effect of cognitive impairment, their use is not recom-
mended for schizophrenia patients with aggression [45].
However, in our findings, the schizophrenia patients with life-
time cannabis use showed more frequent use of high-dose
benzodiazepines compared to those without the lifetime
cannabis use. Thus, high-dose benzodiazepine-related cogni-
tive impairment may be an intervening variable for aggres-
sive behavior in schizophrenia patients with lifetime cannabis
use. Our findings have presented that there are no differen-
ces between patients with and without lifetime cannabis use
with respect to the drug-induced extrapyramidal symptoms
and other adverse-effect profiles. These findings cannot be
simply explained because there have been few reports on
the relationship in the previous studies. Given the condition
that psychotic patients with cannabis use show decreased
neurological soft signs compared to those without cannabis
use [46], the possibility cannot be excluded that the poten-
tial protective effects of cannabis may contribute to non-
differences between the two groups in our findings.
Limitations and strengths
Our study has several limitations. First, the REAP-AP was a
cross-sectional study hence inferences about temporal
causality cannot be drawn. Second, cannabis use was
evaluated in terms of simply its presence or absence rather
than its quanti- tative levels. Third, although there was a
consensus before the initiation of our study, inter-rater
reliability for assessing canna- bis use, psychopathological
characteristics, and adverse events due to psychotropic
drugs were not measured. Fourth, the
NORDIC JOURNAL OF PSYCHIATRY 329
psychotropic drug prescription patterns could be influenced by
non-biological factors including insurance regulations and
psy- chiatrists’ or patients’ preferences; however, these
variables were not controlled. Fifth, there was no information
on other narcotics use in our study, although cannabis use
might be a proxy for narcotics use. Despite these
limitations, our study has presented that aggressive behavior
and long-acting inject- able antipsychotic treatment are the
independent correlates of lifetime cannabis use in Asian
patients with schizophrenia.
Conclusions
Since most of the cannabis users were Southern or
Southeast Asians, haloperidol decanoate and zuclopenthixol
decanoate were the individual long-acting injectable anti-
psychotic drugs to be more frequently used in schizophrenia
patients with cannabis use. Aggressive behavior and long-
acting antipsychotic use associated with the life-time use of
cannabis can partly support the idea that schizophrenia
spectrum disorder may be classified into cannabis-using and
non-using patients from the viewpoints of clinical character-
istics and neurobiology.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This research was supported by grants from Taipei City Hospital (10501-
62-012), Taipei, Taiwan.
Notes on contributors
SCP, CHT, MYC, NS, NS, and YCP conceptualized and designed the study.
SCP, HSO, and YCP performed data analyses and drafted the manuscript.
All authors interpreted the results and revised the manuscript. All
authors read and approved the final version of the manuscript.
ORCID
Seon-Cheol Park http://orcid.org/0000-0003-3691-4624
Hong Seok Oh http://orcid.org/0000-0002-3071-3760
Adarsh Tripathi http://orcid.org/0000-0002-3885-6475
Shih-Ku Lin http://orcid.org/0000-0002-5123-0389
Chay Hoon Tan http://orcid.org/0000-0002-6399-0668
Naotaka Shinfuku http://orcid.org/0000-0002-7390-9077
Yong Chon Park http://orcid.org/0000-0002-3019-5748
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[34] Koen L, Kinnear CJ, Corfield VA, et al. Violence in male patients
with schizophrenia: risk markers in a South African population.
Aust N Z J Psychiatry. 2004;38:254–259.
[35] Soyka M. Neurobiology of aggression and violence in schizophre-
nia. Schizophr Bull. 2011;37:913–920.
[36] Welch KA, Moorhead TW, McIntosh AM, et al. Tensor-based
morphometry of cannabis use on brain structure in individuals at
elevated genetic risk of schizophrenia. Psychol Med. 2013;43:
2087–2096.
[37] Rais M, van Haren NE, Cahn W, et al. Cannabis use and progres-
sive cortical thickness loss in areas rich in CB1 receptors during
the first five years of schizophrenia. Eur Neuropsychopharmacol.
2010;20:855–865.
[38] Szeszko PR, Robinson DG, Sevy S, et al. Anterior cingulate grey-
matter deficits and cannabis use in first-episode schizophrenia. Br
J Psychiatry. 2007;190:230–236.
[39] Haney M, Evins AE. Does cannabis cause, exacerbate or amelior-
ate psychiatric disorders? An oversimplified debate discussed.
Neuropsychopharmacology. 2016;41:393–401.
[40] Ibarra-Lecue I, Mollinedo-Gajate I, Meana JJ, et al. Chronic
cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors
through Akt/mTOR pathway. Neuropsychopharmacol.
2018;43:2028–2035.
[41] Kinoshita Y, Shimodera S, Nishida A, et al. Psychotic-like experien-
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Schizophr Res. 2011;126:245–251.
[42] Manrique-Garcia
schizophrenia E, Zammit
in persons withS,and
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[43] Schoeler T, Monk A, Sami MB, et al. Continued versus discontin-
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[44] Park S-C, Choi MY, Park E, et al. Comparative efficacy and safety
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361–375.
[45] Fond G, Boyer L, Favez M, et al. Medication and aggressiveness
in real-world schizophrenia. Results from the FACE-SZ dataset.
Psychopharmacology. 2016;233:571–578.
[46] Mallet J, Ramoz N, Le Strat Y, et al. Heavy cannabis use prior
psychosis in schizophrenia: Clinical, cognitive and neurological
evidences for a new endophenotype? Eur Arch Psychiatry Clin
Neurosci. 2017;267:629–638.
 Technology Enhanced
Medical Education
International Conference

c c
Presented to:

dr. Erwiani Sutono

for her achievement as:

THE BEST PRESENTER

in Technology in Healthcare Technology

Enhanced Medical Education (THEME)
2019
International Conference
Faculty of Medicine, Hasanuddin University

6–8 December 2019, in Makassar, Indonesia

Dean, hief of Committee,

Prof.dr. Budu, Sp.M(K), M.MedEd, PhD DR.dr. Rina Masadah, Sp.PA(K),

M.Phil, DFM

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 WOSQUAL 2020
The 2nd International Conference On Women and Societal
Perspective On Quality Of Life
Virtual International Conference
Makassar, 26 November 2020
Website: http://wosqual2020.unhas.ac.id
Email: wosqual2020.spsunhas@gmail.com

Date: January 30th 2021

Letter of Acceptance for Fullpaper

To whom it may concern,

The organizing committee of the 2nd International Conference on Women and Societal
Perspective on Quality of Life (WOSQUAL) 2020 is pleased to announce the acceptance of the
manuscript written by Sonny T Lisal, Andi Jayalangkara Tanda, Santiwati Anda, Burhanuddin
Bahar, Isra Wahid, Saidah Syamsuddin titled Association between Cathecol -O-
Methyltransferase (COMT) Val 158 Met Polymorphisms and Psychosocial Stressors in
Torajanese Schizophrenic Patients. Furthermore, this paper will be submitted collectively
together with all manuscripts that have been screened and reviewed by the authority, namely the
Hasanuddin University Publication Management Center (PMC Unhas) to Enfermeria Clinica, a
Q3 journal, indexed by Scopus. The submission time for the manuscript is planned for no later
than the second week of February 2021.
Please note that the editor of the partner journal holds the final decision of the paper’s acceptance.
For further information on this event, please feel free to access our
website http://wosqual2020.unhas.ac.id and email:
wosqual2020.spsunhas@gmailcom.

Sincerely yours,
Committee Chair of WOSQUAL 2020

Ika Yustisia
 Dokumentasi karya yang memperoleh HAKI
Program computer: Deteksi Kejiwaaan: Kamu Hanya Stress, Kamu Tidak Gila, Kamu Bisa
Sembuh Dari Gangguan Jiwa oleh Dr.dr.Saidah Syamsuddin,Sp.KJ
 Nomor : 5565/UN4.20/DL.17/2020

Certificate
This is to certify that the work b y
Sri Purwatiningsih, Saidah Syamsuddin

Black Seed (Nigella sativa) as Adjuvant Therapy Improves Clinical, Cognitive

and
Extrapyramidal Symptoms During Risperidone Treatment in
Schizophrenia
had been presented at

The 2nd International Conference on Women and Societal Perspective on Quality of Life 2020
on November 26th 2020
at Graduate School of Hasanuddin University, Makassar, Indonesia.
Dean of Graduate School Hasanuddin University, Organizing Committee,

Prof. Dr. Ir. Jamaluddin Jompa, M.Sc. Dr. dr. Ika Yustisia, M.Sc
 •
I '· "

PERJANJIAN KERJA SAMA

ANTARA
PEMERINTAH DAERAH KABUPATEN MOROWALI
,DAN FAKULTAS KEDOKTERAN UNIVERSITAS HASANUDDIN MAKASSAR
•

TENT ANG

PENYELENGGARAAN PELAYANAN KESEHATAN MASYARAKAT

OLEH DOKTER SPESIALIS •

DI RUMAH SAKlT UMUM QA~~.~H MQRQWAL_~ KAQ\!PAT~N MQRQWAl:1

NOMOR : 445/3'o.\1/ RSUD-MRW/ l/ 2016
NOMOR : IJ.J\1-r'UN4.7/PM.05/2016

Pada hari ini Rabu Tanggal Empat Belas Bulan Desember Tahun Dua Ribu Enam Belas,
kami yang bertanda tangan dibawah ini:

1. Ors. H. Anwar Hafid, M.Si

Bupatl Morowali bertindak atas nama Pemerintah Kabupaten Morowali selanjutnya
disebut PIHAK PERT AMA
1

21. Prof. Dr. dr. Andi Asadul Islam, Sp.BS

Dekan Fakultas Kedokte.(an Univers.ltc!~ H.c1~anudd.in M~ka~sar bertindak atas. nama
Fakultas selanjutnya disebut PIHAK KEDUA

PASAL I
ALASAN DAN LANDASAN KERJASAMA
Ke.rjasama dilandasi atas pert.imbangan:
a. Keterbatasan tenaga medis yg bertugas di Rumah Sakit Umum Daerah Morowali
Kabupaten Morowali
b. Keterbatasan sumber daya lokal yang handal dalam bidang kedokteran untuk
mendukung pembangunan di Kabupaten Morowali
c. Pentingnya pengembangan dan peningkatan kualitas Sumber Daya Manusia Kabupaten
Morowali
d. Tuntutan kebutuhan masyarakat akan tersedianya Tenaga Dokter Spesialis di Rumah
Sakit Umum Daerah Morowali Kabupaten Morowali.

PASAL 2
DASAR PERTIMBANGAN KERJASAMA
Keriasarna dldasari atas pertimbangan;
,1. Keinginan· masyarakat lokal Kabupaten Morowali tentang ketersediaan tenaga medis,
sehingga pelayanan akan dokter spesialis lebih konsisten dan dalam jangka waktu yang
•

lama.
b. Keberadaan Universitas Hasanuddin Makassar sebagai Perguruan Tinggi Terbaik di
Kawasan Timur Indonesia dalam memperluas hubungan kerjasama di berbagai bidang
baik dengan Pemerintah Daerah maupun swasta atas dasar saling menguntungkan
kedua betan pihak.
c. Fakultas Kedokteran Universitas Hasanuddin Makassar sebagai penyelenggara Teknis
Program Pendidikan Dokter Spesialis (PPDS} di bawah naungan Universitas
Hasanucdin Makassar

PASAL 3
MAKSUD DAN TUJUAN
Maksud perjanjian ini adalah untuk menghasilkan potensi sumber daya manusia tenaga medis
yang berkualitas, berilmu dan berdedlkasi tinggi di bidang pelayanan kesehatan yang meliputi:
a. Kete.rsediaan Tenaga Dokter Spesiali's (PPDS senior) untuk memberikan pelayanan di
Rumah Sakit Umum Daerah Morowali Kabupaten Morowali.
b. Ke.giatan- .kegiatan bersama lainnya dalam bidang pelayanan kesehatan masyarakat dan
penerapan Tri Darrna Perguruan Tinggi antar Faku\tas Kedokteran Universitas
Hasanuddin Makassar dan Pemerintah Daerah Kabupaten Morowali.
c. Kemitraan dalam pemberdayaan Rumah Sakit dan Pengembangan penelitian di· bidang
 •
'

PASAL 4
RUANG LINGKUP KERJASAMA
Ruang lingkup kerjasama meliputi:
a. PIHAK KEDUA akan membantu pelayanan kesehatan di Rumah Sakit Umum Daerah
Morowali Kab.upaten Morowali dengan menyediakan tenaga dokter senior yang
sementara mengikuti Program Pendidikan Dokter Spesialis (PPDS) llmu Obstetri &
Ginekologi, llmu Anestesi, lmu Kedokteran Jiwa, llmu Kesehatan Mata, llmu
Penyakit Dalam, llmu Gizi Klinik, THT dan Radiologi
b, Dokter tersebut akan ditugaskan di Rumah Sakit Umum Daerah Morowali Kabupaten
Morowafi' selama 2 (dua) bulan, selanjutnya akan digantikan ofeh Dokter Senior yang
sementara mengikuti Program Pendidikan Dokter Spesialis (PPDS) lainnya. Apabila
RSUD Morowali teJah memiliki Dokter Spesialis, maka pihak RSUD Morowali Kabupaten
Morowali dapat meminta Residen Bagian lain sebagai pengganti.
c. Dolder yang ditugaskan tersebut harus mematuhi peraturan yang bertaku di lingkungan
RSUD Morowali dan tidak meninggalkan tempat tugas sebelum berakhimya mass
penugasan.
d. Fakultas Kedokteran Universitas Hasanuddin Makassar akan mengirim Tim
Visitasi yang terdiri dari Pimpinan Fakultas Kedokteran UNHAS. TKP-PPDS,
Staf Administrasi dan Supervisor dari Bagian-Bagian yang bersangkutan
guna meningkatkan standar pelayanan Rumah Sakit, Menilai kelanjutan
Kerjasama 1 {satu) kali kunjungan setiap tahunnya, sesuai bagian guna
meningkatkan standar pelayanan Rumah Sakit Umum Daerah Mrowali
Kabupaten Morowali.

PASAL 5
BIAVA PENYELENGGARA
Biaya penyelenggara pada pasal 4, sepenuhnya ditanggung oleh PIHAK PERTAMA yang diatur
dengan rincian sebagai berikut :
a. Biaya insentif untuk PPDS Senior sebesar Rp. 20.000.000,- /bulan termasuk pajak
b. Biaya lnsentif bagi Tim Visitasi sebesar Rp.10.000.000,- per orang 1 x per tahun belum
termasuk pajak, akomodasi, transportasi dan konsumsi
c. Menyediakan biaya Asuransi jiwa/profcsi bagi dokter PPDS Senior sebesar Rp.
1.000.000,- pertahun/ bagian
d. Biaya transportasi Makassar - Morowali Pergi Pulang bagi PPDS Senior 1 x selama
masa tugas di Rumah Sakit Umum Daerah Morowali Kabupaten Morowali.
e. Menyediakan peralatan kesehatan yang dibutuhkan PPDS sesuai standar dari bagian
yang bersangkutan dalam pelaksanaan tugasnya.
f. Menyediakan obat-obatan yang dibutuhkan oleh PPDS sesuai standar dari bagian yang
bersangkutan selama memberikan pelayanan di Rumah Sakit Umum Daerah Morowali
Kabupaten Morowali ..
g. Mendapatkan perlindungan terhadap segala bentuk ancaman bagi keselamatan PPDS
yang bertugas di Rum ah Sakit Umurn Daerah Morowali Kabupaten Morowali..
h. Biaya transportasi bagi Tim Visitasi Makassar - Morowali Pergi Pulang
i. Menyediakan perumahan dan kendaraan bagi PPDS Senior
j. Menerima jasa medik sesuai ketentuan yang berlaku di Rumah Sakit Umum Daerah
MorowaJi Kabupaten MorowaJi ..
k. Menyediakan konsumsi makan dan minum 3 (tiga) kali sehari bagi PPDS Senior
I. Menyediakan biaya Asuransi perjalanan oagi tim visitasi sebesar Rp. 1.000.000,- per
orang
PASAL 6
WAKTU PELAKSANAAN
1. Perjanjian kerjasama inj berJaku 1 (satu) tahun, terhitung sejak perjanjian yaitu dari tanggaJ
1 Januari s/d 31 Desember 2017.
2. Perjanjian ini dapat diakhiri sebelum jangka waktu tersebut dalam ayat ( 1) dengan ketentuan
pihak yang akan mengakhiri perjanjian ini harus memberitahukan maksud tersebut secara
tertulis kepada pihak lainnya paling lambat 3 (tiga) bulan sebelumnya.

PASAL 7
FORCE MAJURE
1. Yang dimaksud dengan force majure adalah peristiwa yang terjadi di IL1ar kemampuan dan
• kP.kuasaan kedua belah pihak yang berakibat tidak dapat dipenuhinya hak dan
0•~1

. .. -- - - .J:-. .... 1,.,., ,.,-1 ~nt~r~ lain: aemoa bumi,

-
•
•

angin topan, banjir bandang, kebakaran besar, tanah longsor, wabah penyakit, pemogokan
umum, huru-hara, perang pemberontakan dan krisis moneter akibat terjadi inflasi, devisit
anggaran, belum tersedianya anggaran dan perubahan kebijakan lainnya dibidang moneter.
2. Apabila terjadi force majure sebagaimana dimaksud ayat (1 ), maka kedua belah pihak
dibebaskan untuk melaksanakan kewajiban-kewajiban yang diluar perjanjian ini apabila
terjadinya force majure sebagaimana dimaksud ayat (1) diatas.

PASAL8
PEMANTAUAN DAN EVALUASI
Pemantauan dan evaluasi dalam pelaksanaan perjanjian ini dapat dilakukan oleh PIHAK
PER'T AMA maupun PIHAK KEDUA secara tersendiri maupun bersama-sama sesuai dengan
kebutuhan dan kesepakatan bersama. Hasil pemantauan dan evaluasi disampaikan kepada
masing-masing pihak untuk dapat dijadikan dasar penyempurnaan pelayanan maupun
peninjauan kembali perjanjian ini.

PASAL 9
PENGAWASAN
Kelangsungan keberhasilan penyelenggara kerja sama dan pembinaan moral menjadi tanggung
jawab PIHAK PERT AMA, untuk pengawasan serta tanggung jawab akademis menjadi
tanggung jawab PIHAK KEDUA.

PASAL 10
PERLINDUNGAN HUKUM
PARA PIHAK secara bersama-sama wajib memberikan perlindungan hukum terhadap PPDS
Senior yang bertugas, apabila selama penugasan berhadapan dengan masalah-masalah
hukum yang berkaitan dengan Praktek Kedokterannya.

PASAL 11
PENUTUP
Perubahan-perub~han materi ~rjanjian dalam perjanjian kerjasama ini akan dituangkan dalam
a~~endum yang d1tandatangan1 oleh kedua belah pihak dan merupakan bagian yang tidak dapat
dipisankan dalam perjanjian kerjasama nu.
Pl~A~PER!~MA d~~ PIHAK KEDUA akan menyelesaikan secara musyawarah bila
mana
t~rJad, persehsahan. Prhhan terakhir penyelesaian akan diajukan ke pengadifan dimana menurut
k etent .. . rundang-undangan yang berlaku .
..,., ~~'$f.T._!EKN~
t."'~ ~-~ \ 1," ~
~
~•.: ~q/J:~ ERTAMA
lllA~.\\
;;:. . ' ~ \.
, j\.. . ~
·t
y~\ \
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( ..., /~J ~. ~Q \
.
(~\1 1 ' ; ,,!J(Q~ c;; ~C' '
·,
' ',~~.
t-..,t,l"l'I
,f'.>' '-I-.... l
~
...!,. .. ~;.,_.---=::,,,,.
, '
I

•
SAKS I-SAKS I • •

NA

1 · Ors. H. Ambo Da e
Kc;tua DPRD K~bu ten Morowali ~

2. Ashar Ma'ruf, SE
·
Kepala Dinas Kesehatan Kab M .
· orowat, ,
3. 9~· Sandra Suaanty, MARS D - ••
rektur
, / ' I
RSUO Morowafi Kab
.
M .
orowalr
•••••••• •••
 ~

· .. , s PERJANJIAN KERJA SAMA

ANT ARA
PEMERINTAH KABUPATEN MOROWALI UTARA
DENG AN
FAKULTAS KEDOKTERAN UNIVERSITAS HASANUDDIN MAKASSAR
TENTANG
PENYELENGGARAAN PELAYANAN KESEHATAN MASYARAKAT
OLEH DOKTER SPESIALIS
DI RUMAH SAKIT UMUM DAERAH KOLONODALE KABUPATEN MOROW ALI
UTARA
NO MOR : 445/ IX/RSUD.K.dale/2016
NOMOR =lf>9;st1/u~11.1J2N6/ p~. o;- / z.£) lb

Pada hari ini Sabtu Tanggal Satu Bulan Oktober Tahun Dua Ribu Enam Belas Belas, kami
yang bertanda tangan dibawah ini :

I. APTRIPEL TUMIMOMOR
Bupati Morowali Utara bertindak atas nama Pemerintah Kabupaten Morowali Utara
(-.., Selanjutnya disebut PIHAK PERT AMA
\..._.,

•
2. Prof.Dr.dr. ANDI ASADUL ISLAM, Sp.BS
Dekan Fakultas Kedokteran Universitas Hasanudclin Makassar bertindak atas nama
Fakultas Kedokteran Universitas Hasanuddin Makassar selanjutnya disebut PIHAK
KEDUA

Memperhatikan

1. Undang-undang Nomor 12 Tahun 2013 Tentang Pembentukan Kabupaten Morowali

Utara di Provinsi Sulawesi Tengah
2. Undang-undang Nomor 36 Tahun 2009 Tentang Kesehatan
31. Undang-undang Nomor 44 Tahun 2009 Tentang Rumah Sakit
4. Permenkes Nomor 129 I Menkes I SK./W2008 Tentang Standar Pelayanan Minimal
Rumah Sakit.

PASAL I .
ALASAN DAN LANDASAN KERJASAMA

Kerjasama dilandasi atas pertimbangan:

a. Keterbatasan tenaga medis yg bertugas di Rumah Sa.kit Umum Daerah Kolonodale

Kabupaten Morowali Utara
b. Keterbatasan sumber daya lokaJ yang handal dalaro bidang kedokteran untuk
mendukung pembangunan di Kabupaten Morowali Utara
c. Pentingnya pengembangan dan peningkatan kualitas Sumber Daya Manusia Kabaupaten
Morowali Utara
d. Tuntutan kebutuban masyarakat akan tersedianya Tenaga Dokter Spesialis di Rumah
Sakit Umum Daerah Kolonodale Kabupaten Morowali Utara.
 ., PASAL 2
I
DASAR PERTIMBANGAN KERJASAMA

Kerjasama didasar atas pertimbangan :

a. Keinginan mansyarakat lokal Kabupaten Morowali Utara tentang ketersediaan tenaga

medis, sehingga pelayanan akan dokter spesialis lebih konsisten dan dalam jangka waktu
yang lama.

b. Keberadaan Universitas Hasanuddin Makassar sebagai Perguruan Tinggi Terbaik di

Kawasan Timur Indonesia dalam memperluas hubungan kerjasama diberbagai bidang
baik dengan Pemerintah Daerah maupun swasta atas dasar saling menguntungkan kedua
belah pihak. .

c. Fakultas Kedokteran Universitas Hasanuddin Makassar sebagai penyelenggara Teknis

Program Pendidikan Dokter Spesialis (PPDS) dibawah naungan Universitas Hasanuddin
Makassar
•

PASAL 3
MAKSUD DAN TUJUAN

- Maksud perjanjian ini adalah untuk menghasilkan potensi somber daya manusia tenaga medis
yang berkualitas, berilmu dan berdedikasi tinggi di bidang pelayanan kesehatan yang meliputi :

a. Ketersediaan Tenaga Dokter Spesialis (PPDS senior) untuk memberikan pelayanan di

Rwnah Sakit Umuro Daerah Kolonodale Kabupaten Morowali Utara.
b. Kegiatan- kegiatan bersarna lainnya dalam bidang pelaynan kesehatan masyarakat dan
penerapan Tri Danna Perguruan Tinggi antar Fakultas Kedokteran Universitas
hasanuddin Makassar dan Pemerintah Kabupaten Morowali U tara.
c. Kemitraan dalam pemberdayaan Rumah Sak.it dan Pengembangan penelitian di bidang
kesehatan.

