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 INDEX

VOLUME 47 • NUMBER 5 • 2020

Editorial
Lithium and Lactation .......................................................................................................................................... 123
Maria Luisa Imaz, Rocio Martin-Santos

Original articles
Prevalence and comorbidity of psychiatric symptomology in Pakistani female adolescents ............. 125
Farzana Ashraf, Najma Najam, Aasia Nusrat

Is there a relationship between thyroid hormone levels and suicide attempt in adolescents? .......... 130
Gamze Gokalp, Emel Berksoy, Sefika Bardak, Gulsah Demir, Sule Demir, Murat Anil

The effect of trauma type on the severity of Post-Traumatic Stress Disorder (PTSD) symptoms ......... 135
Ayşegül Taşdelen Kul, Ibrahim Gündoğmuş

Review articles
Lesion localization and performance on Theory of Mind tests in stroke survivors: a systematic review
.................................................................................................................................................................................. 140
AnaJuliade LimaBomfim, BiancaLetíciaCavalmoretti Ferreira, Guilherme Riccioppo Rodrigues, Octavio Marques Pontes-Neto,
Marcos Hortes Nisihara Chagas

The impact of exercise in improving executive function impairments among children and adolescents
with ADHD, autism spectrum disorder, and fetal alcohol spectrum disorder: a systematic review and
meta-analysis ....................................................................................................................................................... 146
Anjali L. Varigonda, Juliet B. Edgcomb, Bonnie T. Zima

Letter to the editor

Treatment of insomnia with repetitive transcranial magnetic stimulation (rTMS) in a patient with
posttraumatic stress disorder (PTSD) .............................................................................................................. 157
Abdullah Bolu, Ibrahim Gündoğmuş, Taner Öznur, Cemil Çelik

Excessive consumption of tianeptine by a person with former alcohol problem ................................... 159
Jakub Grabowski, Leszek Bidzan

Vortioxetine-induced nausea and its treatment: a case report .................................................................. 160

Calogero Crapanzano, Andrea Politano, Chiara Amendola, Despoina Koukouna, Ilaria Casolaro

Huntington’s disease presenting as mixed state episode ........................................................................... 162

Laiane Tábata Souza Corgosinho, João Antônio Bomfim Silva, Rogério GomesBeato, ViniciusSousa Pietra Pedroso

Treatment of food addiction: preliminary results .......................................................................................... 163

Edgar Luis Lima deOliveira, EmilieLacroix, Andrea Lorena Costa Stravogiannis, Maria deFátima Vasques, CristianeRuiz
Durante, Érica Panzani Duran, Daniela Pereira, JaniceRicoCabral, HermanoTavares

