30 November

2019

METABOLIC SYNDROME IN
SCHIZOPHRENIA WITH
ARIPIPRAZOLE
Elmeida Effendy
Department of Psychiatry
Faculty of Medicine
Universitas Sumatera Utara
Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 1
 CURRICULUM VITAE
 Dr. dr Elmeida Effendy, MKed(KJ),SpKJ (K)
 Riwayat Pendidikan
 Dokter – FK USU 1997
 Psikiater- FK USU 2004
 Magister Kedokteran Jiwa FK USU 2012
 S3 FK USU 2013
 Konsultan Psikiatri Biologi 2014
 Riwayat Pekerjaan
 Dokter PTT Puskesmas Bandar Baru 1997-1999
 Staf Pengajar Dep. Psikiatri FK USU 1999 – sekarang
 Sekretaris Departemen Psikiatri FK USU 2005-2007
 Sekretaris Program Studi Psikiatri FK USU 2007 -2010
 Ketua Program Studi Psikiatri FK USU 2011-2016
 Ketua Departemen Psikiatri FK USU 2017- sekarang
30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell
2
 ◦Outlines
◦Background
◦Metabolic syndrome
◦Schizophrenia
◦Adverse effects of antipsychotic
◦Aripiprazole

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 3

 Background
◦ In addition to adverse effects related to the use of
antipsychotics, the increase of health problems of
schizophrenic population is often associated to a
group of cardiovascular risk factors usually
correlated to greater abdominal fat deposits and
peripheral insulin resistance, which predisposes the
patient not only diabetes, but also to the
development of other comorbidities, such as
obesity, arterial hypertension and dyslipidemia, a
situation named metabolic syndrome

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 4

 The life expectancy of these individuals is reduced by
about 20 % when compared to the general population,
due to clinical conditions of the disease , such as weight
gain, diabetes, metabolic syndrome and cardiovascular
disease

It is necessary to consider antipsychotic’s side

effects due to metabolic syndrome
30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 5
 Metabolic Syndrome

A cluster of conditions that occur together,

increasing risk of heart disease, stroke and type 2
diabetes. These conditions include increased
blood pressure, high blood glucose, excess body
fat around the waist and abnormal cholesterol or
triglyseride levels

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 6

 ◦Studies show that psychiatric patients have a
greater risk of developing metabolic syndrome
◦Data from the Clinical Antipsychotic Trials of
Intervention Effectiveness( CATIE) project,
indicated that around 40 % of these individuals
develop metabolic syndrome : 51,6 % of women
and 36 % of men

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 7

 According to
WHO , the
evaluation of are the main starting
insulin point to evaluate these
resistance and physiological
the alterations
disturbance of
glucose
metabolism

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 8

 ◦According to the The National Cholesterol
Education Program Adult Treatment Panel ,
metabolic syndrome represents the combination
of at least 3 of the following components :
abdominal obesity, alterations in the levels of
triglyserides and HDL lipoproteins, hypertension,
increased fasting blood sugar and
hyperinsulinemia

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 9

 Component of Metabolic Syndrome
◦ Abdominal obesity through abdominal circumference
◦ Men > 102 cm
◦ Women > 88 cm
◦ Triglycerides ≧ 150 mg/dl
◦ HDL cholesterol
◦ Men < 40mg/dl
◦ Women < 50 mg/dl
◦ Blood pressure ≧130 mm Hg ; ≧85 mmHg
◦ Fasting blood glucose ≧110 mg/dl

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 10

 Schizophrenia

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 11

 which reflects in
The factors related to
the development of
a sedentary life
metabolic syndrome style, lack of
in schizophrenic regular physical
patients are partly activity, bad
influenced by aspects eating habits,
of the disease, such use of doping
as the negative substances and
symptoms and
vulnerability to stress
high levels of
smoking

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 12

 On the other hand

the antipsychotics used for the treatment of

schizophrenia have been largely correlated to the
manifestations of these alterations due to propensity of
including weight gain, and its complications,
metabolic alterations such as Diabetes Mellitus type 2,
compromised lipid profile, hypertension, dyslipidemia
and in more severe cases cardiovascular disease
30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 13
 Metabolic risk of antipsychotics
◦High metabolic risk
◦ clozapine, olanzapine
◦Moderate metabolic risk
◦ risperidone, paliperidone, quetiapine
◦Low metabolic risk
◦ aripiprazole, asenapine, cariprazine

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 14

 The mechanism by which antipsychotics cause
metabolic disturbances is still unknown, but it is
assumed that it may be related to the weight gain
and peripheral insulin resistance

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 15

 Metabolic highway
◦Increased appetite and weight gain, progresses
to obesity, insulin resistance, dyslipidemia with
increases in fasting triglyseride levels
◦Ultimately, hyperinsulinemia advances to
pancreatic β cell failure, prediabetes and then
diabetes

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 16

 ◦The binding of atypical antipsychotics to 5 HT2 M
(muscarinic) and /or H1 (histamine) receptors
have been associated to metabolic alterations
that can compromise the patient’s physical well-
being

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 17

 ◦The drug’s affinity to histamine H1 and to 5HT2
serotonin receptors is linked to the weight gain,
while the affinity to muscarinic receptors and its
blockade is linked to anticholinergic adverse
effects, such as dry mouth, constipation, blurred
vision, increased prolactin secretion.