PASAL 4
RUANG LINGKUP KERJASAMA MELIPUTI

a. PIHAK KEDUA akan membantu pelayanan kesehatan di Rumah Sakit Umum Daerah
Kolonodale Kabupaten Morowali Utara denga n menyediakan tenaga dokter senior yang
sementara mengikuti Program Pendidikan Dokter Spesialis (PPDS) Departemen llmu
Penyakit Dalam, llmu Penyakit Saraf, llmu Kedokteran Jiwa, Ilmu Kesehatan
Kulit & Kelamin, limn Patologi Klinik dan Ilm11 penyakit Jantung dan Pembuluh
Darah

b. Dokter te sebut akan dit gaskan di Rumah Sakit Umwn Daerah Kolonodale Kabupaten
Morowali Utara selama 2 (dua) clan 3 (tiga) bulan, selanjutnya akan digantikan oleh
Dokter Senior yang sementara mengikuti Program Pendidikan Dokter Spesialis (PPDS)
lainnya. Dan apabila RSUD Kolonodale Kabupaten Morowali Utara telah memiliki
Dokter Spesialis, maka pihak RSUD Kolonodale Kabupaten Morowali Utara bisa
meminta Residen Bagian lain sebagai pengganti

c. Fakultas Kedokteran Universitas Hasanuddin Makassar akan mengirim Tim Visitasi yaitu
Pimpinan Fakultas Kedokteran UNHAS, TKP-PPDS, Administrasi dan Supervisor dari
Bagian-Bagian yang bersangkutan guna meningkatkan standar pelayanan Rumah Sakit,
Menilai kelanjutan Kerjasama l(satu) kali kunjungan setiap tahunnya, sesuai Bagian
guna meningkatkan standar pelayanan Rumah Sakit Umum Daerah Kolonodale
Kabupaten Morowali Utara.
., '
PASAL 5
BIAY A PENYELENGGARA

Biaya penyelenggara pada pasal 4, sepenuhnya ditanggung oleh PIHAK PERT AMA yang
diatur dengan rincian sebagai berikut :

a. Biaya insentif untuk PPDS Senior sebesar Rp. 18.000.000,- /bulan sudah tennasuk pajak
b. Biaya Insentif bagi Tim Visitasi sebesar Rp. l 0.000.000,- per orang 1 x per tahun belwn
termasuk pajak, akomodasi, transfortasi dan konsumsi
c. Menyediakan biaya Asuransi jiwa/profesi bagi dokter PPDS Senior sebesar Rp.
1.000.000,- pertahun/bagian.
d. Menyediakan biaya Asuransi jiwa bagi Tim Visitasi sebesar Rp. 1.000.000,•
pertahun/orang belwn termasuk pajak.
e. Menerima jasa medik sesuai ketentuan yang berlaku di Rwnah Sakit Umwn Daerah
Kolonodale Kabupaten Morowali Utara
f. Biaya transportasi Makassar - Kolonodale Pergi Pulang bagi PPDS Senior 1 x selama
masa tugas di Rumah Sakit Umum Daerah Kolonodale Kabupaten Morowali Utara.
g. Menyediakan peralatan kesehatan yang dibutuhkan PPDS sesuai standar dari bagian yang
bersangkutan dalam pelaksanaan tugasnya.
h. Menyediakan obat-obatan yang dibutuhkan oleh PPDS sesuai standar dari bagian yang
bersangkutan selama memberikan pelayanan di Rumah Sakit Umum Daerah Kolonodale

c
Kabupaten Morowali Utara.
i. Mendapatkan perlindungan terhadap segala bentuk ancaman bagi keselamatan PPDS
yang bertugas di Rumah Sakit Umum Daerah Kolonodale Kabupaten Morowali Utara.
j. Biaya transportasi bagi Tim Visitasi Ma kassar - Kolonodale Pergi Pulang
k. Menyediakan perumahan clan perabotannya bagi PPDS Senior
I. Menyediakan biaya makan bagi PPDS senior sebanyak Rp. 2.000.000 per orang setiap
bulannya sudah ter masuk pajak.

PASAL 6
WAKTUPELAKSANAAN

1. Perjanjian kerjasama ini berlaku 1 (satu) tahun, terhitung sejak perjanjian yaitu dari
tanggal O 1 Oktober 2016 s/d O 1 Oktober 2017.
2. Perjanjian ini dapat diakhiri sebelum jangka waktu tersebut dalam ayat (1) dengan
ketentuan pihak yang akan mengakhiri perjanjian ini harus memberitahukan maksud
tersebut secara tertulis kepada pihak lainnya paling lambat 3 (tiga) bulan sebelumnya.

PASAL 7
FORCE MAJURE

1. Yang dimaksud dengan force majure adalah peristiwa yang terjadi di luar kemampuan
dan atau kekuasaan kedua belah pihak yang berakibat tidak dapat dipenuhinya hak dan
kewajiban kedua belah pihak. Adapun peristiwa yang dimaksud antara lain: gempa bumi,
angin topan, banjir bandang, kebakaran besar, tanah longsor, wabah penyakit, pemogokan
umum, hura-hura, perang pemberontakan dan krisis monetcr akibat terjadi inflasi, devisit
anggaran, belum tersedianya anggaran dan perubahan kebijakan lainnya dibidang
moneter.
2. Apabila terjadi force majure sebagaimana dimaksud ayat (1 ), maka kedua belah pihak
dibebaskan untuk melaksanakan kewajiban-kewajiban yang diluar perjanjian ioi apabila
terjadinya force majure sebagaimana dimaksud ayat ( 1) diatas.

PASAL8
PEMANTAUAN DAN EV ALUASI
• ••
 .. • •
PASAL 9
PENGAWASAN

Kelangsungan keberhasilan penyelenggara kerja sama dan pembinaan moral menjadi tanggung
jawab PIHAK PERT AMA, untuk pengawasan serta tanggung jawab akademis menjadi
tanggungjawab PIHAK KEDUA.

PASAL 10
PERLINDUNGAN HUiruM

PARA PIHAK secara bersama-saroa wajib memberikan perlindungan huk:um terhadap PPDS
Senior yang bertugas, apabila selama penugasan berhadapan dengan masalah-masalah hukum
yang berkaitan dengan Praktek kedokterannya

PASAL 11
PENUTUP

Perubahan-perubahan materi perjanjian dalam perjanjian kerjasama ini akan dituangkan dalam
addendum yang ditandatangani oleh kedua belah pihak dan merupakan bagian yang tidak dapat
dipisahkan dalam perjanjian kerjasama ini.
PIHAK PERTAMA clan PIHAK KEDUA akan menyelesaikan secara musyawarah bila mana
terjadi perselisihan. Pilihan terakhir penyelesaian akan diajukan ke Pengadilan dimana menurut
ketentuan perundang-undangan yang berlaku.

upati Morowali Utara

(1 SAKS I-SAKS I

NAMA AN GAN

1. dr. I Made Puiawan, M.Kes ••••• •••••••••••••••••••

Direktur RSUD Kolonodale

2. pr. dr. Aidah Juliaty A. Daso, Sp.A(K)

Sekretaris KPPS Dokter Spesialis FK-UNHAS
 PERJANJIAN KERJASAMA
ANTARA
PEMERINTAH KABUPATEN PARIGI MOUTONG
PROVINSISULAWESITENGAH
DEN GAN
FAKULTAS KEDOKTERAN UNIVERSITAS HASANUDDIN MAKASSAR
TENTANG
PENYELENGGARAAN PELAYANAN KESEHATAN MASYARAKAT OLEH
DOKTER PESERTA PROGRAM PENDIDIKAN DOKTER SPESIALIS (PPDS)
SENIOR DI RUMAH SAKIT UMUM DAERAH ANUNTALOKO KABUPATEN
PARIGI MOUTONG

NOMOR: 0'7 / 77 I ll?U D- Anvn}~lc>it-O

NOMOR: /UN4.6/LK.09.01/2019

Pada hari ini Rabu Tanggal 2 Bulan Januari Tahun dua Ribu Sembilan Belas,
kami yang bertanda tangan dibawah ini:

1. H. SAMSURIZAL TOMBOLOTUTU
Adalah Bupati ParigiMoutong, yang diangkat berdasarkan Surat Keputusan
Menteri Dalam Negeri Nomor 131.72-7782 tanggal 10 Oktober 2018
dalam hal ini bertindak untuk dan atas nama Pemerintah Kabupaten
Parigi Moutong yang berkedudukan di Jalan Kampali No. 1 Parigi,
selanjutnya disebut PIHAK KESATU.

2. Prof. dr. BUDU, Ph.D., Sp.M.(K), M.Med.Ed.

Adalah Dekan Fakultas Kedokteran Universitas Hasanuddin Makassar,
yang diangkat berdasarkan Surat Keputusan Rektor Nomor
1317/UN4.1/KEP/2018 tanggal 28 Maret 2018, dalam hal ini bertindak
untuk dan atas nama Fakultas Kedokteran Universitas Hasanuddin, yang
berkedudukan di Jalan Perintis Kemerdekaan KM 10 Makassar 90245,
selanjutnya disebut PIHAK KEDUA.

PIHAK KESATU dan PIHAK KEDUA secara bersama sama disebut PARA
PIHAK. Dengan itikad baik, dan tetap berpedoman kepada ketentuan peraturan
perundang-undangan, maka PARA PIHAK menerangkan dengan ini bersepakat
dan setuju untuk mengadakan kerja sama yang dituangkan dalam perjanjian
kerjasama dengan ketentuan-ketentuan sebagai berikut:

Pasal 1
MAKSUD DAN TUJUAN

(1) Untuk menjamin ketersediaan sumber daya manusia (SDM) pelayanan

kesehatan di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Moutong.
(2) Untuk membantu kelancaran pelayanan kesehatan di Rumah Saki.t Umum
Daerah Anunta.lokoKabupaten Parigi Moutong.
(3) Untuk membantu perencanaan dan peningkatan kapasitas SDM
kesehatan di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Moutong.
(4) Untuk pengembangan layanan Tridarma Perguruan Tinggi.
 Pasal 2
LANDASAN KERJASAMA

Kerjasama dilandasi atas pertimbangan:

a. Keterbatasan tenaga medis yang bertugas di Rumah Sakit Umum Daerah
Anuntaloko Kabupaten Parigi Moutong.
b. Keterbatasan sumber daya lokal yang handal dalam bidang kedokteran
untuk mendukung pembangunan di Kabupaten ParigiMoutong.
c. Pentingnya pengembangan dan peningkatan kualitas Sumber Daya Manusia
Kesehatan di Kabupaten Parigi Moutong.
d. Tuntutan kebutuhan masyarakat akan tersedianya pelayanan tenaga dokter
spesialis di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Mou tong.
e. Keberadaan Universitas Hasanuddin Makassar sebagai perguruan tinggi
terbaik di Kawasan Timur Indonesia dalam memperluas hubungan
kerjasama diberbagai bidang, baik dengan pemerintah daerah maupun
swasta, atas dasar saling menguntungkan PARA PIHAK.
f. Fakultas Kedokteran Universitas Hasanuddin Makassar sebagai
penyelenggara teknis Program Pendidikan Dokter Spesialis (PPDS)dibawah
naungan Universitas Hasanuddin Makassar.

Pasal 3
RUANG LINGKUP
KERJASAMA

Menyiapkan dan memberikan pelayanan kesehatan di Rurnah Sakit Umum

Daerah Anuntaloko Kabupaten Parigi Moutong, berupa tenaga dokter PPDS
Senior yang sementara mengikuti program pendidikan pada Program Studi
llmu Patologi Klinik, Program Studi Ilmu Penyakit Jantung dan Pembuluh
Darah, Program Studi llmu Kedokteran Jiwa, Program Studi
Ilmu Anestesi, dan Program Studi Ilmu Bedah, dengan sistem
monitoring, supervisi dan evaluasi berkesinambungan.

Pasal 4
JANGKA WAKTU PELAKSANAAN

(1) Perjanjian kerjasama ini berlaku untuk jangka waktu 3 (tiga)tahun sejak
ditandatangani PARA PIHAK.
(2) Perjanjian kerjasama ini dapat diakhiri sebelum jangka waktu tersebut
dalam ayat (1), atas persetujuan PARA PIHAK, dengan ketentuan
pemberitahuan disampaikan 3 (tiga) bulan sebelum perjanjian berakhir.

Pasal 5
PENDANAAN
Jasa Penugasan Dokter PPDS Senior dan Tim Visitasi

Jasa penugasan dokter PPDS Senior dan Tim Visitasi ditanggung oleh PIHAK
K.ESATU yang diatur sebagai berikut:
(1) Jasa penugasan dokter PPDSSenior berupa jasa insentif dan jasa medik
a. Jasa insentif sebesar Rp 16.000.000,00 (enam belas juta rupiah)
/orang/bulan (tidak termasuk pajak).
Pihak I Pihak u
 Pasal 2
LANDASAN KERJASAMA

Kerjasama dilandasi atas pertimbangan:

a. Keterbatasan tenaga medis yang bertugas di Rumah Sakit Umum Daerah
Anuntaloko Kabupaten Parigi Moutong.
b. Keterbatasan sumber daya lokal yang handal dalam bidang kedokteran
untuk mendukung pembangunan di Kabupaten Parigi Moutong.
c. Pentingnya pengembangan dan peningkatan kualitas Sumber Daya Manusia
Kesehatan di Kabupaten Parigi Moutong.
d. Tuntutan kebutuhan masyarakat akan tersedianya pelayanan tenaga dokter
spesialis di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Moutong.
e. Keberadaan Universitas Hasanuddin Makassar sebagai perguruan tinggi
terbaik di Kawasan Timur Indonesia dalam memperluas hubungan kerjasama
diberbagai bidang, baik dengan pemerintah daerah maupun swasta, atas
dasar sating menguntungkan PARA PIHAK.
f. Fakultas Kedokteran Universitas Hasanuddin Makassar sebagai
penyelenggara teknis Program Pendidikan Dokter Spesialis (PPDS)dibawah
naungan Universitas Hasanuddin Makassar.

Pasal 3
RUANG LINGKUP KERJASAMA

Menyiapkan dan memberikan pelayanan kesehatan di Rumah Sakit Umum

Daerah Anuntaloko Kabupaten Parigi Moutong, berupa tenaga dokter PPDS
Senior yang sementara mengikuti program pendidikan pada Program Studi
llmu Patologi Klinik, Program Studi Ilmu Penyakit Jantung dan Pembuluh
Darah, Program Studl llmu Kedokteran Jlwa, Program Studi llmu Anestesi,
dan Program Studi Ilmu Bedah, dengan sistem monitoring, supervisi dan
evaluasi berkesinambungan.

Pasal 4
JANGKA WAKTU PELAKSANAAN

(1) Perjanjian kerjasama ini berlaku untuk jangka waktu 3 (tiga) tahun sejak
ditandatangani PARA PIHAK.
(2) Perjanjian kerjasama ini dapat diakhiri sebelum jangka waktu tersebut
dalam ayat (1), atas persetujuan PARA PIHAK, dengan ketentuan
pemberitahuan disampaikan 3 (tiga)bulan sebelum perjanjian berakhir.

Pasal 5
PENDANAAN
Jasa Penugasan Dokter PPDS Senior dan Tim Visitasi

Jasa penugasan dokter PPDS Senior dan Tim Visitasi ditanggung oleh PIHAK
KESATU yang diatur sebagai berikut:
(l) Jasa penugasan dokter PPDSSenior berupajasa insentif dan jasa medik
a. Jasa insentif sebesar Rp 16.000.000,00 (enam belas juta rupiah)
/ orang/bulan ( sudah termasuk pajak).
Pihak I Pihak II
 b. Jasa medik akan diberikan dan diatur dengan kesepakatan PARA PIHAK.
c. Konsumsi makan dan minum sebesar Rp. 110.000,00 (seratus sepuluh
ribu rupiah)/orang/hari (sudah termasuk pajak), biaya transportasi
Makassar - Kabupaten Parigi Moutong pergi pulang sebanyak 1 (satu) kali,
serta biaya listrik dan PDAMselama bertugas.
d. Jasa Insentif dan jasa medik dokter PPDS Senior dibayarkan secara
langsung (LS) ke rekening dokter PPDS Senior yang melaksanakan
pelayanan.

(2) Jasa kunjungan Tim Visitasi

a. Jasa visitasi dibayarkan secara lumpsum Rp 5.000.000,00 (lima juta
rupiah) per orang/hari bagi Pimpinan Fakultas, Rp 4.500.000,00 (empat
juta lima ratus ribu rupiah) per orang/hari bagi pengelola PPDS dan Rp
4.000.000,00 (empat juta rupiah) per orang/hari bagi tenaga
Administrasi, tidak termasuk pajak.
b. Biaya akomodasi, transportasi udara/ darat/laut dan konsumsi selama
melaksanakan tugas visitasi yang besarannya ditetapkan berdasarkan
ketentuan pemerintah.
c. Insentif Tim Visitasi dibayarkan langsung oleh PIHAK KESATU kepada
Tim Visitasi berdasarkan penugasan pada saat melakukan kunjungan.

Pasal 6
INSTITUTIONAL FEE

(1) Institutional fee adalah besaran dana yang dibebankan kepada PIHAK
KESATU untuk dibayarkan kepada PIHAK KEDUA atas kerjasama
pelayanan di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Moutong.
(2) Besarnya Institutional fee adalah 5°/o dari besarnya insentif yang diterima
sesuai kehadiran dokter PPDS Senior sebelum dipotong pajak, per orang per
bulan.
(3) Institutionalfeedibayarkan setiap 6 (enam) bulan, dan ditransfer ke rekening
PIHAK KEDUA pada:
Bank BNI 46 Cabang Makassar
Atas nama Rektor UNHAS
Nomor rekening 009.899.0071
NPWP 00.415.588.3.801.000

Pasal 7
HAK DAN KEWAJIBAN PIHAK KESATU

(1) Hak:
a. Menerima kelengkapan berkas syarat pembuatan Surat Izin Praktek (SIP)
disertai Rincian Kewenangan Klinis (RKK) dokter PPDS Senior seminggu
sebelum pengiriman dokter PPDS Senior.
b. Menerima dokter PPDS Senior untuk ditugaskan di Rumah Sakit Umum
Daerah Anuntaloko Kabupaten Parigi Moutong.

Pihak I Pihak II
 d. Menjaga semua fasilitas yang diberikan oleh PIHAK. KESATU, baik
sarana prasarana pelayanan maupun non pelayanan (rumah dinas,
kendaraan operasional dan fasilitas lainnya)
e. Mematuhi semua peraturan yang berlaku di Rumah Sa.kitUmum Daerah
Anuntaloko Kabupaten Parigi Moutong, termasuk mengajukan surat izin
tertulis disertai alasan kepada PIHA.K KESATU jika akan meninggalkan
tempat tugas.
f. Menjaga narna baik institusi Rumah Sakit Umum Daerah Anuntaloko
Kabupaten Parigi Moutong dan Fakultas Kedokteran Universitas
Hasanuddin.
g. Melakukan monitoring, supervisi dan evaluasi melalui visitasi berkala
sesuai kebutuhan (minimal sekali dalam setahun), terdiri dari unsur
pimpinan Fakultas Kedokteran, pengelola PPDS Senior dan staf
adm:inistrasi.
h. Menyampaikan laporan dan rekomendasi untuk peningkatan kualitas
pelayanan rumah sakit kepada PIHAK KESATU.

Pasal 9
PEMANTAUAN DAN EVALUASI

(1) Pemantauan dan evaluasi dalarn pelaksanaan perjanjian ini dapat dilakukan
oleh PARA PIHAK secara tersendiri maupun bersama-sama sesuai dengan
kebutuhan dan kesepakatan bersama.
(2) Hasil pemantauan dan evaluasi disampaikan kepada PARA PIHAK untuk
penyempumaan pelayanan maupun peninjauan kembali perjanjian ini.
(3) Keberhasilan penyelenggaraan kerjasama dan pembinaan SOMpada Rumah
Sakit Umum Daerah Anuntaloko Kabupaten Parigi Moutong menjacli
tanggung jawab PIHAK KESATU dan pengawasan akademis dokter PPDS
Senior menjadi tanggung jawab PDIA.K KEDUA.

Pasal 10
PENYELESAIAN PERSELISIHAN

(1) Perselisihan yang timbul antara PARA PIHAK sebagai ak.ibat pelaksanaan
perjanjian kerja sama ini akan diselesaikan secara musyawarah untuk
mufakat.
(2)Apabila musyawarah mufakat sebagaimana dimaksud pada ayat ( 1) tidak
tercapai, maka kedua belah pihak bersepakat untuk menyelesaikan
perselisihan tersebut melalui panitia Arbitrase yang dibentuk oleh PARA
PIHAK.

Pasal 11
PERUBAHAN PERJANJIAN

Apabila terjadi perubahan materi dan a.tau ruang lingkup dalam perjanjian
kerjasama ini, maka akan dituangkan dalam adendum kontrak yang
ditandatangani oleh PARA PIHAK dan merupakan bagian yang tidak
terpisahkan dari perjanjian kerjasama ini.

Pihak I Pihak II
 Pasal 12
FORCE MAJEVR.E

(1) Yang dimaksud dengan force majeure adalah peristiwa yang terjadi di luar
kemampuan dan atau kekuasaan PARA PIHAK yang berakibat tidak dapat
dipenuhinya hak dan kewajiban PARA PIHAK. Peristiwa yang dimaksud
antara lain: gempa bumi, tsunami, angin topan, banjir bandang, kebakaran
besar, tanah longsor, wabah penyakit, pemogokan umum, huru-hara, perang
pemberontakan dan krisis moneter akibat terjadi inflasi, defisit anggaran,
belum tersedianya anggaran dan perubahan kebijakan lainnya dibidang
moneter.
(2) Apabila terjadi force majeure sebagaimana dimaksud ayat (1), maka PARA
PIHAK dibebaskan dari kewajiban-kewajiban seperti yang tercantum pada
Perjanjian Kerjasama ini.

Pasal 13
PERUTUP

Demikian Perjanjian Kerjasama ini dibuat dan ditandatangani oleh PARA

PIHAK dalam rangkap 2 (dua) asli, bermaterai cukup dan masing-masing
mempunyai kekuatan hukum yang sama bagi PARA PIHAK.

PIHAK KEDUA,

I' Prof, dr, B

U

Pihak I Pihak ll
 PERJANJIAN KERJASAMA
AN TARA
PEMERINT AH KABUPATEN TOLITOLI
PROVINSI SULAWESI TENGAH DENG
AN
FAKULTAS KEDOKTERAN UNIVERSITAS HASANUDDIN MAKASSAR
TENTANG
PENYELENGGARAAN PELAYANAN KESEHA TAN MASYARAKAT
OLER DOKTER PESERTA PROGRAM PENDIDIKAN DOKTER SPESIALIS
(PPDS) DI RUMAH SAKIT UMUM DAERAH MOKOPIDO KABUPATEN TOLITOLI

NOMOR
NOMOR : 046/UN4.6/HK.07.00/2020

Pada hari ini K.amisTanggal Dua Bulan Januari Tahun Dua Ribu Dua Puluh, kami yang bertanda tangan
dibawah ini :

1. Moh.SalehBantilan, SH., MH
Adalah Bupati Tolitoli, yang diangkat berdasarkan Surat Keputusan Menteri Dalam Negeri
Republik Indonesia Nomor : 131.72.447 Tahun 2016, Tentang Pengangkatan Bupati Tolitoli
Provinsi Sulawesi Tengah, dalam hal ini bertindak dan atas nama Pemerintah Kabupaten Tolitoli
yang berkedudukan dijalan Sumalikat Nomor 19 Tolitoli, selanjutnya disebut PIHAK
PERTAMA.