Lithium and Lactation
Maria Luisa Imaz1
https://orcid.org/0000-0001-7517-9218
Rocio Martin-Santos1,2
https://orcid.org/0000-0003-4150-4726
1Unidad de Salud Mental Perinatal, Servicio de Psiquiatría y Psicología, Hospital Clínic, Departamento de Medicina, Instituto de Neurociéncias, Universidad de Barcelona (UB); Instituto de
Investigación Biomédica August Pi i Sunyer (IDIBAPS), y Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, España.
2National Institute for Translational Medicine (INCT-TM), CNPq, Ribeirão Preto, São Paulo, Brazil.
Received: 21/09/2020 – Accepted: 21/09/2020
DOI: 10.1590/0101-60830000000246
Imaz ML et al. / Arch Clin Psychiatry. 2020;47(5):123-124
Medication use by the nursing mothers is a controversial topic,
with the potential for infants to be exposed via breastmilk. This
ethical dilemma has led to health professionals, authorities, and
parents considering infant formula to be a reasonable alternative to
mitigate risk. As a consequence, there is a lack of evidence about the
safety and efficacy of many medications during lactation, including
lithium1. Decisions to use lithium during the perinatal period are
challenging because information about the efficacy and safety for
the mother-child dyad come from observational studies of lactation
outcomes, which have important limitations and biases2,3.
Breastfeeding is an important public health issue because it
promotes health, prevents disease, and contributes to reducing
health inequalities in mothers and nursing infants. Breastfeeding is
also a great benefit to the environment and society4. Human milk
is uniquely tailored to meet the nutritional needs of human infants,
including premature and ill newborns. It has the appropriate balance
of nutrients provided in easily digestible and bioavailable forms.
Optimal infant and young child feeding practices include exclusive
breastfeeding for the first 6 months of life, if possible, followed
by combining breastmilk with adequate, safe, and appropriate
complementary foods until the infant is at least 1–2 years old5.
According to the US National Centers for Disease Control and
Prevention, there are few contraindications to breastfeeding. These
include maternal infection with HIV, human T-cell lymphotropic
virus type 1 or 2, active untreated tuberculosis, or herpes simplex
lesions on the breast. Additionally, maternal use of illicit street drugs
(i.e., phencyclidine or cocaine), chemotherapeutic agents (drugs
interfering with cell replication), and radioactive isotope therapies
should contraindicate breastfeeding. Concerning the infants
themselves, those with galactosemia should not be breastfed6.
However, a 2012 clinical report by the American Academy of
Pediatrics7 indicated that most medications and immunizations are
safe to use during lactation.
A common reason for never starting or for interrupting
breastfeeding is medication use by the nursing mother. Any
pharmacologic therapeutic decision during lactation should be
guided by the best available evidence and the importance of benefit
for each patient. Factors influencing the decision to breastfeed
converge around the advantages and risks of breastfeeding for the
mother and infant, the socio-demographic and clinical features of
the mother, personal experience and family tradition, the presence
of a support system (whether professional or partner, family,
social), and personal choice. The optimal time to explore women’s
preferences for breastfeeding and to educate the family about
treatment options during breastfeeding is before they conceive
or early in pregnancy8. Options include exclusive breastfeeding,
Address for correspondence: Maria Luisa Imaz, Unidad de Salud Mental Perinatal, Servicio de Psiquiatría y Psicología, Hospital Clínic, Departamento de Medicina, Instituto de Neurociéncias,
Universidad de Barcelona (UB); Instituto de Investigación Biomédica August Pi i Sunyer (IDIBAPS), y Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, España.
Editorial
breastfeeding supplemented with formula, or exclusive formula
feeding.
Bipolar disorder is a chronic mental illness that affects about 350
million people worldwide, equating to 3% of the world population.
It affects men and women in comparable rates, often starting before
age 25 years, without cultural or ethnic variation9,10. There seems
to be a higher risk for women to suffer bipolar II (hypomania),
rapid cycling, and mixed episodes compared with men. Lithium
use for the treatment of bipolar disorder has been reported since
late 1940s11 and was approved in 1970 by the US Food and Drug
Administration (FDA) for the treatment of acute mania and in
1974 for the long-term maintenance of bipolar disorder. It is also
prescribed as adjunctive treatment in major depressive disorder
and for preventing suicidal behavior in patients with affective
disorders12-13.
Women with bipolar disorder are at high risk of symptom
relapse during the perinatal period14. Although its use during the
first trimester has been associated to a dose-dependent increase
risk of congenital malformations15, it has proven to be an effective
preventive treatment during perinatal period16. In relation to
treatment at others stages of life, some peculiarities must be
considered for the management of lithium treatment during the
perinatal period. For example, physiological renal changes during
pregnancy17 may alter the pharmacokinetics of lithium, and its
serum concentrations will decline throughout pregnancy. This
necessitates preferably weekly monitoring in the third trimester
with does adjustment to maintain therapeutic levels18. Lithium
also has a complete placental passage and equilibrates between
the maternal and fetal circulation across a wide range of maternal
concentrations (0.2–2.6 mEq/L)19. It has been shown that neonatal
serum lithium concentrations >0.64 mEq/L may be associated
with an increased rate of neonatal complications such a lethargy,
cyanosis, hypothermia, hypotonia, hypothyroidism, hypoglycemia,
polyuria, respiratory problems, and poor drinking ability19-20.
Postpartum, serum lithium concentrations in the mother gradually
return to their preconception levels, and this presents a risk for
lithium intoxication if women have had their dose increased during
pregnancy. Lithium serum concentration should be measured twice
weekly for the first 2 weeks after delivery and monthly thereafter for
the next 3–6 months18.
Lithium is a cation that transfers easily into breast milk. The
recommendations for its use during breastfeeding vary due to the
high variability of its diffusion into breastmilk, the secondary risk
of lithium toxicity in the newborn, and the risk of relapse associated
with sleep deprivation during the period of exclusive maternal
breastfeeding21. There are limited data about the long-term effects
124 Imaz ML et al. / Arch Clin Psychiatry. 2020;47(5):123-124
of lithium exposure via breastmilk, but it does seem that the risk
of serious adverse events in the nursing infants is relatively low7.
Two recent systematic reviews concerning clinical lactation and
lithium showed that exposure of the nursing infant to lithium is less
during breastfeeding than during pregnancy. However, there was
also a high degree of heterogeneity between the studies, including
exposure durations, the presence of polypharmacy, lithium sampling
times, type of breastfeeding, and age of infants2,3. Nevertheless, it
is certainly plausible that nursing infants would be vulnerable to
the same side effects as adults, including changes in thyroid and
renal functions. In turn, this necessitates regular clinical and blood
monitoring (e.g., serum lithium, thyroid stimulating hormone,
blood urea nitrogen, and creatinine) immediately postpartum and
at regular intervals while breasfeeding22.
Given the many benefits of breastfeeding, some women who
may also benefit from lithium in the postpartum period are likely
to consider breastfeeding. The professionals involved in this
consultation must be adequately trained about the pharmacology
of lactation8. Women should then have an individualized
breastfeeding plan drafted in collaboration with perinatal
psychiatrists, obstetricians, pediatricians, midwives, nurses, and
family physicians. Research in international collaborative networks
would be interesting to increase current evidence to support women
in achieving their breastfeeding goals.
References
1. Amir LH, Grzeskowiak LE, and Kam RL. Ethical issues in use of
medications during lactation. J Hum Lact 2020; 36:34-9.
2. Newmark RL, Bogen DL, Wisner KL, Isaac M, Ciolino JD, Clark CT.
Risk-benefit assessment on infant exposure to lithium through breast
milk: a systematic review of the literature. Int Rev Psychiatry 2019;
31:295-304.
3. Imaz ML, Torra M, Soy D, García-Esteve L, Martin-Santos R. Clinical
lactation studies of lithium: a systematic review. Front Pharmacol. 2019
10;10:e1005.
4. U.S. Department of Health and Human Services, 2011. The surgeon
general’s call to action to support breastfeeding. Department of Health
and Human Services, Office of the Surgeon General. Washington, DC:
U.S.
5. World Health Organización/UNICEF. Global strategy for infant and
young child feeding. 2003. https://www.who.int/nutrition/publications/
infantfeeding/924156228/en/. Accessed August, 2020
6. Centers for Disease Control and Prevention (CDC). Breastfeeding
and special circumstances.https://www.cdc.gov/breastfeeding/
breastfeeding-special-circumstances/index.html. Accessed August,
2020.
7. The American Academy of Pediatrics (AAP). Breastfeeding and the use
of human milk. Pediatrics 2012;129: 827-41.
8. American College of Obstetricians and Gynecologists (ACOG).
Optimizing support for breastfeeding as part of obstetric practice.
ACOG Committee Opinion No. 756. Obstet Gynecol 2018;132:e187–96.
9. Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, Viana MC,
Andrade LH, Hu C, Karam EG, Ladea M, Medina-Mora ME, Ono Y,
Posada-Villa J, Sagar R, Wells JE, Zarkov Z. Prevalence and correlates of
bipolar spectrum disorder in the world mental health survey initiative.
Arch Gen Psychiatry. 2011; 68:241-51.
10. GBD 2017. Disease and Injury Incidence and Prevalence Collaborators.
Global, regional, and national incidence, prevalence, and years lived with
disability for 354 diseases and injuries for 195 countries and territories,
1990–2017: a systematic analysis for the Global Burden of Disease Study
2017. The Lancet 2018; 392:1789-858.
11. Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J
Aust 1949: 2 (10):349-352.
12. Tondo L, Alda M, Bauer M, Bergink V, Grof P, Hajek T, Lewitka U,
Licht RW, Manchia M, Müller-Oerlinghausen B, Nielsen RE, Selo M,
Simhandl C, Baldessarini RJ; International Group for Studies of Lithium
(IGSLi). Clinical use of lithium salts: guide for users and prescribers. Int
J Bipolar Disord. 2019;7:16.
13. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention
of suicide in mood disorders: updated systematic review and meta-
analysis. BMJ. 2013; 346: f3646.
14. Viguera AC, Tondo L, Koukopoulos AE, Reginaldi D, Lepri B,
Baldessarini RJ. Episodes of mood disorders in 2,252 pregnancies and
postpartum periods. Am J Psychiatry. 2011;168:1179-85.
15. Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H,
Cohen LS, Hernandez-Diaz S. Lithium Use in Pregnancy and the Risk of
Cardiac Malformations. N Engl J Med. 2017;376:2245-54.
16. Bergink V, Burgerhout KM, Koorengevel KM, Kamperman AM,
Hoogendijk WJ, Lambregtse-van den Berg MP, Kushner SA. Treatment
of psychosis and mania in the postpartum period. Am J Psychiatry.
2015;172:115-23.
17. Feghali M, Venkataramanan R, Steve C. Pharmacokinetics of drugs in
pregnancy. Semin. Perinatol. 2015;39: 512-9.
18. Wesseloo R, Wierdsma AI, van Kamp IL, Munk-Olsen T, Hoogendijk
WJG, Kushner SA, Bergink V. Lithium dosing strategies during
pregnancy and the postpartum period. Br J Psychiatry. 2017;211:31-6.
19. Newport DJ, Viguera AC, Beach AJ, Ritchie JC, Cohen LS, Stowe ZN.
Lithium placental passage and obstetrical outcome: implications for
clinical management during late pregnancy. Am J Psychiatry. 2005; 162:
2162-70.
20. Kozma C. Neonatal toxicity and transient neurodevelopmental deficits
following prenatal exposure to lithium: Another clinical report and a
review of the literatura. Am J Med Genet A 2005;132A:441-4.
21. Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of
bipolar disorder: Recommendations from clinical practice guidelines. J
Affect Disord. 2017;217:266-80.
22. Viguera AC, Newport DJ, Ritchie J, Stowe Z, Whitfield T, Mogielnicki J,
Baldessarini RJ, Zurick A, Cohen LS: Lithium in breast milk and nursing
infants: clinical implications. Am J Psychiatry 2007; 164:342-5.
 Original article

Prevalence and comorbidity of psychiatric symptomology in Pakistani female

adolescents
Farzana Ashraf1
https://orcid.org/0000-0003-0110-2618

Najma Najam2
https://orcid.org/0000-0002-5013-0212

Aasia Nusrat1
https://orcid.org/0000-0002-0653-4148

1 Department of Humanities, COMSATS University, Lahore, Punjab, Pakistan.

2 Institute of Applied Psychology, University of The Punjab, Lahore, Punjab, Pakistan.

Received: 08/09/2019 – Accepted: 06/04/2020

DOI: 10.1590/0101-60830000000247

Abstract
Background: Previous researchers have demonstrated the co-existence of psychiatric conditions across clinical as well as non-clinical samples in diverse
situations. The present study examined the prevalence and co-morbidity of various psychiatric symptoms (e.g. learning disabilities, depression and anxiety)
in school-age female adolescents. Methods: In a cross-sectional random sampling method, 252 girls from two government schools in Lahore were assessed
by Learning Disabilities Checklist, Children Depression Inventory and the Spence Anxiety Scale. Results: The results demonstrate significant prevalence and
co-morbidity of psychiatric symptoms. Of the 252 participants, 34%, 21% and 68% had significant learning disabilities, depression and anxiety symptoms
respectively. In addition, 27% of them presented symptoms of three studied psychiatric conditions. A highly significant positive correlation was found between
learning disabilities, depression and anxiety symptoms. Methods: There is a dire need for preventative intervention programs to promote mental health at
school level. Further, assessment plans for the screening of psychiatric symptoms in normative samples also need to be put in place.

Ashraf F et al. / Arch Clin Psychiatry. 2020;47(5):125-129

Keywords: Learning disabilities, depression, anxiety, female adolescents.

