Letters to the Editor
Komagino Hospital role of rivastigmine? A case series. Clin Pract.
Tokyo, Japan
Kyosuke Sawada, MD
Jinichi Hirano, MD, PhD
Masaru Mimura, MD, PhD
Taishiro Kishimoto, MD, PhD
Department of Neuropsychiatry
Keio University School of Medicine
Tokyo, Japan
tkishimoto@keio.jp
J.H. has received speaker's honoraria
from Otsuka Pharmaceutical and a grant
from Pfizer Health Research Foundation
and Uehara Memorial Foundation within
the past 3 years. M.M. has received grants
and/or speaker's honoraria from Daiichi
Sankyo, Dainippon-Sumitomo Pharma, Eisai,
Eli Lilly, Fuji Film RI Pharma, Janssen
Pharmaceutical, Mochida Pharmaceuti-
cal, MSD, Nippon Chemipher, Novartis
Pharma, Ono Yakuhin, Otsuka Pharma-
ceutical, Pfizer, Takeda Yakuhin, Tsumura,
and Yoshitomi Yakuhin within the past
3 years. T.K. has received consultant fees
from Dainippon Sumitomo, Novartis, and
Otsuka and speaker's honoraria from
Banyu, Eli Lilly, Dainippon Sumitomo,
Janssen, Novartis, Otsuka, and Pfizer. He
received royalties from UpToDate. Other
authors declare no conflicts of interest.
REFERENCES
1. Fink M. Post-ECT delirium. Convuls Ther.
1993;9:326–330.
2. Selvaraj AG, Praharaj SK. Delayed onset and
prolonged interictal delirium following
electroconvulsive therapy. Psychogeriatrics.
2012;12:211–213.
3. Logan CJ, Stewart JT. Treatment of
post-electroconvulsive therapy delirium and
agitation with donepezil. J ECT. 2007;23:
28–29.
4. Bryson EO, Briggs MC, Pasculli RM, et al.
Treatment-resistant postictal agitation after
electroconvulsive therapy (ECT) controlled
with dexmedetomidine. J ECT. 2013;29:e18.
5. Prakash J, Kotwal A, Prabhu H. Therapeutic
and prophylactic utility of the
memory-enhancing drug donepezil
hydrochloride on cognition of patients
undergoing electroconvulsive therapy: a
randomized controlled trial. J ECT. 2006;22:
163–168.
6. Matthews JD, Siefert CJ, Blais MA, et al. A
double-blind, placebo-controlled study of the
impact of galantamine on anterograde memory
impairment during electroconvulsive therapy.
J ECT. 2013;29:170–178.
7. Van Schaik AM, Rhebergen D, Henstra MJ, et al.
Cognitive impairment and electroconvulsive
therapy in geriatric depression, what could be the
e30 www.ectjournal.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Journal of ECT • Volume 35, Number 3, September 2019
O's family described acute psychotic exacer-
2015;28:780.
8. Lerer B. Electroconvulsive shock and
neurotransmitter receptors: implications for
mechanism of action and adverse effects of
electroconvulsive therapy. Biol Psychiatry.
1984;19:361–383.
9. Lerer B. Studies on the role of brain cholinergic
systems in the therapeutic mechanisms and
adverse effects of ECT and lithium. Biol
Psychiatry. 1985;20:20–40.
10. Williams A, Adetunji B, Odulate A. Tardive
seizure: a case report. J ECT. 2006;22:271.
11. Felkel WC 2nd, Wagner G, Kimball J, et al.
Tardive seizure with postictal aphasia: a case
report. J ECT. 2012;28:180–182.
Clozapine and
Electroconvulsive Therapy Is
an Effective and Safe
Treatment During Pregnancy
A Case Report
To the Editor:
M iss O, a 25-year-old 17 week–pregnant
woman, was admitted in a psychiatric
inpatient unit of a regional hospital owing
to acute psychotic symptoms and disrup-
tive behavior.
She was originally from Morocco, al-
though a resident in Spain since she was
18. She completed her basic compulsory ed-
ucation and later held different low-skilled
jobs but had been unemployed for 1 year at
the time of admittance. She lived with her
sister and had no income. The pregnancy
was unplanned, but the child was welcomed
by Miss O and her family. She was a pri-
mipara and had no stable relationship. Her
body mass index was 24.7, and she had no
other medical problems.
She began to engage in disruptive be-
havior and alcohol and cannabis use at age of
22. At age 24 she had her first nonaffective
psychotic episode requiring hospitalization.