2. Prof. dr, Budu, Ph. D., Sp. M.(K). M. Med.Ed.,

Adalah. Dekan Fakultas Kedokteran Universitas Hasanuddin Makassar, yang diangkat
berdasarkan Surat Keputusan Rektor Nomor : 13171UN4.1IKEP/2018 tanggal 28 Maret 2018,
dalam hal ini bertindak untuk dan atas nama Fakultas Kedokteran Universitas Hasanuddin,
yang berkedudukan di Jalan Perintis Kemerdek.aan KM 10 Makassar 90245, selanjutnya disebut
PIHAK KEDUA.

Pihak pertama dan pihak kedua secara bersama sarna disebut PARA PIHAK. Dengan
itikad baik., dan tetap berpedoman kepada ketentuan peraturan perundang-undangan, maka para
pihak menerangkan dengan ini bersepakat dan setuju untuk mengadakan kerja sama yang
dituangkan dalam perjanjian kerjasama dengan ketentuan-ketentuan sebagai berikut:

PASAL 1
MAKSUD DAN TUJUAN

(1) Untuk menjamin ketersediaan sumber daya manusia (SDM) pelayanan kesehatan di
Rumah.Sakit Umum Daerah (RSUD) Mokopido.
(2) Untuk membantu kelancaran pelayanan kesehatan di RSUD Mokopido.
(3) Untuk membantu perencanaan dan peningkatan kapasitas SDM kesehatan di
RSUD Mokopido.
(4) Untuk pengembangan Layanan Tridarma Perguruan Tinggi.

Pibak f Pihak ll

~ ff/
 PASAL2
LANDASAN KERJASAMA

Kerjasama dilandasi atas pertimbangan :

a. Keterbatasan tenaga medis yang bertugas di RSUD Mokopido Kabupaten Tolitoli.
b. Keterbatasan sumber daya lokal yang handal dalam bidang kedokteran untuk mendukung
pembangunan di Kabupaten Tolitoli.

c. Pentingnya pengembangan dan peningkatan kualitas Sumber Daya Manusia Kesehatan di Kabupaten
Tolitoli.
d. Tuntutan kebutuhan masyarakat akan tersedianya pelayanan tenaga dokter spesialis di RSUD
Mokopido Kabupaten Tolitoli.
e. Keberadaan Universitas Hasanuddin Makassar sebagai perguruan tinggi terbaik di Kawasan
Timur Indonesia dalam memperluas hubungan kerjasama diberbagai bidang, baik dengan pemerintah
daerah maupun swasta, atas dasar saling menguntungkan PARA PIHAK.
f. Fakultas Kedokteran Universitas Hasanuddin Makassar sebagai penyelenggara teknis Program
Pendidikan Dokter Spesialisn (PPDS) dibawah naungan Uiversitas Hasanuddin Makassar.

PASAL3
RUANG LINGKUP KERJASAMA

Menyiapkan dan memberikan pelayanan kesehatan di RSUD Mokopido, berupa tenaga dokter PPDS
yang sementara mengikuti program pendidikan pada Program Studi Ilmu Kesebatan THT -KL,
Program Studi Ilmu kedokteran Jiwa, Program Studi Neurologi dan Program Studi limo
Penyakit Jantung dan Pembuluh Darah, dengan sistem monitoring dan evaluasi
berkesinambungan.

PASAL4
JANGKA WAKTUPELAKSANAAN

(1) Perjanjian kerjasama ini berlaku untuk jangka waktu 3 (tiga) tahun sejak ditandatangani
PARA PIHAK.
(2) Perjanjian kerjasama ini dapat diakhiri sebelum jangka waktu tersebut dalam ayat (1), atas
persetujuan PARA PlHAK, dengan ketentuan pemberitahuan disampaikan 3 (tiga)
bulan sebelum perjanjian berakhir.

PASAL5
PENDANAAN
Jasa Penugasan Dokter PPDS dan Tim Visitasi

Jasa penugasan dokter PPDS dan Tim Visitasi ditanggung oleh PIHAK PERTAMA yang diatur
sebagai berikut :
(1) Jasa penugasan. dokter PPDS berupajasa insentif danjasa medik
a. Jasa insentif sebesar Rp 18.000.000,-/orang/bulan.
b. Jasa medik akan diberikan clan diatur dengan kesepakatan PARA PIHAK.
c. Konsumsi makan dan minum 3 (tiga) kali sehari, biaya transportasi Makassar -
Kabupaten
Tolitoli pergi pulang sebanyak 1 (satu) kali, serta biaya listrik dan PDAM selama bertugas.
d. Jasa Insentif dan jasa medik dokter PPDS dibayarkan secara langsung (LS) ke rekening dokter
PPDS yang melaksanakan pelayanan.

Pihak I.I
(2) Jasa kunjungan Tim Visitasi
a. Jasa v.isitasi dibayarkan secara lumpsum Rp. 5.000.000.- per orang/hari bagi Pimpinan Fakultas
(Dekan dan Manajer PPDS), Rp. 4. 500.000.- per orang/hari bagi pengelola PPDS dan Rp.
4.000.000 per orang/hari bagi tenaga Administrasi, tidak termasuk pajak.
b. Biaya akomodasi, transportasi udara/darat/laut dan konsumsi selama melaksanakan tugas visitasi
yang besarannya ditetapkan berdasarkan ketentuan pemerintah.
c. Insentif Tim Visitasi dibayarkan langsung oleh PIHAK PERTAMA kepada Tim Visitasi
berdasarkan penugasan pada saat melakuk.an kunjungan.

PASAL6
Institutional Fee

(I) Institutional fee adalah besaran dana yang dibebankan kepada PIHAK PERTAMA untuk
dibayarkan kepada PIHAK KEDUA atas kerjasama pelayanan di RSUD Mokopido Kabupaten
Tolitoli.
(2) Besarya Institutional fee adalah 5% dari besarnya insentifyang diterima oleh dokter PPDS sebelum
dipotong pajak, per orang per bulan.
(3) Institutional fee dibayarkan setiap 6 (enam) bulan, dan ditransfer ke rekening PIHAK KEDUA pada:

Bank : BNI 46 Cabang Makassar

Atas nama : Rektor UNHAS
Nomor Rekening : 009.899.0071
NPWP : 00.415.588.3.801.000

PASAL7
Hak dan Kewajiban PIHAK PERTAMA

(1) Rak:
a. Menerima dokter PPDS untuk ditugaskan di RSUD Mokopido Kabupaten Tolitoli.
b. Mendapatkan pelayanan optimal sesuai kompetensi dokter PPDS selama bertugas di
RSUD Mokopido K.abupaten Tolitoli.
c. Mengatur penugasan dokter PPDS secara internal selama masa bertugas.
d. Menyampaikan dan mengajukan permohonan untuk mengakhiri masa tugas dokter PPDS.
e. Menerima kunjungan serta laporan visitasi dari PIHAK KEDUA untuk perbaikan mutu
layanan yang berkelanjutan.

(2) Kewajiban:
a. Melakukan pembayaran sebagaimana diatur pada Pasal (5) dan (6) secara tepat waktu.
b. Menyediakan sarana dan prasarana kesehatan, obat-obatan dan fasilitas kesehatan yang
dibutuhkan untuk pelayanan dokter PPDS sesuai standar yang berlaku.
c. Menyediakan rumah tinggal beserta perabotnya dan kendaraan operasional bagi dokter
PPDS yang bertugas.
d. Memberikan perlindungan kesehatan, hukum, keselamatandan keamanan kepada dokter
PPDS
dan tim visitasi bila diperlukan selama menjalankan tugas.
e. Merencanakan clan mempersiapkan dokter organik rumah sakit sebagai. calon tenaga dokter
spesialis definitif.

Pihak n
 PASAL8
Hak dan Kewajiban PIHAK KEDUA

(1)Hak:
a. Memperoleh pembayaran sebagaimana diatur pad.a Pasal (5) dan (6) secara tepat waktu.
b. Memanfaatkan sarana dan prasarana kesehatan, obat-obatan dan fasilitas kesehatan yang
dibutuhkan untuk pelayanan dokter PPDS sesuai standar yang berlaku.
c. Memanfaatkan rumah tinggal beserta perabotnya dan kendaraan operasional bagi dokter PPDS
yang bertugas.
d. Memperoleh perlindungan kesehatan, hukum, keselamatan dan keamanan bila diperlukan
selama menjalankan tugas.

(2)Kewajiban:
a. Mengirimkan dokter PPDS dari program studi sesuai kesepakatan yang disertai dengan
dokumen yang masih berlaku.
b. Memberikan pelayanan kesehatan sesuai standar kompetensi sepanjang didukung fasilitas
yang memadai, dan atau berdasarkan standar dan prosedur pelayanan kesehatan yang
berlaku di RSUD Mokopido Kabupaten Tolitoli.
c. Menjaga semua fasilitas yang diberikan oleh PIHAK PERTAMA, baik sarana prasarana
pelayanan maupun non pelayanan (rumah dinas, kendaraan operasional dan fasilitas lainnya)
d. Mematuhi semua peraturan yang berlaku di RSUD Mokopido, termasuk mengajukan surat izin
tertulis disertai alasan kepada PIHAK PERTAMAjika akan meninggalkan tempat tugas.
e. Menjaga nama baik institusi RSUD Mokopido Kabupaten Tolitoli dan Fakultas
Kedokteran Universitas Hasanuddin.
f. Melakukan monitoring dan evaluasi melalui visitasi berkala sesuai kebutuhan (minimal
sekali dalam setahun), terdiri dari unsur pimpinan Fakultas Kedokteran, pengelola PPDS
dan staf administrasi.
g. Menyampaikan laporan dan rekomendasi untuk peningkatan kualitas pelayanan rumah
sak.it
kepada PIHAK PERT AMA.

PASAL9
DAN EV ALUASI

1. Pemantauan dan evaluasi dalam pelaksanaan perjanjian nu dapat dilakukan oleh para
PIHAK secara tersendiri maupun bersama-sama sesuai dengan kebutuhan dan
kesepakatan bersama.

2. Hasil pemantauan dan evaluasi disampaikan kepada PARA PIHAK untuk penyempumaan
pelayanan maupun peninjauan kembali perjanjian ini.
3. Keberbasilan penyelenggaraan kerjasama dan pembinaan SDM pada RSUD Mokopido
Kabupaten Tolitoli menjadi tanggung jawab PIHAK PERTAMA dan pengawasan akademis
dokter PPDS menjadi tanggung jawab PIHAK KEDUA.

PASALlO
PENYELESEIAN PERSELISIHAN

(1) Perselisihan yang timbul antara PARA PIHAK sebagai akibat pelaksanaan perjanjian kerja
sama ini ak.an diselesaikan secara musyawarah untuk mufakat.

Pihak II
 (2) Apabila musyawarah mufakat sebagaimana dimaksud pada ayat (1) tidak tercapai, maka kedua
belah pihak bersepakat untuk menyelesaikan perselisihan tersebut melalui panitia Arbitrase
yang dibentuk oleh PARA PIHAK.

PASAL 11
PERUBAHAN PERJANJIAN

Apabila terjadi perubahan materi dan atau ruang lingkup dalam perjanjian kerjasama ini, maka akan
dituangkan dalam adendum kontrak yang ditandatangani oleh PARA PJHAK dan merupakan bagian
yang tidak: terpisahkan dari perjanjian kerjasama ini.

PASAL 12
FORCE MAJEURE

1. Yang dimaksud dengan force mqjeure adalah peristiwa yang terjadi di luar kemampuan
dan atau kekuasaan PARA PIHAK yang berakibat tidak dapat dipenuhinya hak clan kewajiban
PARA PIHAK. Peristiwa yang dimaksud an tara lain: gempa bumi, tsunami, angin topan,
banjir bandang, kebakaran besar, tanah longsor, wabah penyakit, pemogokan umurn, huru•
hara, perang pemberontakan dan krisis moneter akibat terjadi inflasi, defisit anggaran,
belum tersedianya anggaran dan perubahan kebijakan lainnya dibidang moneter.
2. Apabila terjadi force majeure sebagairnana dimaksud ayat (1), rnaka PARA
PIHAK dibebaskan dari kewajiban-kewajiban seperti yang tercantum pada Perjanjian
Kerjasama ini.

PASAL 13
PENUTUP

Demikian Perjanjian Kerjasama ini dibuat dan ditandatangani oleh PARA PIHAK dalam rangkap
2 (dua) asli, bermaterai cukup dan masing-masing mempunyai kekuatan hukum yang sarna bagi
PARA PIHAK.

PIHAK KEDUA,

Pihak II
 PERJANJIAN KERJASAMA
ANTARA
PEMERINTAH KABUPATEN PARIGI MOUTONG
PROVINSISULAWESITENGAH
DEN GAN
FAKULTAS KEDOKTERAN UNIVERSITAS HASANUDDIN MAKASSAR
TENTANG
PENYELENGGARAAN PELAYANAN KESEHATAN MASYARAKAT OLEH
DOKTER PESERTA PROGRAM PENDIDIKAN DOKTER SPESIALIS (PPDS)
SENIOR DI RUMAH SAKIT UMUM DAERAH ANUNTALOKO KABUPATEN
PARIGI MOUTONG

NOMOR: 0'7 / 77 I ll?U D- Anvn}~lc>it-O

NOMOR: /UN4.6/LK.09.01/2019

Pada hari ini Rabu Tanggal 2 Bulan Januari Tahun dua Ribu Sembilan Belas,
kami yang bertanda tangan dibawah ini:

1. H. SAMSURIZAL TOMBOLOTUTU
Adalah Bupati ParigiMoutong, yang diangkat berdasarkan Surat Keputusan
Menteri Dalam Negeri Nomor 131.72-7782 tanggal 10 Oktober 2018
dalam hal ini bertindak untuk dan atas nama Pemerintah Kabupaten
Parigi Moutong yang berkedudukan di Jalan Kampali No. 1 Parigi,
selanjutnya disebut PIHAK KESATU.

2. Prof. dr. BUDU, Ph.D., Sp.M.(K), M.Med.Ed.

Adalah Dekan Fakultas Kedokteran Universitas Hasanuddin Makassar,
yang diangkat berdasarkan Surat Keputusan Rektor Nomor
1317/UN4.1/KEP/2018 tanggal 28 Maret 2018, dalam hal ini bertindak
untuk dan atas nama Fakultas Kedokteran Universitas Hasanuddin, yang
berkedudukan di Jalan Perintis Kemerdekaan KM 10 Makassar 90245,
selanjutnya disebut PIHAK KEDUA.

PIHAK KESATU dan PIHAK KEDUA secara bersama sama disebut PARA
PIHAK. Dengan itikad baik, dan tetap berpedoman kepada ketentuan peraturan
perundang-undangan, maka PARA PIHAK menerangkan dengan ini bersepakat
dan setuju untuk mengadakan kerja sama yang dituangkan dalam perjanjian
kerjasama dengan ketentuan-ketentuan sebagai berikut:

Pasal 1
MAKSUD DAN TUJUAN

(1) Untuk menjamin ketersediaan sumber daya manusia (SDM) pelayanan

kesehatan di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Moutong.
(2) Untuk membantu kelancaran pelayanan kesehatan di Rumah Saki.t Umum
Daerah Anunta.lokoKabupaten Parigi Moutong.
(3) Untuk membantu perencanaan dan peningkatan kapasitas SDM
kesehatan di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Moutong.
(4) Untuk pengembangan layanan Tridarma Perguruan Tinggi.
 Pasal 2
LANDASAN KERJASAMA

Kerjasama dilandasi atas pertimbangan:

a. Keterbatasan tenaga medis yang bertugas di Rumah Sakit Umum Daerah
Anuntaloko Kabupaten Parigi Moutong.
b. Keterbatasan sumber daya lokal yang handal dalam bidang kedokteran
untuk mendukung pembangunan di Kabupaten ParigiMoutong.
c. Pentingnya pengembangan dan peningkatan kualitas Sumber Daya Manusia
Kesehatan di Kabupaten Parigi Moutong.
d. Tuntutan kebutuhan masyarakat akan tersedianya pelayanan tenaga dokter
spesialis di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Mou tong.
e. Keberadaan Universitas Hasanuddin Makassar sebagai perguruan tinggi
terbaik di Kawasan Timur Indonesia dalam memperluas hubungan
kerjasama diberbagai bidang, baik dengan pemerintah daerah maupun
swasta, atas dasar saling menguntungkan PARA PIHAK.
f. Fakultas Kedokteran Universitas Hasanuddin Makassar sebagai
penyelenggara teknis Program Pendidikan Dokter Spesialis (PPDS)dibawah
naungan Universitas Hasanuddin Makassar.

Pasal 3
RUANG LINGKUP
KERJASAMA

Menyiapkan dan memberikan pelayanan kesehatan di Rurnah Sakit Umum

Daerah Anuntaloko Kabupaten Parigi Moutong, berupa tenaga dokter PPDS
Senior yang sementara mengikuti program pendidikan pada Program Studi
llmu Patologi Klinik, Program Studi Ilmu Penyakit Jantung dan Pembuluh
Darah, Program Studi llmu Kedokteran Jiwa, Program Studi
Ilmu Anestesi, dan Program Studi Ilmu Bedah, dengan sistem
monitoring, supervisi dan evaluasi berkesinambungan.

Pasal 4
JANGKA WAKTU PELAKSANAAN

(1) Perjanjian kerjasama ini berlaku untuk jangka waktu 3 (tiga)tahun sejak
ditandatangani PARA PIHAK.
(2) Perjanjian kerjasama ini dapat diakhiri sebelum jangka waktu tersebut
dalam ayat (1), atas persetujuan PARA PIHAK, dengan ketentuan
pemberitahuan disampaikan 3 (tiga) bulan sebelum perjanjian berakhir.

Pasal 5
PENDANAAN
Jasa Penugasan Dokter PPDS Senior dan Tim Visitasi

Jasa penugasan dokter PPDS Senior dan Tim Visitasi ditanggung oleh PIHAK
K.ESATU yang diatur sebagai berikut:
(1) Jasa penugasan dokter PPDSSenior berupa jasa insentif dan jasa medik
a. Jasa insentif sebesar Rp 16.000.000,00 (enam belas juta rupiah)
/orang/bulan (tidak termasuk pajak).
Pihak I Pihak u
 Pasal 2
LANDASAN KERJASAMA

Kerjasama dilandasi atas pertimbangan:

a. Keterbatasan tenaga medis yang bertugas di Rumah Sakit Umum Daerah
Anuntaloko Kabupaten Parigi Moutong.
b. Keterbatasan sumber daya lokal yang handal dalam bidang kedokteran
untuk mendukung pembangunan di Kabupaten Parigi Moutong.
c. Pentingnya pengembangan dan peningkatan kualitas Sumber Daya Manusia
Kesehatan di Kabupaten Parigi Moutong.
d. Tuntutan kebutuhan masyarakat akan tersedianya pelayanan tenaga dokter
spesialis di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Moutong.
e. Keberadaan Universitas Hasanuddin Makassar sebagai perguruan tinggi
terbaik di Kawasan Timur Indonesia dalam memperluas hubungan kerjasama
diberbagai bidang, baik dengan pemerintah daerah maupun swasta, atas
dasar sating menguntungkan PARA PIHAK.
f. Fakultas Kedokteran Universitas Hasanuddin Makassar sebagai
penyelenggara teknis Program Pendidikan Dokter Spesialis (PPDS)dibawah
naungan Universitas Hasanuddin Makassar.

Pasal 3
RUANG LINGKUP KERJASAMA

Menyiapkan dan memberikan pelayanan kesehatan di Rumah Sakit Umum

Daerah Anuntaloko Kabupaten Parigi Moutong, berupa tenaga dokter PPDS
Senior yang sementara mengikuti program pendidikan pada Program Studi
llmu Patologi Klinik, Program Studi Ilmu Penyakit Jantung dan Pembuluh
Darah, Program Studl llmu Kedokteran Jlwa, Program Studi llmu Anestesi,
dan Program Studi Ilmu Bedah, dengan sistem monitoring, supervisi dan
evaluasi berkesinambungan.

Pasal 4
JANGKA WAKTU PELAKSANAAN

(1) Perjanjian kerjasama ini berlaku untuk jangka waktu 3 (tiga) tahun sejak
ditandatangani PARA PIHAK.
(2) Perjanjian kerjasama ini dapat diakhiri sebelum jangka waktu tersebut
dalam ayat (1), atas persetujuan PARA PIHAK, dengan ketentuan
pemberitahuan disampaikan 3 (tiga)bulan sebelum perjanjian berakhir.

Pasal 5
PENDANAAN
Jasa Penugasan Dokter PPDS Senior dan Tim Visitasi

Jasa penugasan dokter PPDS Senior dan Tim Visitasi ditanggung oleh PIHAK
KESATU yang diatur sebagai berikut:
(l) Jasa penugasan dokter PPDSSenior berupajasa insentif dan jasa medik
a. Jasa insentif sebesar Rp 16.000.000,00 (enam belas juta rupiah)
/ orang/bulan ( sudah termasuk pajak).
Pihak I Pihak II
 b. Jasa medik akan diberikan dan diatur dengan kesepakatan PARA PIHAK.
c. Konsumsi makan dan minum sebesar Rp. 110.000,00 (seratus sepuluh
ribu rupiah)/orang/hari (sudah termasuk pajak), biaya transportasi
Makassar - Kabupaten Parigi Moutong pergi pulang sebanyak 1 (satu) kali,
serta biaya listrik dan PDAMselama bertugas.
d. Jasa Insentif dan jasa medik dokter PPDS Senior dibayarkan secara
langsung (LS) ke rekening dokter PPDS Senior yang melaksanakan
pelayanan.

(2) Jasa kunjungan Tim Visitasi

a. Jasa visitasi dibayarkan secara lumpsum Rp 5.000.000,00 (lima juta
rupiah) per orang/hari bagi Pimpinan Fakultas, Rp 4.500.000,00 (empat
juta lima ratus ribu rupiah) per orang/hari bagi pengelola PPDS dan Rp
4.000.000,00 (empat juta rupiah) per orang/hari bagi tenaga
Administrasi, tidak termasuk pajak.
b. Biaya akomodasi, transportasi udara/ darat/laut dan konsumsi selama
melaksanakan tugas visitasi yang besarannya ditetapkan berdasarkan
ketentuan pemerintah.
c. Insentif Tim Visitasi dibayarkan langsung oleh PIHAK KESATU kepada
Tim Visitasi berdasarkan penugasan pada saat melakukan kunjungan.

Pasal 6
INSTITUTIONAL FEE

(1) Institutional fee adalah besaran dana yang dibebankan kepada PIHAK
KESATU untuk dibayarkan kepada PIHAK KEDUA atas kerjasama
pelayanan di Rumah Sakit Umum Daerah Anuntaloko Kabupaten Parigi
Moutong.
(2) Besarnya Institutional fee adalah 5°/o dari besarnya insentif yang diterima
sesuai kehadiran dokter PPDS Senior sebelum dipotong pajak, per orang per
bulan.
(3) Institutionalfeedibayarkan setiap 6 (enam) bulan, dan ditransfer ke rekening
PIHAK KEDUA pada:
Bank BNI 46 Cabang Makassar
Atas nama Rektor UNHAS
Nomor rekening 009.899.0071
NPWP 00.415.588.3.801.000

Pasal 7
HAK DAN KEWAJIBAN PIHAK KESATU

(1) Hak:
a. Menerima kelengkapan berkas syarat pembuatan Surat Izin Praktek (SIP)
disertai Rincian Kewenangan Klinis (RKK) dokter PPDS Senior seminggu
sebelum pengiriman dokter PPDS Senior.
b. Menerima dokter PPDS Senior untuk ditugaskan di Rumah Sakit Umum
Daerah Anuntaloko Kabupaten Parigi Moutong.