Introduction psychiatric symptoms is observed for both genders, though slightly

Some psychiatric manifestation such as learning disabilities (LD),
depressive and anxiety symptoms have emerged as commonly
prevalent illness across the globe1. Estimations of World Health
Organization in 2017 claim that approximately 300 million people are
living with depressive symptoms and 260 million people are suffering
from anxiety symptoms globally2. Though, level of severity of these
symptoms varies, yet large figures directs toward the sensitivity of
psychiatric symptomology in general population. Earlier, when
examining disability adjusted life years (DALYs) for a larger sample
ranging from adolescents to middle aged females, psychiatric
symptomology (anxiety and depressive symptoms) collectively
accounted for 7% of the DALYs3. Particularly for adolescent girls
ages between 15 to 19 years, these symptoms were seen as in the top
five reasons od DALYs across the globe4.
Comorbidity of anxiety and depressive symptoms have been
seen in link with several other psychiatric manifestation across
diverse age groups. As adolescence is period of stressful transition
majority characterized by academic difficulties as well, LD are
seen dominantly linked with depressive and anxiety symptoms5.
Depressive and anxiety symptoms are most commonly co-occurring
psychiatric symptoms and several factors are contributing to this
in their own capacity6. Psychiatric disorders, particularly in young
girls are generally under researched in developing countries such
as Pakistan. A plethora of research has illustrated interesting fact
about gender differences in variations in prevalence of psychiatric
symptomology7-10. Psychiatric symptoms and comorbidities are
more than twice as prevalent in young (ages between 14 to 25 years)
girls than boys but the ratio decreases and almost equalizes with
age6-8. Furthermore, starting from puberty, young girls are more at
greater risk of developing mood symptoms and other mental health
issues globally6. Interestingly, before puberty, similar ratio of several
high rates in boys in some findings7. As both grew older (above 65
years), a decline in prevalence of depressive symptoms is seen and
differences also minimize8,9. An increase in prescriptions of anti-
depressant medication is also an indicator of dominant prevalence
of psychiatric symptoms in females. A Canadian study revealed
prescription ratio of antidepressants twice for young females than
males10. Particularly, being part of collectivist culture, these facilities
predominantly lacks for females. In addition, psychiatric problems
remain under estimated, unidentified and undiagnosed due to
insufficient mental health facilities in developing countries such as
Pakistan. This context also justifies the reason to estimate prevalence
of psychiatric symptomology only in young females.
Many psychiatric symptoms develop during adolescence and are
left unattended, therefore often remain undiagnosed and untreated
even in later life11. The onset of many psychiatric disorders such LD,
depression and anxiety peaks in adolescence and the early years of
adulthood; female adolescents are more prone to these conditions
than male adolescents2,3. In most cases, female have twice the rates of
anxiety, depression and LD12,13. In cases of misdiagnosis or improper
screening, the psychiatric symptomology not only affects adolescents’
present state of mind but hinders their overall development later in
life, in particular, poor school results, violent and aggressive behavior,
poor parent-child relationships and drug abuse, in many cases14.
While addressing psychiatric prevalence, depression is generally
described as a group of affect associated symptoms with 7.4% of
adolescent sufferers worldwide15. Anxiety is a more generalized
condition, therefore a more common mental disorder, which if left
undiagnosed and untreated, may lead to higher risk of poor school
performance, social deficits and substance abuse16,17. LD are a rapidly
rising issue in growing adolescents and manifested through poor
functioning of the psychological processes involved in the ability
to read, write, think, listen and make mathematical calculations18.

Address for correspondence: Farzana Ashraf. Department of Humanities, COMSATS University. Lahore, Punjab, Pakistan. Telephone: 092-332-7868005. E-mail: Farzana.ashraf@cuilahore.edu.pk
126 Ashraf F et al. / Arch Clin Psychiatry. 2020;47(5):125-129
According to the latest available empirical evidence, an estimate
of 3.9% of the population in the South East Asia regions suffer
from depressive disorders19, 8% have generalized anxiety disorders
(GAD)20 and 19% have LD21, with significantly more female sufferers
than male. In the context of female adolescents in Pakistan, 11.06%
were found to have depressive disorders19, 9% GAD20 and 16% had
LD22, and these levels either higher or similar to global estimates.
Rapidly changing lifestyles across the globe, especially in developing
countries, such as Pakistan has a clear influence on the mental health
of individuals in terms of their exhibiting psychiatric symptoms
which suggests the likely co-existence of symptoms. A study of
Pakistani female adolescents’ found 3% coexistence of a severe level
of anxiety and depressive symptoms23 whereas cases of LD with
depression were observed to be 15%22. However, the possible co-
existence of anxiety with LD remains unknown for the adolescent
female population in Pakistan. These studies suggest that adolescents
diagnosed with one psychiatric disorder are likely to suffer from
other psychiatric symptoms as well. In addition, due to certain,
psychological and socio-economic factors, psychiatric symptoms
are likely to be more prevalent in south Asian region, therefore
their detection and treatment needs to be considered carefully. The
research reported here was designed to estimate the prevalence and
comorbidity of psychiatric symptoms (in this case, LD, depression
and anxiety) in female adolescents enrolled in secondary schools in
Lahore, Pakistan.
Materials and methods
Research design
A cross-sectional study was carried out on a sample of Pakistani
female adolescents. These participants were recruited from two
government schools in Lahore city, from January 2019 to May 2019.
Participants
The study participants are 252 girls aged between 12 to 18 years (M
= 14.83, ± 1.20) enrolled in secondary schools
Sampling technique
The sample was recruited using random sampling from two
schools in Lahore. Random sampling is most appropriate sample
selection technique when the purpose is to select a homogenous
sample from larger normative population. Further, it also allows
to control selection bias and judgment error. Furthermore, the
selected two schools are with highest number of students in the city
and represent every sections of population within the city which
makes current study representative of all section of region. After
excluding any unsuitable respondents due to physical disabilities,
intellectual difficulties, visual or hearing impairments, which would
have coloured their responses, a sample of 252 girls remained with a
response rate of 94% well balanced across 3 grade levels, that is., 6th
(31%), 7th (33%), and 8th (49%).
Instruments
To assess the study variables, the standardized paper-pencil measures
of the Learning Disabilities Checklist (LDC)24, Children Depression
Inventory (CDI)25 and Spence Children Anxiety Scale (SCAS)26 were
administered. All three measures have been developed as diagnostic
guidelines of DSM-IVTR and are widely used in clinical as well as
sub-clinical and normative populations. LDC is a 35 item teacher
report screening measure (e.g., item 1; confuses similar looking
letters and numbers) used to assess three forms of LD; reading (n
= 15), writing (n = 10) and mathematics (n = 10) in school going
adolescents between 11 to 18 years old. LDC categorizes at/below
25% scores as mild (without LD) and at/above 75% as severe (with
LD), while scores between 26% to 74% are classified as moderate
(sub-clinical). The responses were scored dichotomously (yes = 1, no
= 0) and composite score ranged between 0 and 35. CDI is a 27 item
self-reporting measure of the severity of depression within five areas
e.g., negative self-esteem, feeling of ineffectiveness, interpersonal
problems, and feeling of anhedonia. Each statement has a three points
scale response (0 to 2) with category ranges 0 to 19 mild, 20 to 39
moderate and above 39, severe depression. SCAS has 45 items and is
a self-reporting measure designed to assess the severity of anxiety in
six domains (e.g., psychological separation, social phobia, obsessions
& compulsions, panic agoraphobia, physical injury and generalized
anxiety). The scores range from 0 to 144 and raw scores parallel to
60 T scores are regarded as severe/elevated, 40 to 50 as moderate and
below 40 as mild levels of anxiety.
Ethical considerations
Ethical approval for the research was obtained from the Institutional
Review Board and the consent of school authorities and the
students’ parents was also obtained. All the relevant authorities and
participants were orally informed about the objectives of the study
and were assured of the privacy of data and the confidentiality of
the information provided. The respondents were assured they could
choose to withdraw from the study at any point during the process.
Data analysis
The data was analyzed using descriptive statistics including the
mean, standard deviation, frequencies, percentages and graphs as
well as inferential statistics such as Pearson correlation analysis.
A confidence interval of 95%, and a p value of <.05 are considered
statistically significant.
Results
The present research was carried out with 252 young girls aged from
12 to 18 years old and enrolled in grades 6th, 7th and 8th. The findings
from statistical analyses demonstrate that 34%, 21% and 68% of the
study participants self-reported severe levels of LD, depression and
anxiety respectively (Table 1). Collectively, 9%, 49% and 42% of
girls’ reported mild, moderate and severe psychiatric symptoms of
LD, depression and anxiety. Table 2.1 illustrates the co-occurrence
of LD, depression and anxiety symptoms; the association of LD with
depression symptoms at a severe level was 10%, whereas in the case of
anxiety symptoms, it was 28%. Depression with anxiety symptoms at
a severe level was 20%. Table 2.2 indicates the co-occurrence of three
psychiatric conditions mild, moderate and severe levels of depression
and anxiety at mild, moderate and severe levels of LD. The results
show that 27% of the study participants with a severe level of LD also
reported symptoms of a severe level of depression and anxiety. Table
3 and Figure 1 show highly significant correlations of LD scores and
its sub-domain, with symptoms of depression and anxiety and their
sub-domains at a minimum p value of < 0.05.
Discussion
The current study examined the prevalence of psychiatric symptoms
in a normative sample of female adolescents and found overall, higher
levels of prevalence compared to those reported in other regional and
international studies19-213. Though high rates of the co-occurrence
of symptoms of the conditions investigated were not observed, yet
these findings provide evidence that the experience and reporting
of psychiatric symptoms across the regions have some common
features and similarities with reports in other South Asian regions
despite differences in cultural circumstances and demographic and
socio-economic factors. One explanation of this co-occurrence
in the present study could be the paper and pencil assessment of
study constructs by the female adolescents may possibly facilitate
 Ashraf F et al. / Arch Clin Psychiatry. 2020;47(5):125-129 127