After that, she had 2 psychotic relapses re-
quiring hospitalization, since clinical re-
mission between these admissions was
only partial, and treatment adherence was
low. Pharmacologically, she presented low
tolerability to olanzapine and quetiapine (se-
dation, drowsiness) and to amisulpride (acute
dystonia). She had good tolerability to low-
dose aripiprazole (ie, 10 mg/d). At the time
of admission, she was only using tobacco.
Initially, Miss O presented with oppo-
sitional attitude, hallucinatory behavior, and
persecution and catastrophe delusions. Miss
© 2019 Wolters Kluwer Health, Inc. All rights reserved.
bation after treatment discontinuation 1 month
earlier. At home, she was restless and sleep-
less. She was verbally aggressive and suspi-
cious toward the family, and she threatened
to ingest bleach.
She was diagnosed with schizophrenia
(Diagnostic and Statistical Manual of Men-
tal Disorders, Fifth Edition, 295.90 [F20.9])
for which haloperidol (4 mg/d) was initially
started, followed by aripiprazole (30 mg/d)
owing to acute dystonia. After initial
improvement, she experienced a clinical
worsening showing verbal auditory halluci-
nations and auto-heteroaggressivity during
the sixth week of treatment (ie, blows to the
abdomen). Because of resistant psychotic
symptoms and self-injurious behavior, treat-
ment with clozapine and electroconvulsive
therapy (ECT) was proposed. Because of
the difficulties involved in performing ECT
in the regional hospital owing to gestational
age (24 weeks), the patient was transferred
to a tertiary hospital. Total Positive and Neg-
ative Symptoms Scale at that time was 98
(28 + 25 + 45).
Electroconvulsive therapy was per-
formed between weeks 24 and 27 of the
pregnancy. Before and after each ECT ses-
sion, fetal cardiotocography was conducted.
A Mecta Spectrum 5000Q was used to de-
liver bitemporal ECT treatment. Twelve ses-
sions were administered, 3 times per week.
Mean electroencephalographic seizure time
was 44 seconds; pulse width, 1 millisecond;
pulse frequency, 20 Hz; amplitude, 0.8 A;
electrical dose,120 mC; and energy, 19.1 to
24.4 J. Anesthetic agents were sodium
thiopental, 200 mg; atropine, 0.5 mg;
and succinylcholine, 50 mg. During ECT
sessions, no uterine contractions occurred,
and the fetal heart rate was stable before
and after stimuli (around 130 bpm). Fetal
sonogram at 24 gestational weeks revealed
no structural abnormalities. No other ad-
verse events were reported.
Clozapine dose was increased grad-
ually up to 250 mg/d (clozapine plasma
levels were 495 ng/mL), and aripiprazole
was withdrawn.
A pharmacogenetics study was con-
ducted, showing Miss O. was a CYP2D6*4
and CYP2C19*2 poor metabolizer. These
results explained her background of low
tolerance to drugs. Unfortunately, CYP1A2
genotyping was not possible.
Gradually, Miss O showed overall clini-
cal improvement of acute psychotic symptoms
with remission of delusions and reduction
of verbal hallucinations, with no further ep-
isodes of auto or hetero-aggression. At that
time, she made the decision to take care of
the baby after childbirth.
Finally, she was transferred back to the
regional hospital, where she continued
Journal of ECT • Volume 35, Number 3, September 2019
clinical improvement until hospital dis-
charge at week 33 of the pregnancy. She
was referred to an outpatient clinic and re-
ceived support from local social services.
Total Positive and Negative Symptoms
Scale at that time was 42 (7 + 13 + 22).
At follow-up, clozapine dose was re-
duced to 200 mg/d because of drowsiness
and dizziness. No agranulocytosis was de-
tected. A forceps-assisted vaginal delivery
was carried out 38 weeks into the pregnancy,
with no perinatal complications. Apgar score
was 9/10/10. Birth weight was 3590 g, and
artificial feeding was started. The newborn's
blood test after birth showed normal white
blood cell count (21  103/μL). The first
days after childbirth, the newborn was hos-
pitalized in a neonatal unit owing to the se-
vere drowsiness of Miss O, which impeded
her ability to take care of her child for most
of the day. However, these symptoms pro-
gressively ameliorated, and discharge was
possible. No seizures, no withdrawal syn-
drome, nor other neonatal complications were
observed. Weekly blood tests conducted on
the newborn over the first month after birth
showed normal white blood cell count.