Pihak I Pihak II
 d. Menjaga semua fasilitas yang diberikan oleh PIHAK. KESATU, baik
sarana prasarana pelayanan maupun non pelayanan (rumah dinas,
kendaraan operasional dan fasilitas lainnya)
e. Mematuhi semua peraturan yang berlaku di Rumah Sa.kitUmum Daerah
Anuntaloko Kabupaten Parigi Moutong, termasuk mengajukan surat izin
tertulis disertai alasan kepada PIHA.K KESATU jika akan meninggalkan
tempat tugas.
f. Menjaga narna baik institusi Rumah Sakit Umum Daerah Anuntaloko
Kabupaten Parigi Moutong dan Fakultas Kedokteran Universitas
Hasanuddin.
g. Melakukan monitoring, supervisi dan evaluasi melalui visitasi berkala
sesuai kebutuhan (minimal sekali dalam setahun), terdiri dari unsur
pimpinan Fakultas Kedokteran, pengelola PPDS Senior dan staf
adm:inistrasi.
h. Menyampaikan laporan dan rekomendasi untuk peningkatan kualitas
pelayanan rumah sakit kepada PIHAK KESATU.

Pasal 9
PEMANTAUAN DAN EVALUASI

(1) Pemantauan dan evaluasi dalarn pelaksanaan perjanjian ini dapat dilakukan
oleh PARA PIHAK secara tersendiri maupun bersama-sama sesuai dengan
kebutuhan dan kesepakatan bersama.
(2) Hasil pemantauan dan evaluasi disampaikan kepada PARA PIHAK untuk
penyempumaan pelayanan maupun peninjauan kembali perjanjian ini.
(3) Keberhasilan penyelenggaraan kerjasama dan pembinaan SOMpada Rumah
Sakit Umum Daerah Anuntaloko Kabupaten Parigi Moutong menjacli
tanggung jawab PIHAK KESATU dan pengawasan akademis dokter PPDS
Senior menjadi tanggung jawab PDIA.K KEDUA.

Pasal 10
PENYELESAIAN PERSELISIHAN

(1) Perselisihan yang timbul antara PARA PIHAK sebagai ak.ibat pelaksanaan
perjanjian kerja sama ini akan diselesaikan secara musyawarah untuk
mufakat.
(2)Apabila musyawarah mufakat sebagaimana dimaksud pada ayat ( 1) tidak
tercapai, maka kedua belah pihak bersepakat untuk menyelesaikan
perselisihan tersebut melalui panitia Arbitrase yang dibentuk oleh PARA
PIHAK.

Pasal 11
PERUBAHAN PERJANJIAN

Apabila terjadi perubahan materi dan a.tau ruang lingkup dalam perjanjian
kerjasama ini, maka akan dituangkan dalam adendum kontrak yang
ditandatangani oleh PARA PIHAK dan merupakan bagian yang tidak
terpisahkan dari perjanjian kerjasama ini.

Pihak I Pihak II
 Pasal 12
FORCE MAJEVR.E

(1) Yang dimaksud dengan force majeure adalah peristiwa yang terjadi di luar
kemampuan dan atau kekuasaan PARA PIHAK yang berakibat tidak dapat
dipenuhinya hak dan kewajiban PARA PIHAK. Peristiwa yang dimaksud
antara lain: gempa bumi, tsunami, angin topan, banjir bandang, kebakaran
besar, tanah longsor, wabah penyakit, pemogokan umum, huru-hara, perang
pemberontakan dan krisis moneter akibat terjadi inflasi, defisit anggaran,
belum tersedianya anggaran dan perubahan kebijakan lainnya dibidang
moneter.
(2) Apabila terjadi force majeure sebagaimana dimaksud ayat (1), maka PARA
PIHAK dibebaskan dari kewajiban-kewajiban seperti yang tercantum pada
Perjanjian Kerjasama ini.

Pasal 13
PERUTUP

Demikian Perjanjian Kerjasama ini dibuat dan ditandatangani oleh PARA

PIHAK dalam rangkap 2 (dua) asli, bermaterai cukup dan masing-masing
mempunyai kekuatan hukum yang sama bagi PARA PIHAK.

PIHAK KEDUA,

I' Prof, dr, B

U

Pihak I Pihak ll
 KEMENTERIAN KESEHATAN R.I
DIREKTORAT JENDERAL BINA UPAYA KESEHATAN
n·
RSUP. Dr. Wahidin SudirohusodoMakassar ~
Jalan !">0rintis Kemerdekaan Km. 11 Tamalar1rea Kode Pos 90245. Telp. (0411) 584675 - 581818, Fax. (0411).587676

i'lornor : HK.05.01/IV.3/252/2014 21 Januari 2014

t 181 : Salinan Perjanjian Kerjasama
FKUH-RSWS

Y JJ ng terhormat,
·J. Ketua Dewan Pengawas
2. Jajaran Direksi
3. Ketua SPI
4. Para Ketua SMF
5. Para Kepala lnstalasi
RSUP dr.Wahidin Sudirohusodo

Dalam rangka optimalisasi kerjasama antara RSUP dr. Wahidin Sudirohusodo

dengan Fakultas Kedokteran Universitas Hasanuddin sebagai salah satu faktor
pendukung upaya peningkatan kualitas pelayanan, pendidikan dan penelitian, maka
dengan ini kami sampaikan salinan perjanjian kerjasama dimaksud.
Demikian disampaikan, atas perhatian dan kerjasamanya diucapkan terima
kasih.
(2) Ruma~ Sa kit Umum Pusat Dr. Wahid in Sudtrohusodo Makassar,
yang selaruutnya dapat disingkat dengan RSWS, adalah. Ruman Sakit Urnurn
Pernerintah
y rig merupakan Unit Pelayanan Teknis Kementerian Kesehatan RI, dalam hal · i~i
berada dibawah Direktorat Jenderal Bina Upaya Kesehatan, yang mempuriyai fungsi
can peran penyelenggaraan pelayanan kesehatan kepada masyarakat dan
sebagai Rumah Sakit Pendidikan Utama bagi Fakultas Kedokteran Universitas
Hasanuddin
Makassar.
(3) Dekan FKUH adalah Pimpinan FKUHyang merupakan penanggung jawab
pelaksanaan pendidikan semua strata dibidang ilmu kedokteran dan keperawatan
dilingkungan FKUH dan bertanggung jawab langsung kepada Rektor Universitas
Hasanuddin
(4) Direktur Utama RSWS adalah pejabat structuraltertinggidiRSWSyang bertanggung
jawab atas pengelolaan RSWS, dan bertanggung jawab langsung kepada
Direktur Jenderal Bina Upaya Kesehatan Kementerian Kesehatan RI
(S) Oirektur di RSWS adalah unsur pimpinan RSWS yang membantu Direktur Utama
dalam menjalankan tugasnya , sesuai dengan bidang tugas masiiig-masing dan
bertanggung jawab kepada Direktur Utama ·
(6) Wakll Dekan FKUH adalah unsur pimpinan FKUH yang membantu Dekan dalam
nenjalankan tugasnya sesuai dengan bidang tugas masing-masing dan
bertanggungjawab kepada Dekan FKUH
(7) Komite Medis RSWS adalah organisasi non struktural yang merupakan perangkat
RSWS untuk menerapkan tatakelola klinis agar staf medis di RSWS terjaga
profesionalismenya dibentuk dan diangkat oleh Direktur Utama RSWS dan
bertanggungjawab kepada Direktur Utama RSWS
(8) Ketua Bagian adalah pejabat fungsional yang mempunyai tugas dan fungsi
membantu pimpinan FKUH dalam pelaksanaan pendidikan , penelitian dan
pengabdian masyarakat di lingkungcJn FKUH , dan bertanggung jawab kepada
Dekan FKUH.
(9) Ketua SMF adalah Pimpinan Staf Medis F ungsional disatu bidang keahlian.
KetuaI
SMI= dipilih dari antara anggota SMF melalui suatu pemilihan yang melibatkan
Direktur Utama RSWS dan Dekan FKUH,dengan persyaratan yang ditentukan
bersama oleh Direktur Utama RSWS dan Dekan FKUH.
(10) Ketua Program Studi adalah pejabat fungsional yang bertugas membantu Ketua
Bagian dalam mengendalikan dan melaksanakan pendidikan dilingkungan
FKUH
(11) Staf Medis Fungsional (SMF) adalah tenaga medis yaitu Dokter, Dokter Gigi,
Dokter Spesialis dan Dokter Gigi pesialis yang bekerja memberikan pelayanan
medis di RSWS
(12) lnstalasi adalah Unit pelayanan non struktural dengan fasilitas dan peralatan
untuk penyelenggaraan pelayanan medis, dan dapat dimanfaatkan untu'c
kepentingan

<Fl(S 'PJ(V'Jf-~VS 201~ 2

 PERJANJIAN KERJASAMA
FAKULTAS
KEDOKTf;RAN UNIVERSITA~ HASANUD.D.IN.
DEN GAN
RUMAH SAKIT UMUM PUSAT Dr.WAHIDIN SUDIROHUSODO MAKASSAR

Norn or FKUH -16/b /H.4.8/PM.05/2013

Norn or HK.05.01/Dirut.lV/ 816 /2013

Pada hari Rabu tanggal Tiga Betas bulan Maret tahun Dua Ribu Tiga Belas (13-03-
2013), kami yang bertanda tangan dibawah ini :

1. Prof.dr.lrawan Yusuf ,Ph.D

Dekan Fakultas Kedokteran Universitas Hasanuddin,dalam hal ini karena
jabatannya, bertindak untuk dan atas nama Fakultas Kedokteran Universitas
Hasanuddin Makassar, dan selanjutnya disebut sebagai PIHAK PE~TAMA.

2. Prof.dr.Abdul Kadir,Ph.D,Sp.THT-KL(K),MARS
Direktur Utama RSUP Dr.Wahidin Sudirohusodo Makassar. dalam hal ini karena
jabatannya, bertindak untuk dan atas nama Rumah Sakit Umum Pusat
Dr.Wahidin Sudirohusodo Makassar, dan selanjutnya disebut sebagai PIHAK
KE DUA.

Kedua belah pihak secara bersama-sama selanjutnya disebut sebagaiPARA

PIHAK.Dalam rangka peningkatan pelayanan kesehatan dan dalam rangka pendidikan
tenaga kesehatan professional di RSUP Dr.Wahidin Sudirohusodo Makassar, PARA
PIHAKbersepakat untuk saling mengikat diri dalam ikatan perjanjian kerjasama dengan
ketentuan sebagai berikut : ,

BAB I KETENTUAN
UMUM Pasal1

Dalam perjanjian kerjasama ini yang dimaksud dengan:

(1) Fakultas Kedokteran Universitas Hasanuddin, yang selanjutnya dapat disingkat
dengan FKUH, adalah lnstitusi Pendidikan Kedokteran dilingkungan Universitas
Hasanuddin Makassar, yang berfungsi sebagai tempat pendidikan, penelitian dan
pengabdian bagi peserta didik dan pendidk di FKUH.
 pendidikan dan penelitian. lnstalasi dipimpin oleh Kepala lnstalasi y~mg diangkat
<Jan diberhentikan oleh Direktur utarna RSWS .
(13) Cosen FKUH adalah tenaga pendidik dengan tugas untuk mendidik dan mengajar
,yang diangkat dan diberhentikan oleh Dekan FKUH. ·
(J.t!) )okter Pemblmbing Klinik adalah dokter organik Kementerian Kesehatan yang
diperbantukan sebagai dosen luar biasa/tenaga pendidik yang ditetapkan oleh
Dekan atas persetujuan Direktur Utama.
(15) Mahasiswa FKUH adalah peserta didik yang terdaftar dan belajar pada program
pendidikan di FKUH untuk semua strata baik dalam pendidikan dokter,dokter
spesialis/sub-spesialis, Keperawatan, Fisioterapi dan Kebidanan.
(16) Saranaadalah segala alat dan perlengkapan yang dimiliki ataupun diadakan oleh
para pihak, yang dipergunakan untuk penyelenggaraan tugas dan fungsi
pelayanan dan pendidikan di RSWS.
(17) Prasarana adalah gedung, bangunan beserta kelengkapannya di RSWS yang
dldirikan oleh pihak kedua ataupun pihak pertama , yang dipergunakan untuk
penyelenggaraan tugas dan fungsi pelayanan dan pendidikan.
(18) Bahan adalan segala bentuk bahan habis pakai yang diperqunakan untuk
penyelenggaraan tugas dan fungsi pelayanan dan pendidikan RSWS.

BAB II
DASAR, TUJUAN DAN STATUS
Pasal2
Dasar

Dasar hukum dari Perjanjian Kerjasama ini adalah :

(1) Kitab Undang Undang Hukum Perdata (KUHPer)

(2) Undang-Undang RI Nomor 29 tahun 2004 tentang Praktik Kedokteran
('?) Undang-Undang RI Nomor 36 tahun 2009· tentang Kesehatan
(4) Undang-Undang RI Nomor 44 tahun 2009 tentang Rumah Sakit
(S) Undang-Undang RI Nomor 8 tahun 1974 tentang Pokok pokok Kepegawaian
sebagaimana telah diubah dengan Undang-Undang RI Nomor 43 tahun 1999
tentang perubahan atas Undang-Undang Nomor 8 tahun 197 4.
(6) Undang Undang RI Nomor 20 tahun 2003 tentang Sistim Pendidikan Nasional
(7) Peraturan Pemerintah RI Nomor 53 tahun 201 o tentang Disiplin Pegawai Negeri
Sip ii
(8) Peraturan Pemerintah RI Nomor 32 tahun 1996 tentang Tenaga Kesehatan
(9) Peraturan Pemerintah RI Nomor 30 tahun 1990 tentang Pendidikan Tinggi
(10) Menteri Kesehatan RI Nomor 2052 tahun 2011 tentang Praktik
Peraturan
Kedokteran
 . aAB Ill
BENTUK KERJA SAMA
Pasal5
Ruang Lingkup Kerja Sama dan Pengorganisasian

(1) Ruang Ungkup Kerja Sama ini meliputi bidang Pelayanan, Pendidikan, Penelitian
dan Pengabdian Masyarakat yang dilaksanakan di RSWS melalui SMF dan
lnstalasi yang ada.
(2) Pengorganisasian Pelayanan, Pendidikan,Penelitian dan Pengabdian Masyarakat
oleh PARA PIHAK tetap mengacu pada kebijakan dan peraturan yang ditetapkan
oleh atasan PARA PIHAK.
(3) Jumlah dan Jenis SMF serta lnstalasi yang melaksanakan kegiatan di RSWS
ditetapkan oleh PIHAK KEDUA.
(4) Ketua SMF diangkat dan ditetapkan oleh Direktur Utama RSWS. setelah dipilih
rnelalui pemilihan di SMF masing-masing yang melibatkan PIHAK PERTAMA
dan PIHAK KEDUA dalam pemilihan dan penetapannya. Ketua Bagian dapat
menjadi Ketua SMF dengan persetujuan PARA PIHAK.
Masa kerja Ketua SMF adalah 4(empat) tahun
(5) Komite Medik RSWS dibentuk oleh PIHAK KEDUA
(6) Ketua dan anggota Komite Medik diangkat dan ditetapkan oleh PIHAK KEDUA,
dengan masa kerja 3(tiga tahun)
(7) Ketua SMF, Ketua Komite Medik bertanggung jawab kepada Direktur Utama RSWS.

Pasal6
Tugas Pokok dan Pengaturan Ketenagaan

(1) Tugas Pokok PIHAK PERTAMA adalah :

a. menyelenggarakan dan melaksanakan
• I
pendidikan dan penelitian
b. membantu menyediakan tenaga untuk penyelenggaraan pelayanan
kesehatan kepada masyarakat yang disslenggarakan oleh PIHAK KEDUA

(2) Tugas pokok PIHAK KEDUA adalah :

a. menyelenggarakan pelayanan kesehatan kepada masyarakat
b. membantu menyediakan tenaga, sarana dan prasarana yang diperlukan
untuk penyelenggaraan pendidikan yang diselenggarakan oleh PIHAK
PERTAMA

(3) Tenaga Medis yang dibutuhkan oleh PIHAK KEDUA atau yang disiapkan oleh
PIHAK PERTAMA untuk melakukan kegiatan di lingkungan PIHAK KEDUA, dapat
melaksanakan tugas pelayanan kesehatan dalam rangka pendidikan&
penelitiandi
(11) Peraturan Menteri Kesehatan RI Nomor 755. tahun 20~ 1 tentanq Penyelenqqsraan
L ') nite Medik di Rumah Sakit . .
(1..:.) I eputusan Menteri Kesehatan RI Nomor 1677 tahun 2005 tentang Struktur
Organisasi RSUP Dr.Wahidin Sudirohusodo Makassar
(L, putusan Menteri Kesehatan RI Nomor 1333 Tahun 1999 tentang Standar
1ayanan Rumah sakit

(14} Keputusan Menteri Kesehatan RI Nomor :1069 tahun 2008 tentang Pedoman
Klas1fikasi dan Standar Rumah Sakit Pendidikan
(15) Keputusan Bersama Menteri Kesehatan Rl,Menteri Pendidikan Nasional dan
Menteri Dalam Negeri RI Nomor : 544/Menkes/SKB/X/81, Nomor 0430 a/1981,
Nomor 324 A tahun 1981 tentang Pembagian tugas , tanggung Jawab dan
penetapan Prosedur sebagai Rumah Sakit Pemerintah yang digunakan untuk
pendidikan Dokter.

Pasal3
Tujuan

(1) Tujuan Umum dari Perjanjian Kerjasama ini adalah agar pemanfaatan dan
pendayagunaan RSWS untuk kegiatan pelayanan dan pendidikan berjalan secara
optimal demikian pula pemanfaatan dan pendayagunaan tenaga medis berjalan
secara harmonis dan efektif.
(2) Secara khusus tujuan dari Perjanpan Kerja Sama ini adalah untuk pengaturan
organisasi , personil, sarana dan prasarana , kegiatan dan pengelolaan dari para
pihak berjalan secara efektif dan efisien , untuk kepentingan peningkatan kualitas
pelayanan kesehatan dan pendidikan profesl di RSWS, agar sating
menguntungkan dan tidak merugikan kepentingan PARA PIHAK.

Pasal.,.4
Status dan Tanggung Jawab

(1) Perjanjian Kerja Sama ini sebagai Pedoman yang mengikat bagi para pihak
dalam penyelenggaraan pelayanan kesehatan dan pendidikan profesi di RSWS
(2) PIHAK PERTAMA melaksanakan kebijakan yang ditetapkan oleh Menteri
Pendidikan dan Rektor Universitas Hasanuddin, dan bertanggung jawab atas
pengelolaan pendidikan mahasiswa FKUH
(3) PIHAK KEDUA melaksanakan kebijakan yang ditetapkan Menteri Kesehatan dan
bertanggung jawab atas pengelolaan pelayanan di RSWS

<P'}(S <rl('l.JJ{-<J?S'I vs 2013 4

 lingkungan PIHAK KEDUA setelah rnendapat persetujuan dari PIHAK KEDUAsesuai
t eraturan, perundanq-undanqan dan ketentuan yc:na beriaku.
(4) Penugasan dan pemberhentian penugasan tenaga medis dari PIHAK PERTAMA
'1'"'9 ditugaskan di RSWS, ditetapkan oleh Direktur Utama RSWS setelah
terlebih dahulu dilakukan koordinasi PARA PIHAK.
(5) Pe ugasan dan pemberhentian penugasan tenaga medis dari PIHAK KEDUA di
Fl<'1JH, ditetapkan oleh Dekan FKUH setelah dilakukan koordinasi PARA PIHAK.
(6) Tenaga medis baik dari PIHAK PERTAMA maupun PIHAK KEDUA yang melakukan
pelayanan kesehatan di RSWS, harus memenuhi persyaratan sesuai peraturan
perundang-undangan yang ada dan setelah mendapat persetujuan dari Direktur
Utama RSWS
(7) Kebijakan tentang kebutuhan tenaga medis para pihak, direncanakan bersama
oleh PARA PIHAK sesuai dengan kewenangan dan kemampuan masing-masing
serta sesuai dengan peraturan perundang-undangan yang berlaku.

Pasat7
Wewenang

(1) PIHAK PERTAMA berwenang mengatur tenaga meets yang dalam tugas sebagai
per.didik mahasiswa FKUH pada berbagai strata pendidikan, serta tunduk pada
peraturan dan ketentuan FKUH.
(2) PIHAK KEDUA berwenang mengatur tenaga medis dalam tugas pelayanan
kesehatan, serta tunduk pada peraturan dan ketentuan RSWS
(3) PIHAK PERTAMA berwenang menetapkan persyaratan, cara dan metoda serta
penilaian pendidikan mahasiswa FKUH
(4) PIHAK KEDUA berwenang menetapkan persyaratan, cara dan metode penilaian
mutu pelayanan medis d! RSWS
(5 PIHAK PERTAMA berwenang memberikan penghargaan ataupun sanksi akademik
kepada tenaga yang melakukan tugas sebagai pendidik mahasiswa FKUH
(6) PIHAKKEDUA berwenang memberikan penghargaan ataupun sanksi administrative
kepada tenaga yang memberikan pelayanan kesehatan di RSWS

Pasal 8
Penggunaan dan pemanfaatan Sarana, Prasarana dan Bahan

(1) Sarana,Prasarana dan bahan yang dipergunakan dalam lingkup kerjasama ini
dapat berasal dari PIHAK PERTAMA, PIHAK KEDUA ataupun pihak lain
(2) PIHAK PERTAMA maupun PIHAK KEDUA berusaha melengkapi sarana dan
··, asarana yang diperlukan untuk tujuan pendidikan profesl · maupun untuk
pelayanan kesehatan kepada rnasyarakat
(3) Semua Sarana, prasarana dan bahan-bahan milik PIHAK PERTAMA yang
ditempatkan di RSWS terdaftar sebagai milik PIHAK PERTAMA . dengan
penggunaan dan pemeliharaannya baik untuk kepentingan pelayanan maupun
pendidikan, diatur atas kesepakatan PARA PIHAK .
(4) Pengadaan bahan untuk kepentingan peserta didik PIHAK PERTAMA, menjadi
tanggung jawab PIHAK PERTAMA, dan pengadaan bahan untuk kepentingan
pelayanan di RSWS menjadi tanggung jawab PIHAK KEDUA
(5) Pengadaan bahan untuk kepentingan penelitian menjadi tanggung jawab pihak yang
melakukan penelitian.

Pasal9
Penggunaan dan Operasionalisasi

(1) Semua prasarana, sarana maupun bahan yang digunakan dalam lingkup keriasarna,
digunakan untuk pengembangan dan peningkatan tugas dan fungsi masing-masing
(2) Sarana, prasarana dan bahar. milik Pihak PERTAMA yang digunakan untuk
kepentingan pelayanan di RSWS, menjadi tanggung jawab PIHAK KEDUA
(3) Sarana , prasarana dan bahan milik PIHAK KEDUA yang rligunakan untuk
kepentingan pendidikan FKUH. menjadi tanggung jawab PIHAK PERTAMA
(4) Semua kegiatan dan tindakan di RSWS yang menyangkut pendidikan dan
penelitian, yang menqqunakan tenaga, sarana ataupun prasarana baik dari PIHAK
PERTAMA maupun PIHAK KEDUA harus disetujui terlebih dahulu oleh PIHAK
KEDUA.
(5) Pengadaan dan penggunaan bahan habis pakai (obat dan alkes) untuk kepentingan
pelayanan di RSWS ditentukan o!eh manajemen RSWS

Pasal10
tnventasrisasi dan Pemeliharaan

(1) PIHAK PERTAMA maupun PIHAK KEDUA, membuat catatan, daftar dan melakukan
inventarisasi terhadap bahan, sarana maupun prasarana yang dimiliki oleh masing•
masing pihak secara terperinci
(2) Pemeliharaan sarana , prasarana maupun bahan yang digunakan dalam lingkup
kerjasama disepakati terlebih dahulu oleh PARA PIHAK
 Pasa!11
Fenyelenggarcian Pelididikar:, .