Table 1. Co-occurrence of learning disabilities, depression and anxiety symptoms (N = 252)

Variables Learning disabilities Depression Anxiety Average
f (%) f (%) f (%) (%)
Mild 40 (16%) - 29 (12%) 9%
Moderate 125 (50%) 198 (79%) 50 (20%) 49%
Severe 87 (34%) 54 (21%) 173 (68%) 42%

Table 2.1. Cross Co-existence of learning disabilities, depression and anxiety (N = 252)
Variables Depression Anxiety
Mild Moderate Severe Mild Moderate Severe
f (%) f (%) f (%) f (%) f (%) f (%)
LD Mild - 40 (15%) - 9(4%) 16 (6%) 15 (6%)
Moderate - 96 (38%) 29 (12%) 12 (5%) 26 (10%) 87 (35%)
Severe - 62 (25%) 25 (10%) 8 (3%) 7 (3%) 72 (28%)
Anxiety Mild - - -
Moderate 29 (12%) 47 (19%) 122 (48%)
Severe - 2 (1%) 52 (20%)
Note: LD: learning disabilities.

Table 2.2. Co-existence of learning disabilities, depression and anxiety (N = 252)

Variables N Anxiety Depression
Mild Moderate Severe
f (%) f (%) f (%)
LD Mild 40 Mild - 9 (23%) -
Moderate - 16 (40%) -
Sever - 15 (37%) -
Moderate 125 Mild - 12 (10%) -
Moderate - 26 (21%) -
Sever - 58 (46%) 29 (23%)
Severe 87 Mild - 8 (9%) -
Moderate - 5 (7%) 2 (1%)
Sever - 49 (56%) 23 (27%)
Note: LD: learning disabilities.

Table 3. Correlations between dimensions of learning disabilities, depression and anxiety

Variables Learning Disabilities Depression
Reading Writing Mathematical Negative Negative Self- Ineffectiveness Interpersonal Anhedonia
Disability Disability Disability Mood esteem Communication
Anxiety
Separation Anxiety .279*** .212*** .200** .258*** .290*** .256*** .296*** .398***
Social Phobia .119 .163** .165** .337*** .149* .141* .309*** .348***
Obsessive Compulsive .187** .187** .325*** .254*** .206** .351*** .242*** .311***
Panic/Agoraphobia .480** .413** .454*** .626*** .504*** .735*** .708*** .697***
Physical Injury .259*** .193** .302** .240** .256** .229** .179** .328**
Generalized Anxiety .168** .053 .184** .243*** .382*** .313*** .261*** .433***
Depression
Negative Mood .219** .232*** .354***
Negative Self Esteem .109 .103 .244**
Ineffectiveness .243*** .334*** .431***
Interpersonal Communication .428*** .436*** .357***
Anhedonia .229*** .156* .319***
*p<.05, **p<.001, ***p<.0001.
r= + 0.36, p<.001.
r=+ 0.28, p<.001.
r= = +. 0.58, p<.0001.
128 Ashraf F et al. / Arch Clin Psychiatry. 2020;47(5):125-129
Figure 1. Correlation matrix of learning disabilities, depression and anxiety in girls (N = 252).
subjectivity and the exaggeration of experiences of psychiatric
symptoms27,28. Furthermore, LDC, CDI, and SASC measures are
standardized and used globally as well as in a local context, yet the
cut off (for CDI and SASC) and the sensitivity and specificity (of all
three measures) have not been tested locally so far.
The current study revealed interesting finding regarding the
coexistence of LD and depression at 15%, which is higher than
previous reports of 10%, which could be due to the dichotomous
classification of LD (with and without) and the homogeneity large
sample sizes in previous reporting22. By contrast, the coexistence of
anxiety and symptoms of depression in the present study of 28%,
is also higher than previous reports of 3%13. The higher prevalence
of anxiety in females could be attributed to the way girls tend to be
brought up in Pakistan. These include submitting to authority, a high
sense of conformity and communal values, which may inculcate in
them anxiety, restlessness, helplessness, a tendency to underestimate
their capabilities, and their resulting dependency on others29. The
unique finding in the current research was the incidence of severe
levels of LD, along with depression and anxiety symptoms at 27%.
Though this is alarming, particularly with respect to the assessment
and management of psychiatric issues at school level, there are
several possible reasons. Along with social and cultural factors,
other factors could be personal and subjective, including academic
stressors, feelings of personal inadequacy, financial dependency, and
perceptions of inability to cope with life circumstances etc.30,31. The
relationship between LD, depression and anxiety symptoms revealed
is in line with previous findings12,17,20,23.
Though examining clinical tendencies in a normative sample
is a strength of this study, the variations between past findings
and the current study results could be due to differences in study
methodologies, assessment tools, cut off points, determined specificity
and the sensitivity of the measuring tools, academic stressors, exam
pressures, disparities in exposures to life stressors in the present and
past, stressful surroundings and gender discrimination32.
Limitations
The present research was conducted with some limitations. For
example, self-reporting and teachers’ report measures were used rather
than formal psychiatric examination and assessment for an objective
identification and diagnosis of psychiatric symptoms. In addition, a
longitudinal study could be used in future research to obtain more
controlled and refined findings – for instance, whether the reported
symptoms appeared to affect exam performance adversely when
compared to the expected performance from class work.
Implications
The findings from current study suggest some workable and
interesting implications in clinical as well as educational field
concerning cautionary and preventive measures as well as
management interventions. Initially, preventive programs aimed
to identify LD, depressive and anxiety symptoms at an early level
(pre-adolescence) may be implemented. The early identification may
facilitate to detect increased levels of psychiatric comorbidities in
high risk children. Such programs may result in significant positive
outcomes reducing psychiatric symptomology in adolescents and
consequently preventing mental health issues and personality
malfunctioning later in adulthood. Early assessment at school level
is most suitable in order to provide preventive measures to large
number of students before psychiatric symptoms demonstrate in
full scale psychiatric disorders.
In addition, along with preventive strategies and identifying
the sub-threshold levels of psychiatric symptoms, reinforcing the
protective factors against the risk factors may also fruitful. The
protective strategies may include effective role of parent, teachers
and peers which could be more beneficial in reducing manifestation
of psychiatric symptoms. Nevertheless, such programs also seem to
be more economically effective as they minimize cost of structured
clinical interventions. In the larger context, given the comorbidity of
psychiatric symptomology specially LD, it might be worth looking
further into the planning multifaceted intervention programs
addressing both screening as well as diagnostic level of psychiatric
symptomologies. Particularly, such programs not only improve
problem solving skills and coping strategies in students but also
minimize the risk of psychiatric comorbidities by backing the
adaptive management of tough and stressful situations. In addition,
domain specific management strategies such as extra sessions to
improve students reading, writing and mathematical disabilities
alone are not enough to overcome psychiatric manifestations. An
integrated program comprising self-regulated learning strategies
and skill based strategies to improve students’ perception about their
abilities at school, should provide more efficient and effective support
by focusing simultaneously on academic, emotional, behavioral and
cognitive aspects33.
Conflict of interest
None.
Funding
None.
Acknowledgment
None.
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 Original article