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 18

 ◦Blockade of H1receptors may interfere with the
supression of appetite mediated by leptin, an
affect that can lead to weight gain and insulin
resistance.
◦Such complications include weight gain,
propensity to diabetes and cardiovascular
disease, which are probably linked to the
antagonist action of certain drugs in these
receptors
30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 19
 ◦Obesity and specifically abdominal obesity
associated to insulin resistance is considered to
be the factor by which the excessive weight
leads to glycemic metabolic dysfunctions
◦The insulin resistance promotes greater liberation
of free fatty acids in the bloodstream, mainly by
the abdominal adipose tissue, consequently less
insulin is reuptaken, leading to the development
of hyperglycemia and greater risk of developing
DM 2
30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 20
 ◦Cardiometabolic risk of certain atypical
antipsychotics cannot simply be explained by
increased appetite and weight gain, some
atypical antipsychotics can elevate fasting
triglyceride levels and cause increased insulin
resistance in a manner that cannot be explained
by weight gain alone

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 21

 ◦Although this happens in many patients with
weight gain alone, it also occurs in some
patients who take atypical antipsychotics and
prior to their gaining significant weight , as if
there is an acute receptor-mediated action of
these drugs on insulin regulation

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 22

 ◦The mechanism of this increased insulin
resistance and elevation of fasting triglyserides
has been vigorously pursued but has not yet
been identified
◦The rapid elevation of fasting triglyserides upon
initiation of some antipsychotics, and the rapid
fall of fasting triglyserides upon discontinuation of
such drugs, is highly suggestive that an unknown
pharmacologic mechanism causes these
changes, although this remains speculative
30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 23
 ◦Adipose tissue, liver and skletal muscle all develop
insulin resistance in response to administration of
certain antipsychotic drugs at least in certain
patients
◦Fasting plasma triglyserides and insulin resistance
can be elevated significantly in some patients
taking certain antipsychotics and this enhances
cardiometabolic risk, moves such patients along
the metabolic highway and functions as another
stepdown the slippery slove towards the diabolical
destination of cardiovascular events and premature
death
30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 24
 ◦ Clinician should monitor patients taking an atypical
antipsychotic and manage the cardiometabolic
risks of atypical antipsychotic
◦ weight and body mass index to detect weight gain,
and fasting glucose to detect the development of
diabetes, get a baseline of fasting triglyseride levels
and determining whether there is a family history of
diabetes
◦ monitoring whether atypical antipsychotics are
causing dyslipidemia and increased insulin resistance
by measuring fasting triglyseride levels before and
after starting an atypical antipsychotic

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 25

 ◦If body mass index or fasting triglyserides
increase significantly, a switch to a different
antipsychotic that does not cause these
problems should be considered
◦In patients who are obese, with dyslipidemia, and
either in a prediabetic or diabetic state, it is
especially important to monitor blood pressure,
fasting glucose and waist circumference before
and after initiating an atypical antipsychotic

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 26

 ◦ Aripiprazole has been associated with

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 27

28
Aripiprazole

◦ has no anti-histaminergic activity,

◦ agonist at 5-HT2C receptors
◦ has a unique 5-HT1A partial agonist
property
◦ generally believed that agonists at
5-HT1A receptors lower blood
glucose levels, while antagonists
decrease blood insulin levels,
thereby leading to hyperglycemia

Mini Symposium Metabolic Syndrome in Schizophrenia -Novell

30 November 2019
 29

◦Decreased insulin levels associated with 5 –HT1 A

antagonism are probably due to a decrease in
pancreatic β- cell responsiveness to blood
glucose levels
◦Treatment with aripiprazole has been associated
with minimal impact on metabolic parameters,
including weight, glucose metabolism and lipids
in patients with schizophrenia

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell

 Given its agonist effects on both 5-HT2C
receptors and 5- HT1 A receptors

aripiprazole might be protective against

weight gain, diabetes and other
metabolic disturbances patients with
schizophrenia

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 30

 Conclusion

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 31

 References
◦ S.M.Stahl. Stah’s Essential Psychopharmacology. Neuroscientific Basis and Practical
Applications. 4 th edition 2013l
◦ Madhubhashinee, Dayabandara, Hanwella R, Ratnatunga S, Seneviratne S, Suraweera
C. Antipsychotic-associated weight

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 32

30 November 2019 Mini Symposium Metabolic Syndrome in Schizophrenia -Novell 33