(1) Penyelenggaraan pendidikan bagi peserta didik FKUH di RSWS diatur dan diawasi
: ~lat·sanaannya berdasarkan ketentuan yang dibuat bersama oleh PARA PIHAK
(2) Penerimaan dan penempatan peserta didik di RSWS harus sepengetahuan PIHAK
KEDUA dengan memperhatikan ketentuan yang berlaku untuk Rumah Sakit
Pendidikan
(3) Peserta didik FKUH yang mengikuti pendidikan di RSWS, dalam tugas pelayanan
kesehatan harus mengikuti peraturan dan ketentuan yang berlaku di RSWS yang
ditetapkan oleh PIHAK KEDUA
(4) Pertanggung jawaban biaya yang timbul akibat proses pendidikan dari PIHAK
PERTAMA di RSWS, diatur dan disepakati bersama oleh PARA PIHAK.

Pasal 12
Penyelenggaraan Penelitian

(1) Semua penelitian yang dilakukan di RSWS harus mendapat persetujuan tertulis
dari PIHAK KEDUA
(2) Pelaksanaan penelitian hanya dapat dilakukan setelah mendapat persetujuan Etika
dari Komite Etik Penelitian FKUH.
(3) Hasil penelitian dilaporkan secara tertulis kepada PARA PIHAK
(4) Biaya yang ditimbulkan di RSWS akibat penyelenggaraan penelitian, ditanggung
oleh pihak peneliti

Pasal13
Penyelenggaraan Pengabdian Kepada Masyarakat
i

(1) Kegiatan pengabdian masyarakat diselenggarakan baik secara masing-masing

institusi maupun secara bersama-sama oleh PARA PIHAK
(2) Penggunaan sarana , prasarana dan bahan dari pihak Kedua baik oleh
PIHAK PERTAMA maupun PIHAK KEDUA untuk tujuan pengabdian masyarakat,
harus dengan persetujuan Pihak Kedua
(3) Penggunaan sarana, prasarana dan bahan dari PIHAK PERTAMA yang ada di
RSWS yang terdaftar sebagai inventaris PIHAK PERTAMA untuk tujuan
pengabdian masyarakat,harus mendapat persetujuan dari PIHAK PERTAMA
dan diketahui oleh PIHAK KEDUA.
 Pasal 14
Penyelenggaraan Pel&yanan Kesehatan ....,.;... .

(1) Kegiatan pelayanan kesehatan di RSWS meliputi kegiatan promotif,preventif,

k1...ratif dan rehabilitative, dan mencakup komponen pelayanan medik, penunjang
medik dan asuhan keperawatan
(2) Semua kegiatan penyelenggaraan pelayanan kesehatan dalam rangka pendidikan
oleh peserta didik FKUH diatur dengan peraturan dan ketentuan yang ditetapkan
bersama oleh PARA PIHAK dan tunduk pada peraturan dan ketentuan yang
berlaku di RSWS
(3) Penyelenggaraan pendidikan profesi di lingkungan RSWS berbasis dan
mengutamakan pelayanan

BAB IV ADMINISTRASI DAN

KEUANGAN Pasal15

(1) Segala kegiatan pelaksanaan fungsi RSWS yang berhubungan dengan

administrasi dan keuangan tunduk pada peraturan dan ketentuan pengelolaan
oleh PIHAK KEDUA
(2) Segala kegiatan pelaksanaan fungsi FKUH yang berhubungan dengan
administrasi dan keuangan tunduk pada peraturan dan ketentuan pengelolaan
oleh PIHAK PERTAMA
(3) Segala kegiatan yang dilakukan bersama oleh PARA PIHAK atau kegiatan dari
PIHAK PERTAMA di RSWS yang menghasilkan dana, maka admin!strasi dan
penggunaannyadiatur dengan kesepakatantertulis para pihak.

BAB·V
BADAN KOORDINASI KERJASAMA RSWS - FKUH
Pasal16

(1) Dalam rangka kelancaran jalannya pelaksanaa Kerjasama, menurut perjanjian

ini dibentuk suatu Sadan Koordinasi (Bakor) antara RSWS - FKUH untuk
melakukan monitoring dan evaluasi.
(2) Tugas Sadan Koordinasi Kerjasama adalah :
a. Mengumpulkan data untuk pelaksanaan sebagaimana mestinya
perjanjian ini.
b. Melakukan pemantauan pelaksanaan perjanjian ini.
c. Melaksanakan penilaian pelaksanaan serta usul perbaikan perjanjian ini.
 d. Melaporkan hasil kerjanya secara berkala kepada Direktur Utama dan
Dekar,.
e. Menentukan hal - hal lain yang terkait dengan pelayanan, pendidikan,
penelitian dan Kerjasama lainnya yang belum tertera dalam Perjanjian ini.
(3) Badan Koordinasi Kerjasama terdiri atas sekurang - kurangnya 7 (tujuh) orang,
sedikitnya 3 (tiga) orang yang ditunjuk oleh FKUH, 3 orang dari RSWS, dan 1
orang perwakilan Komite Medik.
(4) Badan Koordinasi bersidang sekurang - kurangnya sekali dalam dua bulan.
(5) Anggota Badan Koordinasi diangkat dan diberhentikan secara bersama oleh
Para Pihak.
(6) Semua Keputusan Sadan Koordinasi diambil berdasarkan musyawarah dan
mufakat, jika dengan musyawarah tidak dapat diambil keputusan, maka
keputusan harus diambil berdasarkan persetujuan sedikitnya 6 (enam) orang
anggota Sadan Koordinasi.
(7) Anggota Sadan Koordinasi terdiri dari unsur pimpinan, unsur .dari masing -
masing Pihak, unsur SMF dan Komite Medik, yaitu : .
a. Wakil FKUH yang bertanggungjawab pada bidang pendidikan
b. Wakil FKUH yang bertanggungjawab pada bidang SDM
c. Wakil FKUH yang bertanggungjawab pada bidang kerjasama
d. WakilRSWS yang bertanggungjawab pada bidang SDM & Pendidikan
e. WakilRSWS yang bertanggungjawab pada bidang Pelayanan Medik
f. WakilRSWS yang bertanggungjawab pada bidang kerjasama
g. Wakil Komite Medis

BAB VI
PENUTUP
Pasal17
Masa Berlakt:a Perjanjian

(1) Perjanjian Kerjasama ini berlaku selama 5 (lima) tahun terhitung sejak tanggal
ditetapkannya setelah mendapat persetujuan dari atasan PARAPIHAK
(2) Perjanjian bersama ini mengikat PARA PIHAK

Pasal18
Perubahan Perjanjian Kerjasama

(1) Apabila salah satu pihak berkehendak untuk merubah sebagian atau seluruh
materi perjanjian kerjasama ini, maka pihak yang bersangkutan harus
memberitahuan secara tertulis kepada pihak lainnya
(2) Pihak yar,g yang menghendaki perubahan perjanjan kerjasama mengirimkan
usulan perubahan perjanjian kerjasama .tersebut untuk-dibahas oleh .para 1,Jihak.
Pembahasan usulan perubahan dilaksanakan secara musyawarah
untuk mufakat.
(3) Perubahan atas usulan dilakukan selambat-lambatnya 3 (tiga) bulan setelah
usulan diajukan
(4) Perubahan Perjanjian Kerjasama harus dilakukan dalam hal apabila materi
Perjanjian Kerjasama ini bertentangan dengan Peraturan Perundangan yang
berlaku.
(5) Apabila terjadi perbedaan penafsiran atas Perjanjian Kerjasama ini maka para
pihak sepakat untuk melakukan musyawarah untuk mencapai mufakat.
(6) Hal-hal lain yang belum diatur dalam Perjanjian Kerjasama ini akan diatur dalam
keputusan atau petunjuk teknis lainnya yang ditetapkan oleh PARA PIHAK dan
merupakan bagian yang tak terpisahkan dari Perjanjian Kerjasama ini.

Ditetapkan di : MAK.ASSAR
Pada tanggal : 13 Maret 2013

P I HAK KEDUA
RSUP Dr.WAHIDIN SUDIROHUSODO
MAKASSAR

([>}(.J 'Fl(W-'RS'WS 2013 11

 '
.
•
~

, •
. I

PERJANJIAN KERJASAMA
ANTARA. ·
DffiEKTUR RS IBNU SINA YW-UMI MAKASSAR
DENG AN
FAKL11~TAS KEDOKTERAN lJNIVERSITAS HASA.~UDDIN MAKA.SSAR

NOMOR: 001/PEND/RS.IBSIN\\l-UMI/IX/2015
1'10MOR: 7327/UN4.7/PM.09/2015

Pada hari ini Rabu tanggal Tiga Puluh September tahun Dua Ribu Lima Belas, kami yang
bertanda tangan dibawah ini :

1. Dr. dr. H. Dwi Djoko Purnomo, MPH

Direktur RS IBNU SINA YW-lTMI Makassar dalam hat ini bertindak untuk dan atas
nama Rumah Sakit Ibnu Sina YW-UMI Makassar selanjutnya disebut PIHAK

PERT AMA

2. Prof. Dr. dr. Andi Asadul Islam, Sp.BS

•
Dekan Fakultas Kedokteran Universitas Hasanuddin Makassar bertindak atas nama
Fakultas Kedokteran Universitas Hasanuddin selanjutnya disebut PIHAK KEDUA

l\1ENIMBANG :
1. Bahwa RS IBNU SINA YW-UMI Makassar dan Fakultas Kedokteran Universitas
Hasanuddin adalah dua lembaga yang berbeda fungsi dan manajemen.
2. Bahwa RS IBNU SINA YW-UMl Makassar fungsi utamanya adalah
mernberikan pelayanan kesehatan yang bermutu dan terjangkau kepada masyarakat
terutama di Provinsi Sulawesi Selatan pada khususnya disamping fungsi
pendidikan dan
penelitian kesehatan.
3. Bahwa Fakultas Kedokteran Universitas Hasanuddinff'K UNHAS) fungsi utamanya
adalah melaksanakan kegiatan pendidikan bagi peserta didik FK UNHAS disamping
juga kegiatan penelitian dan pengabdian kepada masyarakat.
4. Bahwa dalam melaksanakan fungsinya kedua lembaga tersebut saling membutuhkan
satu dengan yang lain. RS IBNU SINA YW-UM1 perlu tenaga dokter yang
berkualitas dalam melaksanakan pelayanan yang bennutu kepada masyarakat, dan FK
UNHAS memerlukan sarana dan prasarana serta manajemen yang baik dalam
pelaksanaan pendidikan dan penelitian.
 •

• • . '
• • •
•

5. Banwa PIHAK PEllrl~AMA dan PTHAK KEDU.A harus mernikul kewajiban dan
tanggung jawab yang seimbang dan serasi dijiwai oleh semangat saling membantu
demi lancamya pelaksanaan tugas dan fungsi masing-masing.

MENGINGAT:
1. Undang-U11dang Nomor 29 Tahun 2004 tentang Praktek Kedokteran
2. Undang-Undang Nomor 23 Tahun 1992 tentang Kesehatan
3. Undang-Undang Nomor 2 Tahun 1989 tentang Sistem Pendidikan Nasional
4. Undang-Undang Nomor 20 Tahun 2003 Tentang Sistem Pendidikan Nasional
5. Peraturan Pemerintah Nomor 30 Tahun 1990 tentang Pendidikan Tinggi
6. SK Mendikbud Nomor : 109/M/1992 tentang kerjasama antar Perguruan Tinggi di

lembaga.
7. SK Menkes Nomor 436?Menkes/SK/Vl/l 993 tentang berlakunya standar pelayanan
rumah sakit dan standar pelayanan medis di rumah sakit.
8. Peraturan Menteri Kesehatan Nomor : 1419 tahu 2005 tentang Penyelenggaraan
Praktek Dokter dan Dokter Gigi.

MENY AT AKAN :
Bahwa dalam rangka peningkatan pelayanan kesehatan di RS IBNU SINA YW-UMI dan
dalam rangka pendidikan tenaga kesehatan profesional FK UNHAS, PIHAK PERT Alv1A dan
PIHAK KEDUA bersepakat untuk saling mengikat diri untuk bersama-sama mengupayakan
dan menyelenggarakan peningkatan pelayanan kesehatan kepada masyarakat dan
pelaksanaan pendidikan profesi dokter, dokter spesialis (Sp l ) dan dokter subspesialis (Sp2),
maka PIHAK PERT AMA dan PIHAK KEDUA secara bersama-sama:

MEMUTUSKAN :
Menetapkan ikatan kerjasama antar RS IBNU SINA YW-UMI Makassar dan Fakultas
Kedokteran Universitas Hasanuddin dengan ketentuan sebagai berikut :

PASAL 1
KETENTUAN UMUM
1. RS IBNU SINA YW-UMI Makassar adalah jejaring rumah sakit pendidikan
milik
Yayasan Wakaf Universitas Muslim Indonesia yang berkeduduka11 di Makassar,
' . • • \

•
•

mempunyai fungsi selain menyeienggarakan pelayanan kesehatan kepada masyarakat

juga digunakan sebagai jejaring rumah sakit pendidikan bagi sernua strata di bidang

ilmu kedokteran dan ilmu keperaweten.

2. fK UNHAS adalah fakultas kedokteran di lingkungan Universitas Hasanudddin di

Makassar yang mempunyai fungsi pendidikan, penelitian dan pengabdian bagi

pendidik dan peserta didik di FK UNHAS.

3. Direktur RS IBNU SINA YW-UMI adalah jabatan struktural tertinggi di rumah sakit
yang bertanggung jawab atas pengelolaan rumah sakit yang dipimpinnya.
4. Dekan FK UNHAS adalah penanggung jawab pelaksanaan pendidikan semua strata di
bidang ilmu kedokteran dan ilmu keperawatan di dalam lingkungan FK UNHAS.
5. Wakil Direktur RS IBNU SINA YW-UMI adalah unsur pimpinan yang membantu
direktur dalam menjalankan tugasnya sesuai dengan bidang masing-masing clan
bertanggung jawab kepada direktur.
6. Pembantu Dekan FK UNHAS adalah unsur pimpinan di FK UNHAS yang membantu
dekan dalam menjalankan tugasnya sesuai dengan bidang tugasnya masing-masing
dan bertanggung jawab kepada Dekan FK UNHAS.
7. Ketua Bagian dan Ketua Program Studi adalah pejabat fungsional yang bertanggung
jawab kepada Dekan FK UNHAS atas pelaksanaan pendidikan, penelitian dan

pengabd ian kepada masyarakat.

8. Dosen biasa/luar biasa FK UNHAS adalah tenaga pendidik yang khusus diangxat

dengan tugas mengajar/1nembimbing peserta didik di RS IBNU SINA.

9. Mahasiswa FK UNHAS yane terdiri dari mahasiswa program profesi dokter, program
pendidikan dokter spesialis dan program pendidikan dokter subspesialis adalah
peserta didik yang terdaftar dan belajar pada FK UNHAS untuk strata sebagai
berikut:
A. Program Profesi Dokter
Ilmu Penyakit Saraf '

llmu Penyakit Jiwa

Ilmu Kesehatan Anak

Ilmu Kesehatan Kulit dan Kelamin
Ilmu Penyakit Dalam
Ilmu Kebidanan dan Penyakit Kandungan
Ilrnu Bedah
 •

• • I •
'
•

Ilmu Anastesi
- Ilmu Kesehatan Masyarakat

B. Program Pendidikan Dokter Spesialis (SIJ 1)

Ilmu Penyakit Saraf
Ilmu Kedokteran Jiwa
llmu Kesehatan Anak
Ilmu Kesehatan Ku lit dan Kelamin
- Ilmu Penyakit Dalam
llmu Kardiologi
•
Ilmu Patologi Klinik
Ilmu Kebidanan dan Penyakit Kandungan
Ilmu Bedah
Ilmu Anastesi
Ilmu Penyakit THT
Ilmu Penyakit Mata

C. Program Pendidikan Dokter Subspesialis (Sp2)

Bedah : Digestif
- Bedah : Onkologi
Anastesi : Manajemen Nyeri
- Anastesi : Intensive Care
Penyakit Dalam : Ginjal Hipertensi
Penyakit Dalam : Hernatologi
Penyakit Dalam : Gastro Entero Hepatologi
Penyakit Dalam: Endokrin Metabolik
- Penyakit dalarn : Rheumatologi

•
 •

' • • •
•
•

PASAJ.J 2
MAKSUD DAN TUJUAN
Naskah kerjasama ini dimaksudkan untuk digunakan sebagai pedoman bagi pihak yang
terlibat dalam pelaksanaan kerjasama antara RS IBNU SINA YW-UMI Makassar dengan
Fakultas Kedokteran Universitas Hasanuddin.

Tujuan:
a. Memungkinkan para mahasiswa program profesi dokter, program profesi dokter
spesialis (Spl)dan subspesialis (Sp2) memperoleh pengalarnan dalam menangani
kasus-kasus penyakit sesuai dengan kompetensinya.
b. Memungkinkan penggunaan data medis RS IBNU SINA YW-UMI Makassar untuk

bahan penelitian,
c. Untuk pengembangan rumah sakit di masa depan dalam kerjasama pendidikan dan
pelayanan spesialis lainnya.

PASAL3
HAK DAN KEWAJIBAN PIHAK PERTAMA
PIHAK PERT AMA berhak dan berkewajiban :
a. Melaksanakan fungsi utarna pelayanan kesehatan kepada masyarakat dan membantu
menyediakan tenaga, sarana dan prasarana yang dibutuhkan untuk menyelenggarakan
pendidikan mahasiswa FK UN.HAS pada berbagai strata sesuai ruang lingkup
perjanj ian kerjasama ini.
b. Menetapkan jumlah mahasiswa program profesi dokter, program profesi dokter
spesialis (Sp 1) dan subspesialis (Sp2) sesuai kemampuan dan daya tampung lahan
yang ada.
c. Tenaga PTHAK PERTAMA yang dibutuhkan oleh PIHAK KEDUA ditugaskan
bekerja untuk keperluan FK UNHAS atas persetujuan bersama para pihak.
d. PIHAK PERT AMA dan PIHAK KEDUA melakukan koordinasi dalam menyediakan
prasarana dan sarans. yang dibutuhkan dalam rangka pelayanan kesehatan kepada
masyarakat, pendidikan klinis mahasiswa FK UNHAS dan penelitian kedokteran dan
kesehatan yang efektif, efisien dan berkualitas .

•
 •
.
•

•
• \ •
•

PASAL4
HAK DAN tcrw AJIBAN PIHAK KEDUA

PIHAK KEDUA berhak dan berkewajiban:

a. Melaksanakan pendidikan dan penelitian pada berbagai strata dan membantu
•

menyediakan tenaga )'ang dibutuhkan dalam rangka pelayanan kesehatan kepada

masyarakat sesuai ruang lingkup perjanjian kerjasama ini.
b. Memanfaatkan fasilitas/lahan praktek yang disediakan sesuai kebutuhan.
c. Menetapkan Dosen Pembimbing Klinik yang akan ditugaskan di RS IBNU SINA
YW-UMI Makassar setelah dibicarakan bersarna antara PIHAK PERT AMA dan
PIHAKKEDUA
d. Tenaga PIHAK KEDUA yang dibutuhkan oleh PIHAK PERTAMA ditugaskan
bekerja untuk keperluan RS IBNU SINA YW-UMI atas persetujuan para pihak.
e. Biaya yang timbul akibat proses pelaksanaan peserta didik PIHAK KEDUA di
RS IBNU SINA YW-UMI akan diatur oleh ketentuan bersama para pihak.

PASAL 5
TARIF PELA YANAN
Tarif pelayanan akan mengikuti clan menyesuaikan dengan tarif yang berlaku sesuai
dengan aturan di RS IBNU SINA YW-UMI Makassar

PASAL 6
JANGKA WAKTlJ PERJANJIAN
1. Perjanjian kerjasama ini berlaku sejak ditetapkan dan akan ditinjau kembali bila ada
usulan perubahan. Evaluasi pelaksanaan kerjasama ini akan dilakukan secara
periodik
setiap 3 (tiga) tahun sekali.
2. Perubahan isi kerjasama ini dapat dilakukan bila ada kesepakatan kedua belah pihak.

PASAL7
PERLINDUNGAN PESERTA DIDIK
Bila dalam masa tugasnya peserta didik mengalami masalah dalam bidang hukurn (mendapat
tuntutan/pidana oleh pasien) menyangkut resiko medik dan komplikasi medik maka Dokter

Pembimbing Klinik (DPK) dan pihak rumah sakit bertanggung jawab dalam menangani dan
menyelesaikan masalah tersebut.
 •
• • II. 1 •

• . '

PASAL6
PENUTUP
1. Perjanjian kerjasama ini dibuat dalam rangkap 2 (dua) dilengkapi dengan materai
cukup clan mempunyai kekuatan hukum yang sama untuk masing-masing PIHAK
PERTAMA dan PlliAK KEDUA
2. Segala sesuatu yang belum diatur dalam perjanjian ini atau perubahan yang
dipandang perlu oleh kedua belah pihak akan diatur lebih lanjut dalam
perjanjian tambaban (adendum) yang merupakan bagian yang tidak terpisahkan dari
perjanjian.

Ditetapkan di : Makassar
Pada tanggal : 30 September 2015

,,
(,

·~S IBNU SINA YW-UMI

PJ[HAK PERTAMA

SAK.SI-SAK.SI
TANDA l'ANGAN
NAMA

I. . . . . . . . . . . . . . .
1. Prof. dr. Rosdiana Natsir, Ph.D
.
Wakil Dekan I FK UNHAS

2. Prof. dr. Mansyur Arief, Ph.D,

2. . . . . . . . . .
SpPK(K)
J.,I -· •••••••••••••

Sekretaris KPPS FK UNHAS I

3 . •••• •• • ••••••••••••••••
3. cir. Anna Sari Dewi, SpOG
Wadir Pendidikan RS IBNU SINA YW-UMI
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 PERJANJIAN KERJASAMA
ANTARA
PEMERINTAH KABUPATEN
MOROWALI
PROVINSISULAWESITENGA
H DENGAN
FAKULTAS KEDOKTERANUNIVERSITAS HASANUDDIN MAKASSAR
TENTANG
PENYELENGGARAAN PELAYANAN KESEHATAN
MASYARAKAT
OLEH DOKTER PESERTA PROGRAM PENDIDIKAN DOKTER SPESIALIS
(PPDS)
DI RUMAH SAKIT UMUM DAERAHMOROWALIKABUPATEN MOROWALI

NOMOR 445/002.74/MOU/RSMW/2019
NOMOR 2548/UN4.6/LK09.01/2019

Pada hari ini Rabu Tanggal Dua Bulan JanuariTahun Dua Ribu Sembilan Belas,
kami yang bertanda tangan dibawah ini:

1. DRS. TASLIM
Adalah Bupati Morowali, yang diangkat berdasarkan Surat Keputusan Menteri
Dalam Negeri Nomor:131.72-5870 Tahun 2018 Pengangkatan Bupati Morowali
Provinsi Sulawesi Tengah,dalam hal ini bertindak untuk clan atas nama Pemerintah
Kabupaten Morowali yang berkedudukan di Jalan Trans Sulawesi,
Kornp.Perkantoran Bumi Fonuasingko - Bungku, selanjutnya disebut PIHAK
PERTAMA.

2. PROF. DR. BUDU, PH.D., SP.M.(K),M.MED.ED.,

Adalah Dekan Fakultas Kedokteran Universitas Hasanuddin lVIakassar, yang
diangkat berdasarkan Surat Keputusan Rektor Nomor :1317/UN4.l/KEP/2018
tanggal 28 Maret 2018, dalam hal ini bertindak untuk dan atas nama Fakultas
Kedokteran Universitas Hasanuddin, yang berkedudukan di Jalan Perintis
Kemerdekaan KM 10 Makassar 90245, selanjutnya disebut PIHAK KEDUA.