Is there a relationship between thyroid hormone levels and suicide attempt in

adolescents?
Gamze Gokalp1
https://orcid.org/0000-0001-9467-3617

Emel Berksoy2
https://orcid.org/0000-0002-6831-1353

Sefika Bardak2
https://orcid.org/0000-0003-1211-6943

Gulsah Demir2
https://orcid.org/0000-0001-7841-4682

Sule Demir2
https://orcid.org/0000-0002-3531-5729

Murat Anil3
https://orcid.org/0000-0002-2596-4944

1Department of Pediatric Emergency, Faculty of Medicine, Izmir Katip Celebi University, Turkey.
2Department of Pediatric Emergency, Tepecik Education and Research Hospital, Turkey.
3Department of Pediatric Emergency, Faculty of Medicine, Democracy University, Turkey.

Received: 14/03/2019 – Accepted: 17/07/2020

DOI: 10.1590/0101-60830000000248

Abstract
Background: Thoughts about suicide are quite common in adolescent. While such thoughts can be caused by many reasons, the most well-
known of these are mood disorders. There are studies related to coexistence of thyroid pathologies and mood disorders in adult. Objectives:
In this study, we aimed to investigate the difference of thyroid hormone levels in between adolescents with suicide attempt history and
normal population. Methods: The study was prospective and was designed as a case-control study. Demographic characteristics of the
patients were obtained and Serum fT3, fT4 and TSH levels were examined. Results: 222 cases were included in the study, including 101 cases
and 121 controls. As for TSH levels, the mean serum levels of the whole group was 1.96 ± 1.08 mU/L, while the mean serum levels of the
control group was 2.33 ± 1.5 mU/L and the mean serum levels of the case group was 0.50 ± 0.3 mU/L which revealed that the mean serum
levels of the case group was significantly lower (p<0.01). Conclusion: It was found that serum TSH levels were significantly lower in case
group than control group and the individuals with subclinical hyperthyroidism had more suicide attempts than the ones in control group.

Gokalp G et al. / Arch Clin Psychiatry. 2020;47(5):130-134

Introduction
Thoughts about suicide are quite common in adolescent age group.
In a study conducted in the USA in 2011, it was found that 13%
of all adolescents had a suicide planning and 8% of them had a
suicide attempt during one year. However, the completed suicide
attempt is quite rare1,2. According to the 2012 data of Turkish
Statistical Institute, despite the fact that the raw suicide rate in our
country is determined as 3.62, it is impossible to know the certain
number since all cases are not reported3. Despite the rareness of
resulting in death of these suicide attempts, the problems related
to the disengagement from the educational life of the cases and
the morbidity caused by the suicide attempt they have had, are
important on every individual basis. In addition, the increase in
the workload of emergency services and the increase in health
expenditures also pose a national problem. Therefore, it would
be a reasonable approach to determine the factors that may lead
to suicide attempts and to take protective measures against these
factors.
When we evaluate the risk factors of a suicide attempt, having
a history of suicide attempt by the individual or one of their family
member, having a sexual identity disorder (gay, lesbian, bisexual
orientation, transgender identity), having a history of child abuse
and having one or multiple of mood disorders (major depression,
substance use disorders, psychotic disorders) can be encountered4.
Address for correspondence: Gamze Gokalp. Deparment of Pediatric Emergency, Izmir Tepecik Traning and Education Hospital, Turkey. Telephone: +90 505 216 88 14.
E-mail: drgamzegokalp@gmail.com
Many of these risk factors are social problems that cannot be cured
by physicians. Separately from the other factors, mood disorders can
be diagnosed and treated and this gives physicians an opportunity
to prevent a serious problem such as suicide attempt.
Genetic factors, stressful conditions, inadequate social support,
substance use, and various somatic diseases can be observed
in the etiology of mood disorders5. Also, mood disorders may
develop secondarily to several disorders, such as neurological
diseases (Epilepsy, Parkinson's Disease, Cerebrovascular diseases),
infectious diseases (HIV, neurosyphilis), endocrine disorders
(hypothyroidism, diabetes mellitus, parathyroid hormone
disorders), and some vitamin deficiencies6.
From this point of view, we aimed to investigate the effect of thyroid
dysfunction, which is one of the correctable endocrinopathies that
may cause mood disorders, on a suicide attempt.
Methods
This study was carried out between 01.01.2017-31.12.2017 in a
pediatric emergency department of a tertiary university hospital
in the city center. The study was designed as a case-control study.
The approval of the regional ethics committee was obtained, and
the signed informed consent form was obtained from the legal
guardian of the participants.
131 Gokalp G et al. / Arch Clin Psychiatry. 2020;47(5):130-134
Cases
The study group consisted of girls between 14-18 age (According to
WHO’s age classification, between 10-19 age is called as “adolescent
age period” and between 14-24 age is called “young people”.
Therefore, we formed young and adolescent age groups in our
study) who admitted to the pediatric emergency department with
suicide attempt and who accepted to participate in the study. The
control group consisted of the patients who admitted to healthy
child clinic with similar age, gender, and ethnic characteristics but
unknown thyroid hormone levels. Age, gender and ethnic origins
of the study group were obtained. The psychiatric evaluation was
made by a specialist on child and adolescent psychiatry for those
who attempted suicide. No psychiatric evaluation was made
on control group but asked about the previous diagnoses for
psychiatric diseases. The individuals in doubt of any psychiatric
disorders were excluded from the control group. Patients using any
agent that could alter the thyroid axis and/or metabolism, those
lacked data, and those who did not agree to participate in the study
were excluded from the study. Pregnancy status was confirmed with
serum β-hCG levels in addition to the statement of expression, and
those with gestational status were excluded from the study.
Laboratory Analysis
Blood samples of the cases were taken between 8-10 am and
were sent to the laboratory. The samples were run without delay.
All hormonal concentrations were determined by immunoassay
techniques based on enhanced Lumine sense. Normal levels of
thyroid hormones are affected by many factors such as age, race,
sex, chronic diseases, blood lipid levels, and nicotine use. Therefore,
changes may be observed between the reference values ​​in clinical
use. In our study, we used the values ​​given for girls between the
ages of 12 and 19 as reference values ​​in the National Health and
Nutrition Examination Survey (NHANES) 2007-2012 study.
According to this report, normal ranges were stated as 0.6-3.2 μIU
/ ml for TSH, 3-4.3 pg/ml for free T3 (fT3) and 0.6-1ng / dl for free
T4 (fT4)7. Patients with low fT4 levels, normal or low levels of fT3
levels and high levels of TSH compared to the mentioned reference
values, accepted as 'primary hypothyroidism'. Patients with low
levels of TSH and high or normal levels of fT4 and high levels of
T3 are accepted as 'hyperthyroidism'. Patients with low levels of
TSH and normal levels of fT4 and fT3 are classified as 'subclinical
hyperthyroidism'. Patients with high levels of TSH and normal
levels of fT4 and fT3 are classified as 'subclinical hypothyroidism'.
Patients with normal values of T3, T4 and TSH levels, are classified
as 'euthyroidism'.7
Statistical Analysis
In the light of previous studies, the minimum sample size was
calculated as 162 cases (81 case + 81 control) with %80 power. All
data were analyzed in SPSS 20.0 (SPSS Inc. Illinois, US) package
program. Indepentent T test, Chi-square analysis were used
for comparation between groups, relationship and predicting
variables, respectively. The results were presented as mean (standart
deviation) or numbers (%) where appliable. Kruskal Wallis test
used for comparing more than two groups. The alpha-level of
significance was set at p < 0.05.
Results
A total of 222 cases were included in the study, including 101 cases
and 121 controls. All of the participants were in female gender. The
mean age of the case group was 15.6 ± 1.2 years and the control
group had a mean age of 16.04 ± 1 years (p = 0.1). It was observed
that the case and control groups consisted of similar patients in
terms of age. It was found that 92 girls (91.1%) in the case group
consisted of the resident population and 9 (8.9%) were immigrants.
The control group consisted of 119 (98.3%) residents and 2 (1.7%)
immigrants (p = 0.3) (Table 1).
63 patients (62.4%) in the case group were diagnosed with
psychiatric disorders by a pediatric psychiatrist. Among these, 36
(35.7%) were diagnosed with major depression (MD), 21 (20.8%)
with impulsive disorder and 6 (5.9%) with generalized anxiety
disorder (Table 2).
The mean serum T3 level of the whole group was 3.46 ± 0.76
pg/ml (0-5.2), the mean of the control group was 3.43 ± 0.3 pg / ml
(2.8-4.9), while the mean T3 level of the case group was 3.47 ± 0.84
(0-5.2) pg. / ml. (T = 0.18 and P=0.67 (T-Test))
The mean serum T4 level of the whole group was 0.9 ± 0.22 ng/
dl (0.29-2.1), the mean of the control group was 0.90 ± 0.8 ng/dl
(0.6-2.1), while the mean T4 level of the case group was 0.9 ± 0.25
ng/dl (0.29-2.1). (T = 0.43 and P = 0.49 (Test))
The mean serum TSH level of the whole group was determined
as 1.96 ± 1.08 mU/L (0.1-5.5), the mean serum TSH level of the
control group was 2.33 ± 1.5 mU/L (0.6-5.5), while the mean TSH
level of the case group was 0.5 ± 0.3 mU/L (0.1-3.7). The mean TSH
value of the case group was found to be significantly lower (T: 1.3
and P < 0.01 (T-Test) (Table 3).
According to the reference values ​​in NHANES (2007-2012)
study, in whole group serum fT3 level was found to be low in 18
cases (15.9%), normal in 87 cases (78.6%) and high in 6 (5.5%)
patients. fT4 level was found to be low in 3 cases (1.4%), normal
in 176 cases (80%) and high in 41 cases (18.6%). Serum TSH levels
were found to be low in 194 (87.4%) cases, normal in 14 (6.3%)
cases and high in 12 (5.4%) cases. No significant relationship was
found between the case-control group and serum T3 and T4 levels
(p: 0.07 and p: 0.3 (Kruskal-Wallis analysis)). TSH level was found
to be significantly lower in the case group. (p: 0.02 (Kruskal-Wallis
analysis)) (Table 4).
Based on the thyroid status definitions we mentioned before,
no cases were diagnosed as primary hypothyroidism, 12 cases
(5.7%) (all 12 in the control group) were diagnosed as subclinical
hypothyroidism, 6 cases (2.9%) (all 6 in the suicide group) were
euthyroid, 39 cases (18.7%) (22 controls + 17 cases) were diagnosed
as hyperthyroidism and 152 cases (72.7%) (77 controls + 75 cases)
were diagnosed as subclinical hyperthyroidism. The number
of patients diagnosed with subclinical hyperthyroidism were
significantly higher in the case group (p < 0.01) (Chi-square test)
(Table 5).
Discussion
Our study is the first study which investigates the relationship
between thyroid function and suicide attempts in adolescent age
group. According to this, it is found that in suicide group serum
TSH levels were significantly lower than control group.
In addition, individuals with subclinical hyperthyroidism had
more suicide attempts than the control group as a secondary result.
Considering the relationship between suicide attempt and
thyroid function, studies in the adult group are noteworthy.
Although the relationship between thyroid hormones and mood
disorders has been studied on adults, which thyroid disease plays a
role in the etiology of which psychiatric disease is not clear yet. It is
known that, especially when negative symptoms are predominant,
such as in depression, monoamine levels are found to be lower in
cerebrospinal fluid (CSF). Some of the studies at the cellular level
 Gokalp G et al. / Arch Clin Psychiatry. 2020;47(5):130-134 132