Six months after childbirth, Miss O
maintains symptomatic and functional re-
mission and has a good bond with her child.
DISCUSSION
Schizophrenia is considered a risk factor
for a high-risk pregnancy, owing to psycho-
sis interfering with prenatal follow-up and
impairing the mother-child bond. Clozapine
and ECT are a valid option for treatment-
resistant schizophrenia1; however, evidence
regarding safety during pregnancy is lim-
ited. The placental passage of clozapine is
partial, and the half-life value of clozapine
in neonates who were exposed in utero is
92 hours.2 For these reasons, some authors
recommend weekly blood tests on the new-
borns over the first 6 months after birth.3
Electroconvulsive therapy is a safe and
effective treatment option in schizophrenia.
Although main guidelines (American Psy-
chiatric Association 2001 and Royal College
of Psychiatrists 2005) do not state specific
contraindications of ECT during pregnancy,
well-documented cases are scarce (169 cases
since 1941). In recent years, there have been
3 systematic reviews on ECT during preg-
nancy. These reviews collected data from
case reports and case series. Whereas 2 of
them4,5 stated that ECT is safe and effective
in pregnancy, the other one6 found a sur-
prisingly high fetus and newborn mortality
rate (7.2%, ie, 12 deaths among 169 cases)
and high morbidity rates in pregnant women
and children (40% and 24%, respectively).
This latter review showed that the most com-
mon adverse events in pregnant women
were cesarean section, vaginal bleeding,
© 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
uterine contractions, premature labor, and
miscarriages; and for the fetus/child, cardiac
arrhythmias and fetal malformations. Infor-
mation about developmental delay or intellec-
tual disability among these children is limited,
since most studies had no follow-up data.
The different results in this latter review were
owing to the fact that it included all identified
adverse outcomes regardless of likelihood of
causal relationship, thereby overestimating
the risk.7 In addition, pregnancy complica-
tions have been noted in women with mental
health problems (eg, depression) regardless
of treatment. Finally, although safety data
are scarce and with low-grade evidence, it
is generally accepted that ECT should be
considered an option for pregnant women
with severe symptoms (ie, strong suicidal
urges, catatonia, and psychotic symptoms).
In conclusion, this case offers evidence
that ECT combined with clozapine may be
a safe and viable option when a rapid im-
provement of acute psychotic symptoms
during pregnancy is required due to self-
harm behavior.
ACKNOWLEDGMENTS
The authors thank Mr Andrew Pierce
for the English language editing of the
article.
Conrad Molins, MD
Psychiatry Department
Benito Menni CASM
Hospital General de Granollers
Granollers, Spain
cmolins.zambotti@gmail.com
Adriana Fortea, MD
Barcelona Clinic Schizophrenia Unit
Neuroscience Institute
Hospital Clinic of Barcelona
Barcelona, Spain
Institut d'Investigacions Biomèdiques
August Pi I Sunyer
Barcelona, Spain
Miquel Bioque, MD, PhD
Barcelona Clinic Schizophrenia Unit
Neuroscience Institute
Hospital Clinic of Barcelona
Barcelona, Spain
Institut d'Investigacions Biomèdiques
August Pi I Sunyer
Barcelona, Spain
Centro de Investigación Biomédica
en Red de Salud Mental
Madrid, Spain
Department of Medicine
University of Barcelona
Barcelona, Spain
Eva Solé, MD
Barcelona Clinic Schizophrenia Unit
Neuroscience Institute
Letters to the Editor
Hospital Clinic of Barcelona
Barcelona, Spain
Institut d'Investigacions Biomèdiques
August Pi I Sunyer
Barcelona, Spain
Centro de Investigación Biomédica
en Red de Salud Mental
Madrid, Spain
Department of Medicine
University of Barcelona
Barcelona, Spain
Perinatal Mental Health Unit
Hospital Clinic of Barcelona
Barcelona, Spain
Eduard Parellada, MD, PhD
Barcelona Clinic Schizophrenia Unit
Neuroscience Institute
Hospital Clinic of Barcelona
Barcelona, Spain
Institut d'Investigacions Biomèdiques
August Pi I Sunyer
Barcelona, Spain
Centro de Investigación Biomédica
en Red de Salud Mental
Madrid, Spain
Department of Medicine
University of Barcelona
Barcelona, Spain
A.F. has received travel support from
Lundbeck. M.B. has received honoraria from
talks and consultancy of Adamed, honoraria
from consultancy of Ferrer, research support
and honoraria from talks as well as consul-
tancy of Janssen-Cilag, honoraria from talks
and consultancy of Lundbeck, honoraria
from talks and consultancy of Otsuka, and
a research prize from Pfizer. E.P. has re-
ceived honoraria and/or research grants
from the Fondo de Investigación Sanitaria
of the Spanish Ministry of Science and In-
novation, MINECO, Pons Balmes Grant,
Fundació la Marató de TV3 of Catalonia,
Janssen-Cilag, GlaxoSmithKline, Ferrer,
and ADAMED. C.M. and E.S. have nothing
to disclose.