PIHAK PERTAMA dan PIHAK KEDUA selanjutnya secara bersama-sama disebut PARA
PIHAK terlebih dahulu menerangkan hal-hal sebagai berikut:
a. Bahwa PIHAK KEDUA merupakan Perguruan Tinggi Negeri yang berada di
Provinsi Sulawesi Selatan sebagai lembaga pendidikan sesuai dengan Tri
Dharma Perguruan Tinggi; dan
b. Bahwa PIHAK. PERTAMA merupakan penyelanggara urusan pemerintahan Kab.
Morowali menurut asas otonomi dan tugas pembantuan dengan prinsip otonomi
seluas-luasnya dan prinsip Negara kesatuan Republik Indonesia dengan
memperhatikan ketentuan dan peraturan sebagai berikut:

1. Undang-Undang Nomor 51 tahun 1999 tentang pembentukan Kabupaten Buol,

Kabupaten Morowali dan Kabupaten Banggai Kepulauan (Lembaran Negara
Republik Indonesia Tahun 1999 Nomor 1 79, Tambahan lembaran Negara
Republik Indonesia Nomor 3900) sebagaimana telah diubah dengan Undang-
Pihak I Pihak II
 Undang Nomor 11 Tahun 2000 tentang Perubahan Atas Undang-UndangNomor
51 Tahun 1999 tentang Pembentukan Kabupaten Buol,' Kabupaten Morowali
dan Kabupaten Banggai Kepulauan (Lembaran Negara Republik Indonesia
Tahun 2000 Nomor 78, Tambahan Lembaran Negara Republik Indonesia Nomor
3966);
2. Undang-Undang Nomor 20 Tahun 2003 tentang Sistem Pendidikan Nasional
(Lembaran Negara Republik Indonesia Tahun 2003 Nomor 78, Tambahan
Lembaran Negara Republik Indonesia Nomor 4301);
3. Undang-Undang Nomor 14 Tahun 2005 tentang Guru dan Dasen (Lembaran
Negara Republik Indonesia Tahun 2005 Nomor 157, Tambahan Lembaran
Negara Republik Indonesia Nomor 4586);
4. Undang-Undang Nomor ·12 Tahun 2012 tentang Pendidikan Tinggi (Lembaran
Negara Republik Indonesia Tahun 2012 Nomor 158);
5. Undang-UndangNomor 23 tahun 2014 tentang Pemerintahan Daerah
(Lembaran Negara Republik Indonesia Tahun 2014 Nomor 244,
TambahanLembaran Negara Republik Indonesia Nomor 5587) sebagaimana
telah diubah beberapa kali terakhir denganUndang-Undang Nomor 9 Tahun
2015 tentang Perubahan Kedua Atas Undang-Undang Nomor 23 Tahun 2014
tentang Pemerintahan Daerah (Lembaran Negara Republik Indonesia Tahun
2015 Nomor 58, TambahanLembaran Negara Republik Indonesia Nomor 5679);
6. Peraturan Pemerintah Nomor 50 tahun 2007 tentang Jenis dan Tarif
Penerimaan Negara Bukan Pajak Yang Berlaku Pada Badan Koordinasi Survei
Dan Pemetaan Nasional;
7. Peraturan Pemerintah Nomor 66 Tahun 2010 tentang Perubahan Atas
Peraturan Pemerintah Nomor 17 tahun 2010 tentang Pengelolaan dan
Penyelenggaraan Pendidikan (Lembaran Negara Republik Indonesia Tahun 2010
Nomor 112, Tambahan Lembaran Negara Republik Indonesia Nomor 5157);
8. Peraturan Pemerintah Nomor 4 Tahun 2014 ten tang Penyelenggaraan
Pendidikan Tinggi dan Pengelolaan Perguruan Tinggi;
9. Peraturan Menteri Dalam Negeri Nomor 22 Tahun 2009 tentang Petunjuk
Teknis Tata Cara KerjaSama Daerah;
10. Peraturan Menteri Dalam Negeri Nomor 23 Tahun 2009 tentang Tata Cara
Pembinaan dan Pengawasan Kerjasama Antar daerah;
11. Peraturan Menteri Pendidikan Nasional Nomor 20 Tahun 2011 ten tang
Penyelenggaraan Program Studi Di Luar Domisili Perguruan Tinggi (Berita
Negara Republik Indonesia Tahun 2011 Nomor 297);
12. Peraturan Menteri Pendidikan dan Kebudayaan Nomor 14 Tahun 2014 tentang
Kerja Sama Perguruan Tinggi.

Pihak I Pihak Il

.
·~
t
I
 PASAL 1
MAKSUD DAN TUJUAN

(1) Untuk menjamin ketersediaan sumber daya manusia {SDM) pelayanan kesehatan di
Rumah Sakit Umum Daerah (RSUD)Morowali.
(2) Untuk membantu kelancaran pelayanan kesehatan di RSUD Morowali.
(3) Untuk membantu perencanaan dan peningkatan kapasitas SDM kesehatan di RSUD
Morowali;dan
(4) Untuk pengembangan layanan TriDanna Perguruan Tinggi.

PASAL 2
LANDASAN KERJASAMA

Kerjasama dilandasi atas pertimbangan:

a. Keterbatasan tenaga medis yang bertugas di RSUD Morowali Kabupaten Morowali.
b. Keterbatasan sumber daya lokal yang handal dalam bidang kedokteran untuk
mendukung pembangunan di Kabupaten Morowali.
c. Pentingnya pengembangan dan peningkatan kualitas Sumber Daya Manusia
Kesehatan di Kabupaten Morowali.
d. Tuntutan kebutuhan masyarakat akan tersedianya pelayanan tenaga dokter
spesialis di RSUD MorowaliKabupaten Morowali.
e. Keberadaan Universitas Hasanuddin Makassar sebagai perguruan tinggi terbaik di
Kawasan Timur Indonesia dalam memperluas hubungan kerjasama diberbagai
bidang, baik dengan pemerintah daerah maupun swasta, atas dasar saling
menguntungkan PARAPIHAK;dan
f. Fakultas Kedokteran Universitas Hasanuddin Makassar sebagai penyelenggara
teknis Program Pendidikan Dokter Spesialis (PPDS) dibawah naungan Universitas
Hasanuddin Makassar.

PASAL3
RUANG LINGKUP KERJASAMA

Menyiapkan dan memberikan pelayanan kesehatandi RSUD Morowali.berupa tenaga

dokter PPDS yang sementara mengikuti program pendidikan pada Program Stucli Jlmu
Anestesi, Program Studi Dmu Kedokteran Jiwa, Program Studi llmu Kesehatan
Mata, dan Program Studi Ilmu Obsestri&Gynekologi dengan system monitoring dan
evaluasi berkesinambungan.

Pihak I Pihak ll
 PASAL 4
JANGKA WAKTU PELAKSANAAN

(I) Perjanjian kerjasama ini berlaku untuk jangka waktu 3 (tiga) tahun sejak
ditandatangani PARAPIHAK;dan
(2) Perjanjian kerjasama ini dapat diakhiri sebelum jangka waktu tersebut dalam ayat
(1), atas persetujuan PARAPIHAK,dengan ketentuan pemberitahuan disampaikan 3
(tiga) bulan sebelum perjanjian berakhir.

PASALS
PENDANAAN
JasaPenugasanDokter PPDS dan Tim Visitasi

Jasa penugasan dokter PPDS dan Tim Visitasi ditanggung oleh

PIHAKPERTAMAyang diatur sebagai berikut:
(1) Jasa penugasan dokter PPDS berupajasa insentif danjasa medik
a. Jasa insentif sebesar Rp 20.000.000,- /orang/bulan, termasuk pajak
b. Jasa medik akan diberikan dan diatur dengan kesepakatan PARAPIHAK.
c. Konsumsi makan dan minum 3 (tiga) kali sehari, biaya transportasi Makassar -
Kabupaten Morowali pergi pulang sebanyak 1 ( satu) kali, serta biaya listrik dan
PDAMselama bertugas; dan
d. Jasa Insentif dan jasa medik dokter PPDS dibayarkan secara langsung (LS) ke
rekening dokter PPDS yang melaksanakan pelayanan.
(2) Jasa kunjungan Tim Visitasi
a. Jasa vi.sitasi dibayarkan secara lumpsumRp 5.000.000,- per orang/hari bagi
Pimpinan Fakultas, Rp 4.500.000,- per orang/hari bagi pengelola PPDS dan Rp
4.000.000 per orang/hari bagi tenaga Administrasi, tidak termasuk pajak.
b. Biaya akomodasi, transportasiudara/darat/laut dan konsumsi selama
melaksanakan tugas visitasi yang besarannya ditetapkan berdasarkan ketentuan
pemerintah; dan
c. Insentif Tim Visitasi dibayarkan langsung oleh PIHAK PERTAMAkepada Tim
Visitasi berdasarkan penugasan pada saat melakukan kunjungan.

PASAL6
Institutional Fee

(1) Institutional fee adalah besaran dana yang dibebankan kepada PIHAK PERTAMA
untuk dibayarkan kepada PIHAK KEDUA atas kerjasama pelayanan di RSUD
Morowali Kabupaten Morowali.
(2) Besamya Institutional fee adalah5°/o dari besarnya insentif yang diterima oleh dokter
PPDS sebelum dipotong pajak, per orang per bulan; dan
(3) Institutional fee dibayarkan setiap 6 (enam) bulan, dan ditransfer ke rekening PlHAK
KEDUApada:
Bank BNI 46 Cabang Makassar
Atas nama Rektor UNHAS
Nomor rekening 009.899.0071
NPWP 00.415.588.3.801.000

Pihak I Pibak l1
 PASAL 7
Hak dan Kewajiban PIHAK PERTAMA

(1) Hak:
a. Menerima dokter PPDS untuk ditugaskan di RSUD Morowali Kabupaten
Morowali.
b. Mendapatkan pelayanan optimal sesuai kompetensi dokter PPDS selama
bertugas di RSUD MorowaliKabupaten Morowali.
c. Mengatur penugasan dokter PPDS secara internal selama masa bertugas.
d. Menyampaikan dan mengajukan permohonan untuk mengakhiri masa tugas
dokter PPDS; dan
e. Menerima kunjungan serta laporan visitasi dari PIHAKKEDUAuntuk
perbaikan mutu layanan yang berkelanjutan.

(2) Kewajiban:
a. Melakukan pembayaran sebagaimana diatur padaPasal (5) dan (6) secara tepat
wak.tu.
b. Menyediakan sarana dan prasarana kesehatan, obat-obatan dan fasilitas
kesehatan yang dibutuhkan untuk pelayanan dokter PPDS sesuai standar yang
berlak.u.
c. Menyediakan rumah tinggal beserta perabotnya dan kendaraan operasional bagi
dokter PPDS yang bertugas.
d. Memberikan perlindungan kesehatan, hukum, keselamatan dan keamanan
kepada dokter PPDS dan tim visitasi bila diperlukan selama menjalankan tugas;
dan
e. Merencanakan dan mempersiapkan dokter organik rumah sakit sebagai calon
tenaga dokter spesialis definitif.

PASAL 8
Hak dan Kewajiban PIHAK KEDUA

(1) Hak:
a. Memperoleh pembayaran sebagaimana diatur pada Pasal (5) dan (6) secara
tepat waktu.
b. Memanfaatkan sarana dan prasarana kesehatan, obat-obatan dan fasilitas
kesehatan yang dibutuhkan untuk pelayanan dokter PPDS sesuai standar yang
berlaku.
c. Memanfaatkan rumah tinggal beserta perabotnya dan kendaraan operasional
bagi dokter PPDS yang bertugas; dan
d. Memperoleh perlindungan kesehatan, hukum, keselamatan dan keamanan bila
diperlukan selama menjalankan tugas.

(2) Kewajiban:
a. Mengirimkan dokter PPDS dari program studi sesuai kesepakatan yang disertai
dengan dokumen yang masihberlaku.
b. Memberikan pelayanan kesehatan sesuai standar kompetensi sepanjang
didukung fasilitas yang memadai, dan atau berdasarkan standar dan prosedur
pelayanan kesehatan yang berlaku di RSUD MorowaliKabupaten Morowali.

Pihak I Pihak II
 c. Menjaga semua fasilitas yang diberikan oleh PIHAKPERTAMA,baik sarana
prasarana pelayanan maupun non pelayanan (rumah dinas, kendaraan
operasional dan fasilitas lainnya)
d. Memat uhi semua peraturan yang berlaku di RSUD termasuk
Morowali .
'
mengajukarrstn-at izin tertulis disertai alasan kepada PIHAK PERTAMAjika
akan meninggalkan tempat tugas.
e. Menjaga nama baik institusi RSUD MorowaliKabupaten Morowalidan Fak:ultas
Kedokteran Universitas Hasanuddin.
f. Melakukan monitoring dan evaluasi melalui visitasi berkala sesuai kebutuhan
(minimal sekali dalam setahun), terdiri dari unsur pimpinan Fakultas
Kedokteran, pengelola PPDS dan staf administrasi; dan
g. Menyampaikan laporan dan rekomendasi untuk peningkatan kualitas
pelayanan rumah sakit kepada PIHAK. PERTAMA.

PASAL9
PEMANTAUAN DAN EVALUASI

1. Pemantauan dan evaluasi dalam pelaksanaan perjanjian ini dapat dilakukan oleh
para PIHAKsecara tersendiri maupun bersama-sama sesuai dengan kebutuhan
dan kesepakatan bersama.
2. Hasil pemantauan dan evaluasi disampaikan kepada PARA PIHAK untuk
penyempumaan pelayanan maupun peninjauan kembali perjanjian ini; dan
3. Keberhasilan penyelenggaraan kerjasama dan pembinaan SDMpada RSUD
Morowali KabupatenMorowalimenjadi tanggung jawab PIHAK PERTAMAdan
pengawasan akademis dokter PPDS menjadi tanggungjawab PIHAKKEDUA.

PASAL 10
PENYELESAIAN PERSELISIHAN

(1) Perselisihan yang timbul antara PARAPIHAKsebagaiakibat pelaksanaan

perjanjian kerja sama ini akan diselesaikan secara musyawarah untuk mufakat; dan
(2) Apabila musyawarah mufakat sebagaimana dimaksud pada ayat (1) tidak tercapai,
maka kedua belah pihak bersepakat untuk menyelesaikan perselisihan tersebut
melalui panitia Arbitrase yang dibentuk oleh PARAPIHAK.

PASAL 11
PERUBAHAN PERJANJIAN

Apabila terjadi perubahan materi dan atau ruang lingkup dalam perjanjian kerjasama
ini, maka akan dituangk.an dalam adendum kontrak yang ditandatangani oleh PARA
PIHAKdan merupakan bagian yang tidak terpisahkan dari perjanjian kerjasama ini.

PASAL 12
FORCE MA.JEURE

1. Yang dimaksud dengan forcemajeure adalah peristiwa yang terjadi di luar

kemampuan dan atau kekuasaan PARA PIHAK yang berakibat tidak dapat
dipenuhinya hak dan kewajiban PARAPIHAK.Peristiwa yang dimaksud antara lain:
gempa bumi, tsunami, angin topan, banjir bandang, kebakaran besar, tanah
longsor, wabah penyakit, pemogokan umum, huru-hara, perang pemberontakan
dan krisis
PihakI Pihak IJ
 moneter akibat terjadi inflasi, defisit anggaran, belum tersedianya anggaran dan
perubahan kebijakan lainnya dibidang moneter; dan
2. Apabila terjadi forcemajeure sebagaimana dimaksud ayat (1), maka PARAPIHAK
dibebaskan dari kewajiban-kewajiban seperti yang tercantum pada Perjanjian
Kerjasama ini.

PASAL 13
PENUTUP

Demikian Perjanjian Kerjasama ini dibuat dan ditandatangani oleh PARAPIHAKdalam

rangkap 2 (dua) asli, bermaterai cukup dan masing-masing mempunyai kekuatan
hukumyang sama bagi PARAPIHAK.

PIHAK KEDUA,

BUDU, PH.D,SP.MtK),M.MED.ED. /1
Bupati Kabupaten Morowali an Fakultas Kedokteran Unhas tt.,.

Pihakl Pihakll

(
> t -
 CERTIFICATE OF COLLABORATION

Hereby we declare the coJlaboration between:

Full name: Takuro Furusawa, Ph.D

Position : Associate Professor
Affiliation: Department of Ecology and Environment, Graduate School of Asian and African Area S
tudies, Kyoto University
Address: Research Bldg. No. 2, Yoshida-Honmachi, Sakyo-ku, Kyoto 606-8501 JAPAN
As will be known as the FIRST PARTY

Altogether with

Full name: Prof. Andi Jayalangkara Tanra, MD, Ph.D

Position : Professor, Head of Department
Affiliation: Department of Psychiatry, Faculty of Medicine, Hasanuddin University
Address Perintis Kemerdekaan Rd. Km. 11, Tamalanrea, RSP Bldg 5th Floor, Makassar, lNDON
ESIA
As will be known as the SECOND PARTY

The detail of collaboration:

Type Joint research collaboration
Theme Genetic epidemiology of mental disorder in Indonesia
Duration : April 2016 - March 2019

Thank you for your kindly understanding and cooperation

Takuro Furusawa Kyoto, 16th April 2018,

m.
;= 6'06-8501 Ji( ~ a EH*
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(~ftWF~2~ffil)
tl*fk'ffl7~7'779tJJ& .1\·
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illii!l~i
 'w JitffB:*~
Graduate School of Asian and African Area Studies
Kyoto University KYOTO UNIVERSITY

Research Bldg. No. 2, Yoshida-Honmachl, Sakyo-ku, Kyoto 606-8501

JAPAN DrTakuro Furusawa (Tel: +81·75-753-7835/Fax: +81-75-753-7834)

CERTIFICATE OF COLLABORATION
Hereby we declare the collaboration between:

Full name: Takuro Furusawa, Ph.D

Position : Associate Professor
Affiliation: Department of Ecology and Environment, Graduate School of Asian and African Area S
tudies, Kyoto University
Address: Research Bldg. No. 2, Yoshida-Honmachi, Sakyo-ku, Kyoto 606-8501 JAPAN
As wiJI be known as the FIRST PARTY

Altogether with

Full name: Prof. Andi Jayalangkara Tanra, MD, Ph.D

Position : Professor, Head of Department
Affiliation: Department of Psychiatry, Faculty of Medicine, Hasanuddin University
Address : Perintis Kemerdekaan Rd. Km. 11, Tamalanrea, RSP Bldg 5th Floor, Makassar, INDON
ESIA
As will be known as the SECOND PARTY

The detail of collaboration:

Type Joint research collaboration
Theme Genetic epidemiology of mental disorder in Indonesia
Duration : April 2016 - March 2019

Thank you for your kindly understanding and cooperation

lnternational Joint Research Network

I Kyoto U I Hasanuddin U I

•
J

if?'

Official Approval of Joint Research

iiij@.jii Experiment Social Psychological Scale

Coping with Contemporary Health Issues in Indonesia

Increase of Depression and Mental Stresses

Cii&·Si Society and Cu ltmc Westernization of Society

Further International Academic Network Further Projects for Indonesian Issues

 Dokumentasi Kuliah Tamu Psikiatri Anak dan Remaja oleh Dr.dr.Veranita
Pandia,Sp.KJ(K),M.Kes dan Psikiatri Adiksi oleh dr. Luh Nyoman Alit Aryani,Sp.Kj(K)
22 Februari 2019
Dokumentasi Visiting Lecture by Prof. Anthony Albert Grace,Ph.D (Department of Neuroscience,
University of Pittsburgh)

03 Maret 2019
Dokumentasi Special Lecture by Prof.Masatoshi Inagaki (Shimane University) Sucide Prevention Among
Patients Admitted to Emergency Departments for Suicidal Behavior

07 Agustus 2019
Dokumentasi Kuliah Tamu “Terapi Realitas pada Depresi” oleh Dr. dr. Gusti Ayu Maharatih, Sp.KJ (K),
M.Kes

21 Agustus 2019
Dokumentasi Workshop Psikoterapi Dinamik oleh dr. Sylvia D.Elvira, Sp.KJ(K) dan dr.Petrin Redayani
8-9 Februari 2020
Dokumentasi Peserta, Psychiatry update on depression and bipolar disorder
NTB, September 2020
Peserta, bimbingan teknis pengukuran tingkat kesiapan inovasi bagi para peneliti UNHAS
Dokumentasi Penguji, NBE FK UGM Yogyakarta
Agustus 2020
Dokumentasi Penguji NBE

Bandung, 2020
Dokumentasi NBE FK USU
28 Januari 2020
Dokumentasi Menjaga Kesehatan Mental Anak Selama Pembelajaran Jarak Jauh Dimasa Pandemi
20 Oktober 2020
Dokumentasi pemateri mendidik anak dengan baik, banar dan menyenangkan sekolah Islam Athirah
9 Oktober 2020
Pengabdian Masyarakat, Pemateri ADHD
24 Agustus 2020
Pengabdian Masyarakat, Pemateri Membantu
anak menumbuhkan kepercayaan dirinya
29 Juni 2020
 Dokumentasi Pemateri Cara cepat
memarahi anak saat mereka berbuat salah

6 Juli 2020
Dokumentasi Membangun Kedekatan dengan Anak

18 Mei 2020
Dokumentasi Pengabdian Masyarakat, Pemateri Mengatasi
anak usia sekolah yang masih mengompol

11 Mei 2020
Dokumentasi Mengatur Jadwal Kegiatan Anak Selama di Rumah

4 Mei 2020
Dokumentasi Pemateri, Mengatasi anak yang selalu konsumtif
22 Juni 2020
Dokumentasi Cara tepat Membantu Anak dengan Bipolar Disorder

31 Agustus 2020
Seminar Edukasi-Kohati 2019; Komisariat kedokteran gigi universitas hasanuddin,
november 2019
Dokumentasi Pengabdian Masyarakat, Deteksi Dini gangguan jiwa dan NAPZA
2019
 i :
a Diber kan Kepada
•
dr. Erlyn Limoa, Ph.D, Sp.l(J
Atas Partisipas i nya Sebagai:

bekerja 1ama dengan

Perhlmpunan Dolder Speslalls Kedokteran Jlwa Indonesia
(PDSKJI) Cabang Makassar
~ Scanned with CamScanne
Dokumentasi Juri Konas IX PDSKJI

Balikpapan 24-27 Oktober 2019

 2·1 27 Oktober 201<1
Hote l Gr.,n Senviur B 1l1kpapAn

D t beri kan kepada:

dr. Erlyn Limoa, SpKJ, Ph.D

sebagai:

JURI
RESEARCH AWARD

PEHRTA: 15SKP, PEMBICARA: 12 SKP, MODERATOR:• SKP, PANITIA: 2 SKP

SK PB IOI N0:10IOIPB/A.'11012018

!cs] Scanned with CamScanner

Dokumentasi Pemateri, Sumbangsih dan bakti dalam penyuluhan mental pada kaum muda
lewat ceramah di GKY Palopo SULSEL
9 Desember 2019
Dokumentasi Panitia, Konas IX PDSKJI sebagai Panitia Simposium
24-27 Oktober 2019
 Tema Penelitian : Penyakit Non Infeksi

USULAN PENELITIAN
PENELITIAN DASAR UNHAS
TAHUN 2020

HUBUNGAN ANTARA POLIMORFISME GEN RESEPTOR CATHECOL-O-

METHYL TRANSFERASE (COMT) VAL158MET DENGAN RESPON TERAPI
DAN FUNGSI KOGNITIF PASIEN SKIZOFRENIA YANG MENDAPATKAN
TERAPI RISPERIDON

TIM PENGUSUL
Dr. dr Saidah Syamsuddin, SpKJ NIDN: 0014017005 (Ketua)
dr. Erlyn Limoa, Ph.D, Sp.KJ NIDN: 0017117705 (Anggota 1) dr.
Tri Anny Rakhmawati (Anggota 2)
dr. Ahyani Muslimin (Anggota 3)