Table 1. Gender, Ethnicity and Age Properties

All cases Non-suicide control The cases who had suicide attempt
(N=222) (N=121) (N=101) p
N% N% N%
Ethnicity 0.3
Inhabitant 211 95 119 98.3 92 91.1
Immigrant 11 5 2 1.7 9 8.9
Total 222 100 121 100 101 100
Where do they live?
With Family 182 78 119 91.5 63 62.4 0.4
Homeless 7 3.1 1 0.7 6 5.9
Married 6 2.3 0 0 6 5.9
Public shelter 10 4.5 1 0.7 9 8.9
Unknown 27 12.7 10 7.1 17 16.9
Total 222 100 142 121 101 100
Age (year)
16.04±1 15.6±1.2
Mean ± SD Min/max 15.8±1.1 14/18 0.1
14/17 14/18

Table 2. Properties Of Suicide Attempters

N %
Diagnosed psychiatric disorder 63 62.4
Major depressive disorder 36 35.7
Impulsie disorder 21 20.8
Generalized anxiety disorder 6 5.9
No- diagnosed psychiatric disorder 38 37.6
Total 101 100

Table 3. The Results of Student T test Analysed For Serum fT3, fT4 and TSH levels
The cases who had
All Cases Non-suicide
suicide attempt
N=222 Control N=121 P T
N=101
(Mean ± SD) (Mean ± SD)
(Mean ± SD)
Free T 3 (pg/ml) 3.46 ± 0.76 3.43 ± 0.30 3.47 ± 0.84 0.67 0.18
Free T 4 (ng/dl) 0.90 ± 0.22 0.9 ± 0.80 0.90 ± 0.25 0.49 0.43
TSH (mU/L) 1.96 ± 1.08 2.33 ± 1.5 0.50 ± 0.3 <0.01 1.3

Table 4. The Relationship Between Case-Control Groups And The Groups Classified by fT3, fT4 and TSH Levels (Kruskal-Wallis Analysis)
All Cases Non-suicide control The cases who had suicide attempt
(N = 222) (N = 121) (N = 101) P
N (%) N (%) N (%)
fT3 0.07
Low 18 15.9 3 13.6 14 13.9
Normal 87 78.6 19 86.4 81 80.2
High 6 5.5 0 0 6 5.9
Total 108 100 22 100 104 100
fT4 0.3
Low 3 1.4 0 0 3 3
Normal 176 80 95 78.5 81 80.2
High 41 18.6 24 19.8 17 16.8
Total 220 100 119 100 101 100
TSH 0.02
Low 194 87.4 99 81.8 95 94.1
Normal 14 6.3 8 6.6 6 5.9
High 12 5.4 12 9.9 0 0
Total 220 100 119 100 101 100
133 Gokalp G et al. / Arch Clin Psychiatry. 2020;47(5):130-134