REFERENCES
1. Petrides G, Malur C, Braga RJ, et al.
Electroconvulsive therapy augmentation in
clozapine-resistant schizophrenia: a prospective,
randomized study. Am J Psychiatry. 2015;172:
52–58.
2. Imaz ML, Oriolo G, Torra M, et al. Clozapine use
during pregnancy and lactation: a case-series
report. Front Pharmacol. 2018;9:264.
3. Gentile S. Antipsychotic therapy during early
and late pregnancy. A systematic review.
Schizophr Bull. 2010;36:518–544.
4. Anderson EL, Reti IM. ECT in pregnancy:
a review of the literature from 1941 to 2007.
Psychosom Med. 2009;71:235–242.
www.ectjournal.com e31
Letters to the Editor
5. Pompili M, Dominici G, Giordano G, et al.
Electroconvulsive treatment during pregnancy:
a systematic review. Expert Rev Neurother. 2014;
14:1377–1390.
6. Leiknes KA, Cooke MJ, Jarosch-von Schweder
L, et al. Electroconvulsive therapy during
pregnancy: a systematic review of case studies.
Arch Womens Ment Health. 2015;18:1–39.
7. Sinha P, Goyal P, Andrade C. A meta-review of
the safety of electroconvulsive therapy in
pregnancy. J ECT. 2017 Jun;33:81–88.
Effects of Repeated Sessions
of Transcranial Direct Current
Stimulation on Major
Depressive Disorder
and Cognition
To the Editor:
W e report the following 2 cases to
highlight the importance of keeping
into account cognitive functioning when
assessing the efficacy of transcranial direct
current stimulation (tDCS) for the treatment
of major depressive disorder (MDD). Major
depressive disorder is often associated with
mild cognitive impairment (MCI), which
further worsens the patient's condition.1 An-
odal tDCS of the left dorsolateral prefrontal
cortex (DLPFC) is beginning to demonstrate
its efficacy in the treatment of MDD2 and
has potentials for enhancing cognitive func-
tioning in MCI.3
We evaluated therapeutic effects of 6
sessions of anodal tDCS of the left DLPFC
in two 79-year-old men who were experienc-
ing a 24-month episode of MDD. Patient 1
(P1; 17 years of education) was diagnosed
with MCI on prior standard neuropsycho-
logical evaluation. Patient 2 (P2; 8 years
of education), who had a family history of
degenerative diseases, had manifested gait
instability for the last 3 years. In this patient,
fluorine‐18‐fluorodeoxyglucose positron
emission tomography examination, per-
formed 6 months before, showed reduced
bilateral parietotemporal metabolism com-
patible with Alzheimer disease. Pharmaco-
logical treatment (P1: lorazepam 1 mg/die,
alprazolam 0.5 mg/die; P2: lorazepam
3 mg/die, quetiapine 300 mg/die, amisulpride
50 mg/die, duloxetine hydrochloride 60 mg/die,
zolpidem 20 mg/die) was maintained con-
stant throughout the study.
We also assessed the patients' cogni-
tive functioning and independence on daily
activities. Because age-related physiologi-
cal decline mainly affects right hemisphere
functions, and given the evidence that brain
stimulation modulates spatial attention,4
e32 www.ectjournal.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Journal of ECT • Volume 35, Number 3, September 2019
we additionally evaluated tDCS effects on
spatial cognition. Patients signed a written
informed consent. As in previous studies,2
tDCS was administered by placing the anode
over the F3 site (according to the 10–20 inter-
national electroencephalography system) and
the cathode (as reference electrode) over the
contralateral supraorbital area. Direct current
was generated by a Newronika HDCstimulator
(Newronika s.r.l.) and delivered via a pair
of square scalp electrodes with a surface
of 25 cm2 covered with conductive rubber
and saline-soaked synthetic sponges. On
the first day, tDCS was applied for only
15 minutes with an intensity of 1 mA. Be-
cause patients tolerated well this stimula-
tion duration, for subsequent sessions, tDCS
was administrated for 20 minutes at the
same intensity. The 6 stimulation sessions
were administered every other day over a
2-week period.