FAKULTAS KEDOKTERAN
UNIVERSITAS HASANUDDIN
MAKASSAR
2020
 HAI.AMAN PENGESA HAN

Judul Penelitiaa : Hubungan Amara Polimorfisme Gen Reseptor Cat:heool-0-Methyl

Transferase (COMT) VallS8Met Dengan Respon Terapi Dan
Fu:ngsi Kognitif Pasiea Skizofrenia Yang Mendapatkan Terapi
Risperidon
Tema Penelitian : Peayakit Non lnfeksi
Output Penelitian : Publikasi Jumal International Bereputasi
Ketua Peneliti
a. Nama Lengkap : Dr. dr. Saidah Syamsuddin, Sp.KJ
b. Jenis Kelarnin : Perempuan
c. NIDN : 0014017005
d. Jabatan Fungsional : Lektor Kepala
e. Jabatan Struktural : Kepala Program Studi Departemen llmu Kedokteran Jiwa
f. Telpon/ email
Anggota Peneliti 1
-
: 08114104876 / 1Jic,, am70u tpuiiil.wu1

a. Nania Lengkap ; dr. Erlyn Limoa, Pb.D, Sp.KJ

b. Jenis Kelamin : Perempuan
c. NIDN : 0017117705
d. Jabatan Fungsional : Asisten Ahli
e. Jabatan Struktural : Sekretaris Program Studi Departemen Ilrnu Kedokteran Jiwa
f. Telpon f email : 085299277779 / t:rh 1tfi1:1ll I i Cl l!llli:Ul .l:0111
Anggota Peneliti 2
a. Nama Leugkap . dr. Tri Anny Raklunawaii
b. Jellis Kelamin : Perempuan
c. NIDN
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa
e, Telpon f email : 085348849040 I AnnyC'liimouLl1 ct wua1l.1:orn
Anggota J>eneliti 3
a. Nama Leugkap . dr. Ahyani Musliiuin
b. Jenis Kelamin : Perempuan
c. NIDN
d. Jabatan : Mab:asiswa Sp- I Deparremen Ilmu Kedoktera:n Jiwa
e. Telpon I email : 08114444825 / aJ1ya111mu:,l11nin;u 1una1l 1.:om
 IDENTITAS DAN URAIAN UMUM

1. Judul Penelitian : Hubungan Antara Polimorfisme Gen Reseptor Cathecol-O-Methyl

Transferase (COMT) Val158met Dengan Respon Terapi Dan
Fungsi Kognitif Pasien Skizofrenia Yang Mendapatkan Terapi
Risperidon
2. Tim Peneliti
Bidang Instansi Alokasi Waktu
No Nama Jabatan
Keahlian Asal (jam/minggu)
1. Dr. dr Saidah Syamsuddin, Sp.KJ Ketua Psikiatri
Unhas 30
Biologi
2. dr. Erlyn Limoa, Ph.D, Sp.KJ Anggota 1 Psikiatri
Unhas 25
Biologi
3. dr. Tri Anny Rakhmawati Anggota 2 Psikiatri Unhas 20
4. dr. Ahyani Muslimin Anggota 3 Psikiatri Unhas 20

3. Objek Penelitian : Manusia

4. Masa Pelaksanaan :
Mulai : Bulan Maret, Tahun 2020
Berakhir : Bulan Desember, Tahun 2020
5. Usulan Biaya Universitas Hasanuddin : Rp 100.000.000,-
6. Lokasi Penelitian : RS Wahidin Sudirohusudo dan jejaringnya
7. Instansi lain yang terlibat :-
8. Temuan yang ditargetkan :
Mengetahui peranan gen pada respon pengobatan pada pasien skizofrenia
9. Konstribusi mendasar pada suatu bidang ilmu :
Penemuan etiologi dan patofisiologi skizofrenia penting untuk memberi arah
pengobatan rasional. Sejumlah peneliti memperkirakan keberagaman genetik
mendasari gambaran klinis dan hasil terapi skizofrenia.
10. Jurnal Ilmiah yang menjadi sasaran :
Schizophrenia Research and Treatment
11. Rencana luaran :
Under reviewed Jurnal Internasional Bereputasi tahun 2020 dan publikasi Jurnal
Internasional Bereputasi tahun 2021.
 DAFTAR ISI

Halaman Pengesahan

Identitas dan Uraian Umum

Ringkasan

Bab 1. Pendahuluan 1

Bab 2. Renstra dan Peta Jalan Penelitian Perguruan Tinggi 4

Bab 3. Tinjauan Pustaka 5

Bab 4. Metode Penelitian 10

Bab 5. Biaya dan Jadwal Penelitian 13

Daftar Pustaka 16

Lampiran
RINGKASAN

HUBUNGAN ANTARA POLIMORFISME GEN RESEPTOR CATHECOL-O-

METHYL TRANSFERASE (COMT) VAL158MET DENGAN RESPON TERAPI
DAN FUNGSI KOGNITIF PASIEN SKIZOFRENIA YANG MENDAPATKAN
TERAPI RISPERIDON

Skizofrenia termasuk dalam 10 besar penyakit yang menyebabkan disabilitas pada orang
dewasa muda dan produktif. Pengobatan penyakit skizofrenia saat ini dapat dilakukan
dengan obat antipsikotik. Faktor genetik dipercaya dapat mempengaruhi respon pemberian
antipsikotik. Setiap polimorfisme yang terjadi pada gen-gen dapat memberikan efek klinis
dan respon pengobatan yang berbeda pada penyakit skizofrenia. Penelitian sebelumnya
menunjukkan adanya polimorfisme gen reseptor Dopamine D2 Reseptor (DRD2),
Dopamine Transporter (DAT) dan reseptor Serotonin (5-HT2A) mempunyai hubungan
dengan respon terapi.
Jenis penelitian ini merupakan penelitian case control dengan pendekatan kohort prospektif
Penelitian ini dilakukan di Rumah Sakit Wahidin Sudirohusodo dan jejaringnya pada bulan
Maret 2020 sampai Desember 2020. Sebanyak 100 pasien didiagnosis skizofrenia
berdasarkan DSM V dengan onset gejala ≥ 6 bulan berusia 20 – 45 tahun, dirawat inap di
rumah sakit ≥1 bulan dan mendapatkan terapi risperidon dan 100 orang orang sehat
sebagai kontrol dilakukan pemeriksaan darah untuk melihat polimorfisme gen reseptor
COMT Val158Met dan dilakukan penilaian respon terapi dengan skala PANSS dan CGI
pada awal masuk UGD, minggu 1,2,3,4 dan fungsi kognitif dengan skala MOCA-Ina pada
minggu 2, 3 dan 4. Menghubungkan polimorfisme gen reseptor COMT Val158Met pasien
skizofrenia dengan respon terapi dan fungsi kognitif pada kelompok skizofrenia yang
mendapat risperidon.
Tujuan penelitian untuk melihat adanya hubungan polimorfisme gen reseptor COMT
Val158Met dengan respon terapi dan fungsi kognitif pasien skizofrenia yang mendapat
terapi risperidon.
Hasil penelitian berupa artikel ilmiah yang dapat memperkaya ilmu pengetahuan dan akan
dibawakan pada acara ilmiah tingkat nasional dan akan dimuat di jurnal internasional yang
bereputasi.

Keyword : Skizofrenia, Risperidon, COMT Val158Met, fungsi kognitif, respon terapi

 Tema Penelitian : Penyakit Non Infeksi

USULAN PENELITIAN
PENELITIAN DASAR UNHAS
TAHUN 2020

ANALISIS HUBUNGAN ANTARA POLIMORFISME GEN RESEPTOR

CATHECOL-O-METHYL TRANSFERASE (COMT) rs740603 DAN rs4818
DENGAN SKIZOFRENIA YANG DALAM POPULASI MASYARAKAT TORAJA

TIM PENGUSUL
Dr. dr Sonny T.Lisal, SpKJ NIDN: 0016066701 (Ketua)
Prof.dr. A.Jayalangkara Tanra, Ph.D, Sp.KJ(K) NIDN: 0021015602 (Anggota 1)
dr. Santiwati Anda (Anggota 2)
dr. Otto Parandangi (Anggota 3)

FAKULTAS KEDOKTERAN
UNIVERSITAS HASANUDDIN
MAKASSAR
2020
 HALAMAN PENGESAHAN

Judul Penelitian : Analisis Hubungan Antara Polimorfisme Gen Reseptor Cathecol-

O-Methyl Transferase (COMT) rs740603 dan rs4818 Dengan
Skizofrenia Yang Diwariskan Dalam Populasi Masyarakat Toraja
Tema Penelitian : Penyakit Non Infeksi
Output Penelitian : Publikasi Jurnal International Bereputasi
Ketua Peneliti
a. Nama Lengkap : Dr. dr. Sonny T.Lisal, Sp.KJ
b. Jenis Kelamin : Laki-Laki
c. NIDN : 0016066701
d. Jabatan Fungsional : Lektor Kepala
e. Jabatan Struktural : Kepala Departemen Ilmu Kedokteran Jiwa
f. Telpon/ email : 0811414868 / stlisal@gmail.com
Anggota Peneliti 1
a. Nama Lengkap : Prof.dr. A.Jayalangkara Tanra, Ph.D, Sp.KJ(K)
b. Jenis Kelamin : Laki-Laki
c. NIDN : 00210156602
d. Jabatan Fungsional : Lektor kepala
e. Jabatan Struktural : Dosen Program Studi Departemen Ilmu Kedokteran Jiwa
f. Telpon / email : 08164388981 / ajtanra@yahoo.com
Anggota Peneliti 2
a. Nama Lengkap : dr. Santiwati Anda
b. Jenis Kelamin : Perempuan
c. NIDN :-
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa
e. Telpon / email : 08114094797/ sanwagf97@yahoo.com
Anggota Peneliti 3
a. Nama Lengkap : dr. Otto Parandangi
b. Jenis Kelamin : Laki-Laki
c. NIDN :-
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa
e. Telpon / email : 08114447858 / otto_parandangi@yahoo.com

Waktu Penelitian : Maret 2020 – Desember 2020

Biaya Diusulkan ke Unhas : Rp 100.000.000,-

Makassar, 14 Januari 2020

Mengetahui, Ketua Peneliti

Dekan Fakultas Kedokteran

Prof. dr. Budu, Ph.D, Sp.M (K)K, M.Med.Ed Dr. dr. Sonny T.Lisal, Sp.KJ
NIP. 196612311995031009 NIP. 196706161995031001

Menyetujui,
Ketua Lembaga Penelitian dan Pengabdian Masyarakat

Prof. Dr. Andi Alimuddin, M.Si

NIP. 196208181987021001
 IDENTITAS DAN URAIAN UMUM

1. Judul Penelitian : Analisis Hubungan Antara Polimorfisme Gen Reseptor Cathecol-

O-Methyl Transferase (COMT) rs740603 dan rs4818 Dengan
Skizofrenia Yang Diwariskan Dalam Populasi Masyarakat Toraja
2. Tim Peneliti
Bidang Instansi Alokasi Waktu
No Nama Jabatan
Keahlian Asal (jam/minggu)
1. Dr. dr Sonny T.Lisal, Sp.KJ Ketua Psikiatri
Unhas 30
Biologi
2. Prof.dr. A. Jayalangkara Tanra, Anggota 1 Psikiatri
Unhas 30
Ph.D, Sp.KJ (K) Biologi
3. dr. Santiwati Anda Anggota 2 Psikiatri Unhas 30
4. dr. Otto Parandangi Anggota 3 Psikiatri Unhas 30

3. Objek Penelitian : Manusia

4. Masa Pelaksanaan :
Mulai : Bulan Maret, Tahun 2020
Berakhir : Bulan Desember, Tahun 2020
5. Usulan Biaya Universitas Hasanuddin : Rp 100.000.000,-
6. Lokasi Penelitian : RS Wahidin Sudirohusudo dan jejaringnya
7. Instansi lain yang terlibat :-
8. Temuan yang ditargetkan :
Mengetahui peranan gen pada pasien skizofrenia
9. Konstribusi mendasar pada suatu bidang ilmu :
Penemuan hubungan gen COMT dengan skizofrenia pada suatu populasi membantu
peneliti memperkirakan keberagaman genetik mendasari gambaran klinis skizofrenia.
10. Jurnal Ilmiah yang menjadi sasaran :
Neuropsychiatry (London)
11. Rencana luaran :
Publikasi Jurnal Internasional Bereputasi tahun 2021
 DAFTAR ISI

Halaman Pengesahan
Identitas dan Uraian Umum
Ringkasan
Bab 1. Pendahuluan 1
Bab 2. Renstra dan Peta Jalan Penelitian Perguruan Tinggi 4
Bab 3. Tinjauan Pustaka 5
Bab 4. Metode Penelitian 10
Bab 5. Biaya dan Jadwal Penelitian 13
Daftar Pustaka 16
Lampiran
 ANALISIS HUBUNGAN ANTARA POLIMORFISME GEN RESEPTOR
CATHECOL-O-METHYL TRANSFERASE (COMT) (rs740603 dan rs4818)
DENGAN SKIZOFRENIA YANG DIWARISKAN DALAM POPULASI
MASYARAKAT TORAJA

Skizofrenia adalah penyakit kompleks yang diderita 1% dari populasi dunia, sehingga
diperlukan usaha yang cukup besar untuk mengidentifikasi gen yang rentan terhadap
penyakit ini. Beberapa bukti menunjukkan bahwa Catechol-O-methyltransferase (COMT)
sebagai gen utama yang menujukkan kerentanan skizofrenia, bukan hanya karena
mengkodekan kunci dopamine enzim katabolik tetapi juga karena memetakan letak
sindrom velocardiofacial dari kromosom 22q11, yang telah lama dikaitkan dengan
kecenderungan penyakit. Beberapa studi kasus-kontrol dan berbasis keluarga telah
dilakukan untuk memeriksa kemungkinan hubungan COMT dengan gangguan ini; Namun,
penelitian ini telah menghasilkan hasil yang saling bertentangan.
Gen yang mengkode Catechol O-methyltransferase (COMT), enzim katabolik dopamin,
memiliki keterkaitan yang tidak konsisten dengan skizofrenia meskipun terdapat bukti
yang konsisten dengan disfungsi dopaminergik di korteks prefrontal (PFC) dari
skizofrenia. Hal tersebut mungkin akibat heterogenitas genetik, penelitian ini menyelidiki
apakah gen COMT itu terkait dengan perkembangan dan gejala skizofrenia secara genetis
relatif pasien skizofrenia yang diwariskan dalam populasi masyarakat Toraja. Kami
menganalisis dua polimorfisme (rs740603 dan rs4818) dari gen COMT dalam studi kasus-
kontrol dari 200 pasien (100 pasien skizofrenia yang diturunkkan dan 100 pasien control
yaitu skizofrenia yang tidak ada turunan). Psikopatologi pasien dinilai menggunakan
Sindrom Positif dan Negatif Skala (PANSS). Kami tidak menemukan perbedaan signifikan
dalam genotipe rs740603 dan rs4818 dan distribusi alel antara pasien dan kelompok
kontrol. Analisis sifat kuantitatif oleh Program UNPHASED menunjukkan bahwa
haplotype rs740603 dan rs740603 (G) -rs4818 (G) adalah terkait dengan gejala negatif
pada pasien skizofrenia, terutama di kalangan pasien wanita. Dengan demikian,
polimorfisme gen COMT mungkin tidak berkontribusi terhadap kerentanan terhadap
skizofrenia, tetapi dapat berkontribusi pada gejala skizofrenia negatif di antara populasi
suku Toraja.
Jenis penelitian ini merupakan penelitian case control dengan pendekatan kohort prospektif
Penelitian ini dilakukan rumah singgah Sangalla Tana Toraja pada bulan Maret 2020
sampai Mei 2020. Populasi penelitian ini adalah pasien skizofrenia yang diturunkan di
Kab. Tana Toraja 100 orang dan pasien skizofrenia yang menjalani rawat inap di Rumah
Sakit Wahidin Sudirohusodo jejaringnya 100 orang (control) yang secara sukarela ikut
dalam penelitian ini. Sampel pada penelitian adalah pasien skizofrenia yang menjalani
rawat inap di Rumah Sakit Wahidin Sudirohusodo dan jejaringnya yang memenuhi kriteria
inklusi dan ekslusi. Sampel diambil mulai bulan Januari 2020 sampai dangan Maret 2020
dengan cara Consecutive Sampling, yaitu semua pasien yang memenuhi kriteria penelitian
sampai sampel yang diperlukan terpenuhi.
Melakukan pengambilan sampel darah untuk genotip reseptor serotonin pada kelompok
skizofrenia 3 generasi dan kontrol. Melakukan penilaian PANNS Membandingkan genotip
reseptor COMT (rs740603 dan rs4818) pasien skizofrenia yang diturunkan dengan
kelompok kontrol. Menghubungkan genotip resptor COMT (rs740603 dan rs4818) dengan
pada kelompok skizofrenia.tiga generasi dan skizofrenia tanpa ada riwayat turunan.

Keyword : kasus kontrol; analisa hubungan, Schizophrenia; polimorfisme COMT rs4818 ,

polimorfisme COMT rs740603, Populasi Toraja
 Tema Penelitian : Penyakit Non Infeksi

USULAN PENELITIAN
PENELITIAN DASAR UNHAS
TAHUN 2020

KADAR INTERLEUKIN 6 DAN 8 PADA PASIEN GANGGUAN PEMUSATAN

PERHATIAN dan HIPERAKTIVITAS (GPPH)

TIM PENGUSUL
Dr.dr. H.M. Faisal Idrus, Sp.KJ(K) NIDN 0008105702 (Ketua)
dr. Andi Suhera Syauki, M.kes, SpKJ NIDN 0023127705 (Anggota 1)
dr. Rinvil Renaldi, M.Kes, Sp.KJ(K) NIDN 0006048208(Anggota 2)

FAKULTAS KEDOKTERAN
UNIVERSITAS HASANUDDIN
MAKASSAR
2020
 HALAMAN PENGESAHAN

Judul Penelitian :KADAR INTERLEUKIN 6 DAN 8 PADA PASIEN GANGGUAN

PEMUSATAN PERHATIAN dan HIPERAKTIVITAS (GPPH)
Tema Penelitian : Penyakit Non Infeksi
Output Penelitian : Publikasi Jurnal International Bereputasi
Ketua Peneliti
a. Nama Lengkap : Dr.dr. H.M. Faisal Idrus, Sp.KJ(K)
b. Jenis Kelamin : Laki-laki
c. NIDN : 0008105702
d. Jabatan Fungsional : Lektor
e. Jabatan Struktural :-
f. Telpon/ email : 081524966494/ faisalidrus.dr@gmail.com
Anggota Peneliti 1
a. Nama Lengkap : dr. Andi Suheyra Syauki, M.Kes.,SpKJ
b. Jenis Kelamin : Perempuan
c. NIDN : 0023127705
d. Jabatan Fungsional : Asisten Ahli
e. Jabatan Struktural :-
f. Telpon / email : (+62) 812 413 0106 / herasyauki@gmail.com
Anggota Peneliti 2
a. Nama Lengkap : dr. Rinvil Renaldi, M.Kes.,SpKJ(K)
b. Jenis Kelamin : Laki-laki
c. NIDN : 000608208
d. Jabatan Fungsional :-
e. Jabatan Struktural :-
Telpon / email : 08124297497 / rinvilrenaldi@gmail.com
Anggota Peneliti 3
a. Nama Lengkap : dr. Lilik Haryani
b. Jenis Kelamin : Perempuan
c. NIM : C106216207
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa
e. Telpon / email : 081355631356 /lilikharyani84@gmail.com

Anggota Peneliti 4
a. Nama Lengkap : dr. Yuliastuty
b. Jenis Kelamin : Perempuan
c. NIDN : C106216204
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa
e. Telpon / email : 08114455310 / dizzalingga@gmail.com
 IDENTITAS DAN URAIAN UMUM

1. Judul Penelitian : Kadar Interleukine 6 dan 8 Pada Pasien Gangguan Pemusatan

Perhatian dan Hiperaktivitas (GPPH)
2. Tim Peneliti
Bidang Instansi Alokasi Waktu
No Nama Jabatan
Keahlian Asal (jam/minggu)
1. Dr. dr Faisal Idrus, Sp.KJ(K) Ketua Psikiatri
Unhas 30
Biologi
2. dr. A. Suhera syauki, M.Kes, Anggota 1 Psikiatri
Unhas 25
Sp.KJ Biologi
3. dr. Rinvil Renaldi, M.Kes, Anggota 2 Psikiatri
Unhas 25
Sp.KJ(K) Biologi
4. dr. Lilik Haryani Anggota 3 Psikiatri Unhas 20
5. dr. Yuliastuty Anggota 4 Psikiatri Unhas 20

3. Objek Penelitian : Manusia

4. Masa Pelaksanaan :
Mulai : Bulan Maret, Tahun 2020
Berakhir : Bulan Desember, Tahun 2020
5. Usulan Biaya Universitas Hasanuddin : Rp 100.000.000,-
6. Lokasi Penelitian : RS Wahidin Sudirohusudo dan jejaringnya
7. Instansi lain yang terlibat :-
8. Temuan yang ditargetkan :
Mengetahui peranan faktor inflamasi pada patogenesis GPPH
9. Konstribusi mendasar pada suatu bidang ilmu :
Penemuan etiologi dan patogenesis GPPH penting untuk memberi arah pengobatan
rasional. Sejumlah peneliti memperkirakan factor proinflamasi mendasari patogenesis
GPPH.
10. Jurnal Ilmiah yang menjadi sasaran :
Child and adolescene psychiatry mental health
11. Rencana luaran :
Publikasi Jurnal Internasional Bereputasi tahun 2021
 DAFTAR ISI

Halaman Pengesahan

Identitas dan Uraian Umum

Ringkasan

Bab 1. Pendahuluan 1

Bab 2. Renstra dan Peta Jalan Penelitian Perguruan Tinggi 4

Bab 3. Tinjauan Pustaka 5

Bab 4. Metode Penelitian 10

Bab 5. Biaya dan Jadwal Penelitian 13

Daftar Pustaka 16

Lampiran
RINGKASAN

HUBUNGAN INTERLEUKINE 6 DAN 8 PADA PASIEN GPPH

Gangguan Pemusatan Perhatian dan Hiperaktivitas (GPPH) adalah salah satu gangguan
Neurodevelopmental yang paling umum di antara anak-anak dengan perkiraan tingkat
prevalensi 5% hingga 11% di antara anak-anak sekolah. GPPH ditandai oleh hiperaktif,
impulsif, dan / atau kurangnya perhatian yang tidak sesuai dengan usia perkembangan
anak. Tingkat IL-6 yang meningkat dapat mengubah jalur saraf otak yang sedang
berkembang dan memengaruhi perhatian dan daya ingat melalui efeknya pada
neurogenesis dan plastisitas sinaptik dalam korteks prefrontal dan hippocampus. Perubahan
perkembangan dan fungsi otak normal ini dapat berperan dalam patogenesis ADHD. Enam
sitokin saliva (interleukin (IL) -1β, IL-8, IL12p70, faktor perangsang koloni granulosit (G-
CSF), interferon gamma (IFN-γ), dan faktor pertumbuhan endotel vaskular (VEGF)) secara
signifikan terkait dengan adanya GPPH. Peningkatan kadar interleukin 6 dan 8 pada pasien
anak dengan GPPH di beberapa penelitian sebelumnya masih menunjukan hasil yang
berbeda- beda, oleh karena itu peneliti tertarik untuk melakukan penelitian tersebut,
terutama pada pasien GPPH di Makassar.
Jenis penelitian ini merupakan penelitian case control dengan pendekatan kohort prospektif
Penelitian ini dilakukan di Rumah Sakit Wahidin Sudirohusodo dan jejaringnya pada bulan
Maret 2020 sampai Mei 2020. Populasi penelitian ini adalah pasien GPPH yang berobat
pertama kali di Rumah Sakit Wahidin Sudirohusodo dan jejaringnya dan orang normal 60
orang (kontrol) yang secara sukarela ikut dalam penelitian ini. Sampel pada penelitian
adalah pasien GPPH yang berobat pertama kali di Rumah Sakit Wahidin Sudirohusodo dan
jejaringnya yang memenuhi kriteria inklusi dan ekslusi. Sampel diambil mulai bulan
Januari 2019 sampai dangan Maret 2019 dengan cara Consecutive Sampling, yaitu semua
pasien yang memenuhi kriteria penelitian sampai sampel yang diperlukan terpenuhi.
Melakukan pengambilan sampel saliva untuk IL-6 dan IL-8 pada kelompok GPPH dan
kontrol. Melakukan penilaian gejala dengan skala ACRS pada pasien GPPH pada saat
datang berobat pertama kali dan kontrol.