Table 5. The Relationship Between Case-Control Groups According To Thyroid Status (Chi Square Analyses)
All Cases Non-suicide Control The cases who had suicide attempt
N = 209 N=111 N=98 P
N% N% N%
Primary Hypothyroidism 0 0 0 0 0 0 -
Subclinical hypothyroidism 12 5.7 12 10.8 0 0 -
Eythyroidism 6 2.9 0 0 6 6.2 -
Hyperthyroidism 39 18.7 22 19.8 17 17.3 0.06
Subclinical hyperthyroidism 152 72.7 77 69.4 75 76.5 <0.01

that attempts to elucidate the etiology, indicates that this is related
to low TSH levels. In a study that supports this hypothesis, high
levels of TRH in CSF was found in patients with severe depressive
symptoms8. For example, in a study investigating the mechanisms
of suicidal behavior at the cellular level, it was reported that TRH
overactivity stimulates 5-HT activity in depressed patients and
shows a compensatory response to decreased 5-HT levels9. In
another study investigating the mechanisms of suicidal behavior
at the cellular level, 5-HIAA (Hydroxyindolacetic acid) and HVA
(Homovanillic acid) levels were found to be lower in CSF10. In
another study supporting the hypothesis that the elevation in TSH
is involved in the etiology of mood disorders, a negative correlation
is found between the maximum TSH response and the levels of
HVA and 5-HIAA in CSF11. When the studies examining the clinical
implications of these mechanisms are analyzed, it is observed that
hypothyroidism is a risk factor for the patients who have dominant
negative symptoms such as major depressive disorder. For example,
Jokinen et al. found a negative correlation between T3 levels and
depression scale in their study on the patients who had suicide
attempt in Sweden12. Gold et al. also reported that hypothyroidism
increases the risk of depression13. Frey et al. also showed coexistence
between hypothyroidism and depression14.
Some studies suggest that hyperthyroidism increases suicidal
thoughts in patients with psychosis. For example, Jose et al. reported
that patients with schizophrenia had suicidal thoughts and that
hyperthyroidism was a risk factor15. Similarly, Sinai et al. stated
that higher T4 levels increases aggression and suicide attempts16.
In a cohort study of 43,633 patients with hyperthyroidism
retrospectively analyzed, Abraham-Nordling et al. stated that
patients with hyperthyroidism have a 1.6-fold higher risk in terms
of suicidal attempts17. Bauer et al. stated that 10% of individuals
with hyperthyroidism had a psychiatric disorder18. The mechanism
of this condition was explained by the fact that thyroid hormones
increase the number and intensity of B-adrenergic receptors
in both the peripheral and central nervous system, resulting in
increased catecholaminergic activity19. It is also observed that the
increase in excitatory neurotransmitters with over-activation of the
sympathetic nervous system also triggers manic episodes, psychotic
attacks and anxiety disorders17. Similarly with the above studies, we
observed lower TSH levels in suicide group than in control group
while fT3 and fT4 levels were normal in both groups. Subclinical
hyperthyroidism was higher in case group than in control group
while clinical hyperthyroidism was not.
In some studies, no relationship was found between thyroid
status and direct suicidal behavior. For example, Duval et al.
examined the thyroid axis in depressed patients who attempted
suicide and reported that hormones belonging to the HPT
(Hypothalamic Pituitary Thyroid) axis were found to be normal in
the early period20.
Conclusion
As a result, the exact relationship between thyroid status and
suicidal attempts is not clear. The probable reasons are heterogeneity
of study groups, multiple factors that change thyroid hormone
levels, and geographic location of the cases. However, the euthyroid
condition will undoubtedly provide both mood stabilization and
the unlikelihood of suicidal thought. From this point of view, in
terms of preventive health measures, physicians who are interested
in adolescent age group should ask for endocrinology consultation
when they encounter abnormal values while they are assesing
thyroid levels of patients. We believe that our study will contribute
to the literature in this respect and think that it will lead to more
studies.
Acknowledgments
We would like to thank to the social service specialist and pediatric
psychiatrist for their contribution to this study.
Funding
The authors received no financial support for the research and/or
authorship of this article.
Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the
authorship and/or publication of this article
Contributors
Design, data collection, writing and critical inspection-Gamze
Gokalp
Design, data collection writing -Emel Berksoy
Design, data collection-Sefika Bardak
Design, data collection -Gulsah Demir
Design, data collection-Sule Demir
Design and critical inspection-Murat Anil
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 Original article

The effect of trauma type on the severity of Post-Traumatic Stress Disorder (PTSD)
symptoms
Ayşegül Taşdelen Kul1
https://orcid.org/0000-0002-3681-735X

Ibrahim Gündoğmuş1
https://orcid.org/0000-0002-1921-1495

1 Department of Psychiatry, Gülhane Training and Research Hospital, Ankara/Turkey

Received: 27/03/2019 – Accepted: 07/08/2020

DOI: 10.1590/0101-60830000000249

Abstract
Objective: The high prevalence of trauma exposure calls for detailed research on how trauma type affects the development of Post-Traumatic Stress Disorder
(PTSD). Therefore, the aim of our study was to investigate the effects of the type of trauma on the severity of symptoms, anxiety, depression, and dissociative
experiences in the PTSD patient population. Method: The sample of the study consists of 80 volunteer PTSD patients (20 sexual trauma, 20 work accidents,
20 traffic accidents and 20 combat related trauma). Once the severity of symptoms was determined in all subjects by the Clinician-Administered PTSD Scale
(CAPS), Beck Depression Inventory, Beck Anxiety Inventory and Dissociative Experiences Scale (DES) were applied. Results: A statistically significant
difference were found between trauma types with regard to age, time without treatment, and the total and subscale scores obtained in DES and CAPS. It was
found that in the group that has PTSD diagnosis related to sexual trauma, the length of the time without treatment, DES and CAPS scores. Conclusion: The
study we conducted showed that PTSD continued more severe and resistant after a sexual trauma. Moreover, specific type of trauma was significant in PTSD
patients.

Kul AT et al. / Arch Clin Psychiatry. 2020;47(5):135-139

Keywords: Post-Traumatic Stress Disorder (PTSD), trauma type, severity, sexual trauma.

Introduction severity and variety of psychiatric symptoms. Then, the population

In the general population, lifelong trauma exposure shows a
high prevalence of 70-89%1-3. Nevertheless, trauma-induced
psychopathologies such as Post-Traumatic Stress Disorder (PTSD)
are reported at a much lower rate of about 8.3%2. The development
of PTSD is associated with the meaning of the victim assigns to
the trauma and individual differences4,5. While most PTSD patients
recover in a few months without any intervention, some patients
have to deal with symptoms for years6. As the clinical prognosis of
PTSD very variable, researchers decided to investigate the clinical
presentation of the type and number of traumas; whether these had
any effect on the diagnosis of PTSD7. Given the evidence, traumatic
events could lead to other psychiatric disorders, such as depression
and anxiety in addition to PTSD. These were important to clarify
the relation of traumatic experiences and symptoms of the PTSD5,7,8.
Furthermore, it was required to investigate the types of trauma
affected the severity of the symptoms such as depression, anxiety
and dissociative experiences in PTSD patients.. In a study conducted
with a sample of 602 people in 2018, Guina et al. compared the
trauma types with PTSD severity. The same study identified more
severe symptoms in PTSD cases due to post war period and sexual
traumas9. Smith et al. also compared severity of trauma types with
PTSD symptoms, as well as comorbid anxiety and depression. They
found that symptom severity and comorbid psychiatric disorders
were higher in PTSD patients who experienced sexual trauma. In
Turkey, the relationship between the trauma types and symptom
severity was studied in PTSD patients and the comparison of PTSD
patient groups with sexual and non-sexual traumas, showed more
severe symptoms in the former group10. This study investigated the
hypothesis that the type of trauma would have an impact on the
Address for correspondence: Ayşegül Taşdelen Kul, Department of Psychiatry, Gülhane Training and Research Hospital , Emrah Mahallesi, Gen. Dr. Tevfik Sağlam Cd No:11, 06010 Keçiören, Ankara,
Turkey. Telephone: +905321346150. Email: aysegultasdelenkul@gmail.com
of PTSD patients was screened to identify any relation between the
trauma types and symptom severity, as well as comorbid psychiatric
symptoms (anxiety, depression and dissociative experiences).
Method
Sample
Study sample consisted of 80 PTSD patients who were treated and
followed-up in the Gülhane Training and Research Hospital from
May 2017 through July 2018. The diagnosis of PTSD was made by
two experienced psychiatrists according to the diagnostic criteria
of the Diagnostic and Statistical Manual of Mental Disorders-5
(DSM-5)11. In accordance with the hypothesis of the study, the
first 20 patients with inclusion criteria for each type of trauma
were included in the study. The study included 20 cases of PTSD
developed due to sexual trauma, 20 cases developed after work
accidents, 20 after traffic accidents, and a final 20 related to
traumas developed in military conflict. Only patients who applied
psychiatry for the first time, having no treatment and therefore
diagnosed as PTSD for the first time were included in the study. The
primary psychopathology of all subjects were PTSD. All subjects
participated voluntarily and they were all above 18 years old, none
of them having psychotic and/or affective disorders diagnosis,
mental retardation, head trauma, or organic psychiatric disorders
and whole patients displayed the cognitive functions required to
complete the study. The study started with the approval of local
ethics committee. All rights of the study subjects and all stages of
the study are protected under the Declaration of Helsinki.
136 Kul AT et al. / Arch Clin Psychiatry. 2020;47(5):135-139