The patients' depressive symptoms and
quality of life were evaluated on the Hamilton
Rating Scale for Depression (HAM-D)
and the Short Form Test–36 (SF-36), re-
spectively. The SF-36 is composed of 9
dimensions: physical functioning, role-
physical, bodily pain, general health, vi-
tality, social functioning, role-emotional,
mental health, changing in health state.
The patients' level of independence was
rated by the examiner with the help of
the caregiver using the Katz Index of In-
dependence in Activities of Daily Living
(ADL) and the Lawton-Brody Instrumen-
tal Activities of Daily Living Scale
(IADL). Cognitive functioning was assessed
using the Montreal Cognitive Assessment
(MoCA), Verbal Fluency tests (phonemic
and semantic), and the Line Bisection Task
(LBT; ie, ten 20-cm lines). The above tests
were administered 1 week before the stimula-
tion (T0) and 2 weeks after the end of treat-
ment (T3), whereas a brief assessment,
consisting exclusively of the LBT and ver-
bal fluency, was administered immediately
before (T1) and 2 days after treatment (T2).
The HAM-D, SF-36, and ADL and IADL
questionnaires were referenced to the last
4 weeks.
Both patients tolerated well tDCS with-
out complications. P1 showed improvement
on the HAM-D [T0 = 9 (mild depression);
T3 = 6 (no depression)] and on the MoCA
[T0 = 20/30 (cognitive decline); T3 = 23/
30 (cutoff score)—total MoCA score of 23
or above is considered to be normal]. How-
ever, he showed a decrement in 5 of the 9
SF-36 subscales (ie, role-physical, general
health, vitality, role-emotional, and mental
health). P2 manifested improvement on the
HAM-D [T0 = 13 (mild depression); T3 = 6
(no depression)], the ADL [T0 = D (depen-
dent); T3 = A (independent)], and the
IADL [T0 = 1/5; T3 = 2/5] questionnaires.
© 2019 Wolters Kluwer Health, Inc. All rights reserved.
Furthermore, he showed amelioration in
2 of 9 SF-36 dimensions (bodily pain
and social functioning). However, in this
patient, improvement in depression and daily
living activities was associated with signif-
icant worsening of cognitive functioning
as revealed by the MoCA score (from
T0 = 20/30 to T3 = 14/30).
Both patients showed a spatial atten-
tion rightward bias (about +10 mm or more)
on the LBT before (T1: P1 = +9 mm;
P2 = +12 mm) and soon after treatment
(T2: P1 = +18 mm; P2 = +15 mm) that dis-
appeared at follow-up (T3: P1 = 0 mm;
P2 = +4 mm). Only P1 showed some im-
provement in phonemic fluency at T2
(T0 = 2, T1 = 1, T2 = 4, and T3 = 2),
whereas no changes were observed for
P2 for the patients' semantic fluency.
These findings are in line with pre-
vious studies showing improvement of
depression after anodal tDCS of the left
DLPFC. Mood improvement was accom-
panied by improved spatial attention in
both patients. However, after treatment,
verbal and phonemic fluency showed no
(P2) or minimal change (P1), and cogni-
tive functioning (MoCA) improved in
1 patient (P1) and worsened in the other
(P2). Worsening of cognitive functioning
after tDCS might be explained by the se-
verity and/or the type of the neurocognitive
condition of P2 (eg, prefrontal tDCS might
have further worsened the activity of the
posterior regions). Surprisingly, P1, who
showed amelioration in both mood and
cognitive scales, manifested a decrement
in the quality of life subscales. We hy-
pothesize that the improved cognitive
functioning of P1 might have increased
awareness of the disease and quality of
life.5 In line with this hypothesis, P2’s
worsened cognitive functioning might have
further impaired awareness of the disease,
as revealed by improved evaluations of
quality of life. These findings suggest a
possible dissociation of tDCS effects on
mood and cognition.2 Future investigations
in large groups of patients are needed to
understand differential effects of tDCS
treatment on depression, cognition,2 and
awareness of symptom amelioration.5
Marco Ninghetto, MSc
Roberto Gammeri, MSc
Roberta Miccolis, MSc
SAMBA (SpAtial, Motor &
Bodily Awareness) Research Group
Department of Psychology
University of Turin
Turin, Italy
Marcello Nobili, MD
Academy of Medicine of Turin
Turin, Italy