Keyword : GPPH, IL-6 dan IL-8, ACRS

 Tema Penelitian : Penyakit Non Infeksi

USULAN PENELITIAN
PENELITIAN DASAR UNHAS
TAHUN 2020

PENAMBAHAN PROBIOTIK SEBAGAI TERAPI TAMBAHAN

PADA PASIEN SKIZOFRENIA YANG MENDAPAT TERAPI
ANTIPSIKOTIK ATIPIKAL

dr. Erlyn Limoa, Ph.D, Sp.KJ NIDN 0017117705 (Ketua)

Dr. dr Saidah Syamsuddin, SpKJ NIDN 0014017005 (Anggota 1)
dr. Mirna M.Zain NIM C106216206(Anggota 2)
dr. Herwina NIM C106216206 (Anggota 3)

FAKULTAS KEDOKTERAN
UNIVERSITAS HASANUDDIN
MAKASSAR
2020
 Halaman Pengesahan

Judul Penelitian : Penambahan Probiotik Sebagai Terapi Tambahan Pada Pasien

Skizofrenia Yang Mendapatkan Terapi Antipsikotik Atipikal

Tema Penelitian : Penyakit Non Infeksi

Output Penelitian : Publikasi Jurnal Internasional Bereputasi

Ketua Penelitian

a. Nama Lengkap : dr. Erlyn Limoa,Ph.D,Sp,KJ

b. Jenis Kelamin : Perempuan
c. NIDN : 0017117705
d. Jabatan Fungsional : Asisten Ahli
e. Jabatan Struktural : Sekertaris Program Studi Departemen Ilmu Kedokteran
Jiwa f. Telpon/ Email : 085299277779/ erlynliem17@gmail.co m
Anggota Penelitian 1

a. Nama Lengkap : Dr.dr. Saidah

b. Jenis Kelamin : Syamsuddin,Sp,KJ Perempuan
c. NIDN : 0014017005
d. Jabatan Fungsional Lektor Kepala
:
e. Jabatan Struktural : Ketua Program Studi Departemen Ilmu Kedokteran
Jiwa
f. Telpon/ Email :
08114104876/ idasyam70@gmail. com
Anggota Penelitian 2

a. Nama Lengkap : dr. Mirna M.Zain

b. Jenis Kelamin : Perempuan
c. NIM : C106216206
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran
Jiwa e. Telpon/ Email : 081355631481/ mirna07mz@gmail. com
Anggota Penelitian 3

a. Nama Lengkap : dr. Herwina

b. Jenis Kelamin : Perempuan
c. NIM : C106216205
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa
 e. Telpon/ Email : 08114154716/herwinasabaruddin82@gmail.co m
Waktu Penelitian : Maret 2020-Desember 2020

Biaya Diusulkan ke Unhas : Rp. 100.000.000,-

 Identitas dan Uraian Umum

1. Judul Penelitian : Penambahan Probiotik Sebagai Terapi Tambahan Pada

Pasien
Skizofrenia Yang Mendapatkan Terapi Antipsikotik Atipikal.
2. Tim Peneliti :
Alokasi
Bidang Instansi
No Nama Jabatan waktu
Keahlian Asal
(Jam/minggu)
1 dr. Erlyn Limoa, Ph.D, SpKJ Ketua Psikiatri UNHAS 30
2 Dr. dr. Saidah Syamsuddin, SpKJ Anggota 1 Psikiatri UNHAS 30
3 dr.Mirna M.Zain Anggota 2 Psikiatri UNHAS 30
4 dr.Herwina Anggota 3 Psikiatri UNHAS 30

3. Objek Penelitian : Manusia

4. Masa pelaksanaan :
Mulai Penelitian : Bulan Maret tahun 2020
Berakhir Penelitian : Bulan Desember tahun 20210
Submit : Tahun 2021
5. Usulan biaya Universitas Hasanuddin : Rp. 100.000.000,-
6. Lokasi Penelitian : RS Wahidin Sudirohusodo dan Jejaringnya
7. Instansi Yang terlibat :-
8. Temuan Yang ditargetkan :
Mengetahui efek probiotik sebagai terapi tambahan pada pasien skizofrenia
yang mendapatkan penambahan terapi Antipsikotik Atipikal.

9. Kontribusi Mendasar pada suatu bidang ilmu :

Penemuan kemajuan terapi pada kedokteran jiwa khususnya pada pasien skizofrenia
10.Jurnal Ilmiah Yang Menjadi Sasaran :

Journal of Neuroinflammation, Progress Neuropsychopharmacology & Biological

Psychiatry

11.Rencana Luaran :

Under Review Jurnal Internasional Bereputasi tahun 2021

 DAFTAR ISI

Halaman Pengesahan
Identitas dan Uraian Umum
Ringkasan.
Bab I.Pendahuluan………………………………………………………………...1
Bab II.Renstra dan Peta Jalan Penelitian………………………………………… 3
Bab III. Tinjauan Pustaka………………………………………………………... 3
Bab IV. Metode Penelitian………………………………………………………. 6
Bab V. Biaya dan Jadwal penelitian……………………………………………... 9
Daftar Pustaka……………….…………………………………………………….…10
Lampiran
 PENAMBAHAN PROBIOTIK SEBAGAI TERAPI TAMBAHAN PADA PASIEN
SKIZOFRENIA YANG MENDAPAT TERAPI ANTIPSIKOTIK ATIPIKAL

RINGKASAN

Skizofrenia adalah salah satu gangguan mental yang memerlukan perawatan jangka
panjang dan biaya perawatan yang cukup besar. Telah banyak penelitian yang
dilakukan untuk mencari penyebab dari gangguan ini dengan tujuan didapatkannya terapi
yang lebih optimal. Penelitian akhir-akhir ini menemukan adanya peranan neuroinflamasi
dan sistem imun dalam patofisiologi gangguan skizofrenia. Dalam studi kami terdahulu,
kami menemukan bahwa minosiklin, sebuah anti biotik yang memiliki efek anti inflamasi,
dapat dipakai sebagai terapi tambahan untuk memperbaiki perilaku skizofrenia pada hewan
coba, dan juga menurunkan aktivasi mikroglia sebagai tanda penurunan neuroinflamasi di
otak hewan coba tersebut. Sebagai tambahan lagi, penggunaan terapi elektrokonvulsi yang
memperbaiki perilaku skizofrenia pada hewan coba, juga memperbaiki neuroinflamasi di
otak hewan.

Probiotik adalah mikroorganisme menguntungkan yang memodulasi respons imun inang

dengan mempengaruhi komposisi mikrobiota usus. Pada manusia, pemberian probiotik oral
diketahui mengembalikan inflamasi normal, meningkatkan kapasitas anti-sistemik.
Fungsi otak yang meningkat setelah suplementasi probiotik dikaitkan dengan Gut brain axis,
yaitu, berbagai cara komunikasi antara bakteri yang menghuni usus manusia dan sistem saraf
pusat. Sebagai contoh, mikroorganisme probiotik berinteraksi dengan sistem kekebalan
tubuh bawaan, mempengaruhi sekresi pro dan antiinflamasi (Tomasik, et.al 2015).

Penelitian ini kami ingin melihat efek anti inflamasi dari probiotik dan prebiotik,
terhadap perbaikan gejala penderita skizofrenia dan penurunan sitokin TNF alfa sebagai
penanda reaksi inflamasi. Penelitian ini merupakan studi experimental dengan desain double
blind. Studi ini akan dilakukan selama 1 tahun di RS Wahidin Sudirihusodo dan Jejaringnya
dengan mengamati penderita skizofrenia yang mendapat terapi antipsikotik risperidone dan
probiotik serta pada kelompok skizofrenia yang mendapat terapi antipsikotik risperidone da
n plasebo. Pemeriksaan darah, psikiatrik dan respon terapi akan dilakukan sesuai dengan
protocol di RS Wahidin Sudirohusodo dan Jejaringnya.

Keywords: Probiotik, Skizofrenia, TNF alfa

 Tema Penelitian : Penyakit Non Infeksi

USULAN PENELITIAN
PENELITIAN DASAR UNHAS
TAHUN 2020

PERBANDINGAN KADAR KORTISOL RAMBUT SEBELUM DAN SETELAH

TERAPI METYLPHENIDATE PADA PASIEN DENGAN GANGGUAN
PEMUSATAN PERHATIAN DAN HIPERAKTIVITAS (GPPH)

TIM PENGUSUL

dr. Rinvil Renaldi, M.Kes, Sp.KJ(K) NIDN : 0006048208 (Ketua)

Dr. dr. H. M. Faisal Idrus, Sp.KJ(K) NIDN : 0008105702 (Anggota 1)
dr. A. Suheyra Syauki, M.Kes, Sp.KJ NIDN : 0023127705 (Anggota 2)

FAKULTAS KEDOKTERAN
UNIVERSITAS HASANUDDIN
MAKASSAR
2019

i
 HALAMAN PENGESAHAN

Judul Penelitian : Perbandingan Kadar Kortisol Rambut Sebelum dan Setelah

terapi metylphenidate pada pasien dengan Gangguan
Pemusatan Perhatian dan Hiperaktivitas (GPPH)
Tema Penelitian : Penyakit Non Infeksi
Output Penelitian : Publikasi Jurnal Nasional Bereputasi
Ketua Peneliti :
a. Nama Lengkap : dr. Rinvil Renaldi, M.Kes, Sp.KJ (K)
b. Jenis Kelamin : Laki-laki
c. NIDN : 0006048208
d. Jabatan Fungsional :-
e. Jabatan Struktural :-
f. Telepon/Email : 08124297497 / rinvilrenaldi@gmail.com

Anggota Peneliti 1
a. Nama Lengkap : Dr. dr. H.M.Faisal Idrus, Sp.KJ(K)
b. Jenis Kelamin : Laki-laki
c. NIDN : 0008105702
d. Jabatan Fungsional : Lektor
e. Jabatan Struktural :-
f. Telpon/ email : 081355473741

Anggota Peneliti 2
a. Nama Lengkap : dr. A. Suheyra Syauki, M.Kes, Sp.KJ
b. Jenis Kelamin : Perempuan
c. NIDN : 0023127705
d. Jabatan Fungsional : Asisten Ahli
e. Jabatan Struktural :-
f. Telpon/ email : 08124130106 / herasyauki@gmail.com

Anggota Peneliti 3

a. Nama Lengkap : dr. Yuliastuty

b. Jenis Kelamin : Perempuan
c. NIM : C106216204
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa
e. Telpon/Email : 08114455310/ dizalingga@gmail.com

Anggota Peneliti 4
a. Nama Lengkap : dr. Lilik Haryani
b. Jenis Kelamin : Perempuan

ii
 c. NIM : C106216207
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa
e. Telpon/Email : 081355631356/ lilikharyani84@gmail.com

Waktu Penelitian : Maret 2020 – Desember 2020

Biaya Diusulkan ke UNHAS : Rp. 100.000.000,-

Makassar, 15 Januari 2020

Mengetahui,
Dekan Fakultas Kedokteran Ketua Peneliti

Prof. dr. Budu, Ph.D, Sp.M (K)K, M.Med.Ed dr. Rinvil Renaldi, M.Kes, Sp.KJ (K)
NIP : 196612311995031009 NIP : 19820406 200804 1 002

Menyetujui,
Ketua Lembaga Penelitian dan Pengabdian Masyarakat

Prof. Dr. Andi Alimuddin, M.Si

NIP. 196208181987021001

iii
 IDENTITAS DAN URAIAN UMUM

1. Judul Penelitian : Perbandingan Kadar Kortisol Rambut Sebelum dan Setelah terapi
metylphenidate pada pasien dengan Gangguan Pemusatan Perhatian
dan Hiperaktivitas (GPPH)
2. Tim Peneliti
No Nama Jabatan Bidang Instansi Asal Alokasi waktu
keahlian (jam/minggu)

dr. Rinvil Renaldi, Psikiatri Anak

1 M.Kes, Sp.KJ (K) Ketua dan Remaja UNHAS 30

Dr. dr. H. M. Faisal Psikiatri

2 Idrus, Sp.KJ (K) Anggota 1 Biologi UNHAS 25
Dr. A. Suheyra
Syauki, M.Kes, Psikiatri
3 Sp.KJ Anggota 2 Biologi UNHAS 25

4 dr. Yuliastuty Anggota 3 Psikiatri UNHAS 20

5 dr. Lilik Haryani Anggota 4 Psikiatri UNHAS 20

3. Objek Penelitian : Manusia

4. Masa Pelaksanaan :
Mulai : Bulan Maret, Tahun 2020
Berakhir : Bulan Desember, Tahun 2020
5. Usulan Biaya Universitas Hasanuddin : Rp 100.000.000,-
6. Lokasi Penelitian : RS Wahidin Sudirohusudo dan jejaringnya
7. Instansi lain yang terlibat :-
8. Temuan yang ditargetkan :
Mengetahui perbandingan kadar kortisol rambut sebelum dan setelah terapi metylphenidate
pada pasien dengan Gangguan Pemusatan Perhatian dan Hiperaktivitas (GPPH)
9. Konstribusi mendasar pada suatu bidang ilmu :

iv
 Untuk melihat peran neurosteroid dalam hal ini kortisol pada respon pengobatan pasien
Gangguan Pemusatan Perhatian dan Hiperaktivitas (GPPH)

10. Jurnal Ilmiah yang menjadi sasaran :

Child and Adolescent Psychiatry and Mental Health
11. Rencana luaran :
Publikasi Jurnal Internasional Bereputasi tahun 2021

v
 DAFTAR ISI

Halaman Pengesahan

Identitas dan Uraian Umum

Ringkasan

Bab 1. Pendahuluan 1

Bab 2. Renstra dan Peta Jalan Penelitian Perguruan Tinggi 4

Bab 3. Tinjauan Pustaka 6

Bab 4. Metode Penelitian 16

Bab 5. Biaya dan Jadwal Penelitian 18

Daftar Pustaka 19

Lampiran

vi
RINGKASAN
PERBANDINGAN KADAR KORTISOL RAMBUT SEBELUM DAN SETELAH
TERAPI METYLPHENIDATE PADA PASIEN DENGAN GANGGUAN
PEMUSATAN PERHATIAN DAN HIPERAKTIVITAS (GPPH)

Gangguan Pemusatan Perhatian dan Hiperaktivitas (GPPH) adalah kondisi yang ditandai
dengan gejala gangguan dalam memusatkan perhatian dan/atau aktivitas impulsivitas yang
berlebih. GPPH merupakan gangguan neuropsikiatri pada masa kanak-kanak dan remaja,
dengan prevalensi yang dilaporkan sebesar 3–10% di antara anak-anak usia sekolah di seluruh
dunia. Gejala utama GPPH adalah kurangnya perhatian, hiperaktif, dan impulsif, yang
memiliki dampak negatif yang signifikan pada aspek fungsi global. Studi terdahulu yang
dilakukan pada anak usia 4 tahun, mengungkapkan terdapat hubungan antara kortisol saliva
dan masalah mental emosional pada anak. Metylphenidate memberikan efek pengobatan pada
dimensi perilaku dan kognitif pada pasien GPPH . Pengukuran kadar kortisol selama
pengobatan Metylphenidate berguna untuk mengetahui kemajuan atau efektivitas terapi pada
GPPH.

Jenis penelitian ini merupakan studi longitudinal dengan pendekatan desain kohort prospektif
dengan analisis pre dan post untuk mengetahui pengaruh pemberian terapi metylphenidate
terhadap kadar kortisol rambut pada pasien Gangguan Pemusatan Perhatian dan Hiperaktivitas
(GPPH). Penelitian ini dilakukan di Rumah Sakit Wahidin Sudirohusodo dan jejaringnya pada
bulan Maret 2020 sampai Desember 2020 dengan cara Consecutive Sampling, yaitu semua
pasien yang memenuhi kriteria penelitian sampai sampel yang diperlukan terpenuhi.

Mengukur kadar kortisol rambut sebelum terapi, pada minggu keempat dan minggu ke delapan
terapi methylphenidate. Mengukur skor Abbreviated Conners’ Rating Scale (ACRS), sebelum
terapi, pada minggu keempat, dan minggu ke delapan terapi methylphenidate. Membandingkan
kadar kortisol rambut sebelum terapi, pada minggu keempat dan minggu ke delapan terapi
methylphenidate. Membandingkan skor Abbreviated Conners’ Rating Scale (ACRS), sebelum
terapi, pada minggu keempat, dan minggu ke delapan terapi methylphenidate.

Keyword : Gangguan Pemusatan Perhatian dan Hiperaktivitas (GPPH), Kortisol, respon terapi,
ACRS

vii
 Tema Penelitian : Penyakit Non Infeksi

USULAN PENELITIAN
PENELITIAN DASAR UNHAS
TAHUN 2020

EFEKTIVITAS REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION

(rTMS) DIBANDINGKAN DENGAN FLUOXETINE TERHADAP
PENINGKATAN BDNF PADA DEPRESI PASCA STROKE ISKEMIK

TIM PENGUSUL

dr. Andi Suheyra Syauki, M.Kes Sp.KJ NIDN 0023127705 (Ketua)

Dr. dr. Sonny Teddy Lisal, Sp.KJ NIDN 0016066701 (Anggota 1)

dr. Rinvil Renaldi, M.Kes.,SpKJ(K) NIDN 000608208 (Anggota 2)

FAKULTAS KEDOKTERAN
UNIVERSITAS HASANUDDIN
MAKASSAR
 2020
HALAMAN PENGESAHAN

Judul Penelitian : EFEKTIVITAS REPETITIVE TRANSCRANIAL MAGNETIC

STIMULATION (rTMS) DIBANDINGKAN DENGAN
FLUOXETINE TERHADAP KADAR BDNF PADA DEPRESI
PASCA STROKE ISKEMIK
Tema Penelitian : Penyakit Non Infeksi
Output Penelitian : Publikasi Jurnal International Bereputasi
Ketua Peneliti
a. Nama Lengkap : dr. Andi Suheyra Syauki, M.Kes Sp.KJ
b. Jenis Kelamin : Perempuan
c. NIDN : 0023127705
d. Jabatan Fungsional : Asisten Ahli
e. Jabatan Struktural : Dosen Program Studi Departemen Ilmu Kedokteran Jiwa
f. Telpon/ email : (+62) 812 413 0106/herasyauki@gmail.com
Anggota Peneliti 1
a. Nama Lengkap : Dr. dr. Sonny T.Lisal, Sp.KJ
b. Jenis Kelamin : Laki-Laki
c. NIDN : 0016066701
d. Jabatan Fungsional : Lektor Kepala
e. Jabatan Struktural : Kepala Departemen Ilmu Kedokteran Jiwa
f. Telpon/ email : 0811414868 / stlisal@gmail.com
Anggota Peneliti 2
a. Nama Lengkap : dr. Rinvil Renaldi, M.Kes.,SpKJ(K)
b. Jenis Kelamin : Laki-laki
c. NIDN : 000608208
d. Jabatan Fungsional : -
e. Jabatan Struktural :-
f. Telpon / email : 08124297497 / rinvilrenaldi@gmail.com
Anggota Peneliti 3
a. Nama Lengkap : dr. Herwina
b. Jenis Kelamin : Perempuan
c. NIM : C106216205
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa e.
Telpon / email : 08114154716 / herwinasabaruddin82@gmail.com
Anggota Peneliti 4
a. Nama Lengkap : dr. Mirna M.Zain
b. Jenis Kelamin : Perempuan
c. NIM : C106216206
d. Jabatan : Mahasiswa Sp-1 Departemen Ilmu Kedokteran Jiwa
 IDENTITAS DAN URAIAN UMUM

1. Judul Penelitian : EFEKTIVITAS REPETITIVE TRANSCRANIAL MAGNETIC

STIMULATION (rTMS) DIBANDINGKAN DENGAN FLUOXETINE
TERHADAP PENINGKATAN BDNF PADA DEPRESI PASCA STROKE
ISKEMIK
2. Tim Peneliti
Bidang Instansi Alokasi Waktu
No Nama Jabatan
Keahlian Asal (jam/minggu)
1. Dr. Andi Suheyra Syauki, M.Kes Ketua Psikiatri
Unhas 30
Sp.KJ Biologi
2. Dr. dr. Sonny Teddy Lisal, Sp.KJ Anggota 1 Psikiatri
Unhas 30
Biologi
3. dr. Rinvil Renaldi, M.Kes, Anggota 2
Psikiatri Unhas 30
Sp.KJ(K)
4. dr. Herwina Anggota 3 Psikiatri Unhas 30
5. dr. Mirna M Zain Anggota 4 Psikiatri Unhas 30

3. Objek Penelitian : Manusia

4. Masa Pelaksanaan :
Mulai : Bulan Maret, Tahun 2020
Berakhir : Bulan Desember, Tahun 2020
5. Usulan Biaya Universitas Hasanuddin : Rp 100.000.000,-
6. Lokasi Penelitian : RS Wahidin Sudirohusudo dan jejaringnya
7. Instansi lain yang terlibat :-
8. Temuan yang ditargetkan :
Mengetahui peranan kadar BDNF dalam respon pengobatan pada pasien depresi pasca
stroke
9. Konstribusi mendasar pada suatu bidang ilmu :
Penemuan kemajuan terapi pada kedokteran jiwa khususnya pada pasien depresi
pasca stroke.
10. Jurnal Ilmiah yang menjadi sasaran :
Neuropsychiatry (London)
11. Rencana luaran :
Publikasi Jurnal Internasional Bereputasi tahun 2021
 DAFTAR ISI

Halaman Pengesahan
Identitas dan Uraian Umum
Ringkasan
Bab 1. Pendahuluan 1
Bab 2. Renstra dan Peta Jalan Penelitian Perguruan Tinggi 4
Bab 3. Tinjauan Pustaka 5
Bab 4. Metode Penelitian 10
Bab 5. Biaya dan Jadwal Penelitian 13
Daftar Pustaka 16
Lampiran
RINGKASAN
EFEKTIVITAS REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION
(rTMS) DIBANDINGKAN DENGAN FLUOXETINE TERHADAP
PENINGKATAN BDNF PADA DEPRESI PASCA STROKE ISKEMIK

Depresi biasanya dijumpai pada minggu pertama setelah stroke, dapat menetap
beberapa minggu bahkan sampai beberapa bulan. Berbagai faktor diduga berhubungan
dengan kejadian depresi pasca stroke seperti riwayat depresi sebelum stroke, lesi patologis
tertentu akibat stroke, gangguan bahasa, status fungsional yang buruk, dan isolasi sosial.
Brain-Derived Neurotrophic Factor (BDNF) adalah faktor neurotrofik penting yang
didistribusikan secara luas di sistem saraf pusat. BDNF sangat penting untuk kelangsungan
hidup, pertumbuhan dan pemeliharaan neuron dalam sirkuit otak yang mengontrol emosi
dan kognisi. Beberapa penelitian menyebutkan bahwa neuroplastisitas yang terjadi pada
gangguan depresi pada umumnya terkait dengan tingkat BDNF.
Repetitive transcranial magnetik stimulation (rTMS) juga dapat mengaktifkan
brain- derived neurotrophic factor/extracellular signal-regulated kinase (BDNF/ERK)
signaling pathway untuk meningkatkan proliferasi sel dalam hipokampus. Beberapa studi
menyebutkan efektivitas repetitive Transcranial Magnetic Stimulation (rTMS) pada pasien
depresi pasca stroke.
Penelitian ini kami ingin melihat efektivitas repetitive transcranial magnetic stimulation
(rtms) dibandingkan dengan fluoxetine terhadap kadar bdnf pada depresi pasca stroke
iskemik. Penelitian ini merupakan studi experimental dengan desain double blind. Studi ini
akan dilakukan selama 1 tahun di RS. Wahidin Sudirohusodo dan jejaring dengan
mengamati penderita depresi pasca stroke yang mendapat terapi rTMS penderita depresi
pasca stroke yang mendapat terapi fluoxetine. Pemeriksaan darah, psikiatrik dan respon
terapi akan dilakukan sesuai dengan protocol di RS. Wahidin Sudirohusodo dan jejaring.

Kata kunci: BDNF, depresi pasca stroke,stroke iskemik rTMS, fluoxetine