Study Design Results

All subjects were duly informed about the study and their signed
consents were obtained. Psychiatrists cross-referenced patients
for a reconciliation of diagnoses with DSM-5 criteria. Subjects
were included in the study only when both psychiatrists accepted
the diagnosis. Detailed histories of trauma were obtained through
interviews and the clinician applied the PTSD scale. Moreover, all
subjects completed a sociodemographic data sheet, in addition to
Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI)
and Dissociative Experiences Scale (DES). All data were analyzed
under the appropriate data set.
Data collection tools
Sociodemographic Data Sheet: Sociodemographic data of all
study subjects, such as age, gender, marital status, employment
status, socioeconomic status and education are recorded in this
sheet.
Clinician-Administered PTSD Scale (CAPS) is a scale
developed by Blake et al. in 1990 to be applied by clinicians in order
to determine the frequency and severity of PTSD symptoms12.
Tamer et al. validated the Turkish version in 199913. The scale
comprises 17 questions designed to evaluate PTSD symptoms
and 8 to evaluate the symptoms accompanying PTSD. It is a scale
between 0-136, with scores increasing in number as the severity of
PTSD increases. Furthermore, it has subscales of ‘re-experiencing,’
‘avoidance and blunting’ and ‘hyper-arousal.’
DES is a self-report questionnaire with 28 items developed by
Bernstain and Putnam to measure the frequency of dissociative
experiences14. Each question is scored on a scale of 0-100 and
an average score is obtained. A score of 30 or above suggests the
presence of a dissociative disorder. The Turkish validity and
reliability were confirmed by Şar et al. 15.
BDI was developed by Beck et al. in 1988 to assess the
severity of depressive symptoms16. It is a Likert type self-reporting
questionnaire consisting of 21 items to be scored on a scale of 0-63.
The score increases with the severity of depression. It investigates
the symptoms of depression related to cognitive, emotional,
physical, and motor functions. The Turkish validity and reliability
study was conducted by Hisli et al. 17.
BAI was developed by Beck et al. to assess the severity of
anxiety18. It is a self-reporting questionnaire consisting of 21 items
to be scored on a scale of 0-63. Each item is scored between from
0-3 in the Likert type. High scores indicate an increased severity of
anxiety. The Turkish validity and reliability study was performed by
Ulusoy et al. in 199319.
Statistical Analysis
The descriptive statistics of the sociodemographic datas were
obtained from patients shown as mean ± standard deviation in
number (percentage). Chi-square analysis was used to compare
Descriptive sociodemographic datas of study subjects were
presented in Table 1. The mean age of the subjects were 33.61 ± 7.01
years and 37 (46.3%) were female. Approximately half were married
(42, 52.5%) and again half were in employment (43, 53.8%).
Table 2 shows the average and compared values of the clinical
scales according to the types of traumas that the study subjects had
experienced. According to this, there are statistically significant
differences between the groups in terms of age, time without
treatment, DES, and the total and subscale scores of PTSD-T (p
values are 0.041, <0.001, <0.001, 0.029, 0.019, 0.006 and 0.016,
respectively). Figure 1 is a graphical representation of mean values.
PTSD patients with a history of sexual trauma scored
statistically higher in BDI, DES, CAPS avoidance/blunting, CAPS
hyper-arousal and CAPS total than the subjects who developed
PTSD following a work accident (p values are 0.013, <0.001, 0.020,
0.001, and 0.017, respectively). PTSD patients with history of sexual
trauma scored statistically higher in DES, CAPS re-experiencing,
CAPS avoidance/blunting, CAPS hyper-arousal and CAPS total
compared to subjects who developed PTSD following a traffic
accident (p values are <0.001, 0.023, 0.020, 0.002, and 0.001,
respectively). PTSD patients with history of sexual trauma scored
statistically higher in DES, CAPS avoidance/blunting and CAPS
total than those who developed PTSD following a military trauma
(p values are <0.001, 0.012, and 0.045, respectively). Subjects who
developed PTSD following a work accident scored statistically
higher in CAPS re-experiencing than those who developed
PTSD following a traffic accident (p value is 0.004). Subjects who
developed PTSD following a military trauma and those following a
traffic accident showed no difference in BDI, BAI, DES and CAPS
scores.
Discussion
The main aim of this study was to determine how the type of trauma
affected PTSD symptoms, anxiety, depression, and dissociative
experiences. The most important result of the study were that
symptom severity, time without treatment, and dissociative
experiences that were found, significantly higher in PTSD patients
with a history of sexual trauma in accordance with the existing
literature7,10,20,21. As for the severity of anxiety and depression, no
significant difference were found according to the type of trauma.
Our study is also considering that research is rather limited in
Turkey on the relations between the types of trauma inducing PTSD
120.00
100.00
80.00
60.00
40.00
20.00
0.00
Dura�on of Beck Anxiety Beck Dissocia�ve CAPS Total
Untreatment Inventory Depression Experiences Score*
Period
(month)**
Score Inventory
Score
Scale Score**

categorical data between groups. After checking the consistency Sexual Trauma 16.00 38.35 37.80 41.70 103.70
of continuous variables for normal distribution, two continuous Traffic Accident 7.50 32.80 32.90 26.40 93.90
Combat Trauma 4.05 33.60 34.25 30.70 95.30
variables were compared using the Mann-Withney U test for Work Accident 14.85 34.45 30.65 29.00 95.25
those meeting the non-parametric analysis criteria and Kruskall-
Sexual Trauma Traffic Accident Combat Trauma Work Accident
Walls Test was used for comparison where there were more than
two continuous variables. Statistical analysis was performed with Figure 1. Graphic representation of the time without treatment, Beck Depression Inventory,
the software SPSS 20.0 for Windows and ≤0.05 was taken as a Beck Anxiety Inventory, Dissociative Experiences Scale and CAPS scale according to types of
trauma
statistically significant value.
 Kul AT et al. / Arch Clin Psychiatry. 2020;47(5):135-139 137

Table 1: Descriptive sociodemographic data on the study subjects

Variable Mean ± SS/ n (%)
Age (years) 33.61 ± 7.01
Gender
Female 37 (46.3)
Male 43 (53.8)
Marital Status
Married 42 (52.5)
Single 26 (32.5)
Separated/Divorced 12 (15)
Employment Status
Employed 43 (53.8)
Unemployed 37 (46.2)
Body Mass Index (kg/m2) 23.80 ± 2.79
Smoking
Yes 28 (35.0)
No 52 (65.0)
Alcohol
Yes 23 (28.8)
No 57 (71.2)
Substance
Yes 11 (13.8)
No 69 (86.2)

Table 2: Average and compared values of the clinical scales according to the types of trauma the study subjects experienced

Sexual Traffic Combat Work

Trauma Accident Trauma Accident
Variable X2 p
(n:20) (n:20) (n:20) (n:20)
Mean ± SS Mean ± SS Mean ± SS Mean ± SS

Age (years) 30.35 ± 6.22 34.20 ± 7.49 33.40 ± 7.83 36.50 ± 5.95 8.232 0.041*
Body Mass Index (kg/m2) 22.60 ± 3.21 24.40 ± 2.77 23.70 ± 2.93 24.50 ± 1.82 5.001 0.172
Time without treatment after trauma (months) 16.00 ± 11.75 7.50 ± 8.54 4.05 ± 2.41 14.85 ± 16.38 26.344 <0.001**
Beck Anxiety Inventory Score 38.35 ± 12.73 32.80 ± 10.61 33.60 ± 10.03 34.45 ± 7.19 3.805 .283
Beck Depression Inventory Score 37.80 ± 9.20 32.90 ± 8.29 34.25 ± 9.45 30.65 ± 4.42 5.802 .122
Dissociative Experiences Scale Score 41.70 ± 6.47 26.40 ± 13.67 30.70 ± 12.23 29.00 ± 7.32 23.571 <0.001**
Re-experiencing 30.60 ± 3.70 27.00 ± 4.03 28.95 ± 4.46 31.00 ± 4.16 9.214 0.027*
Avoidance/Blunting 38.90 ± 2.26 36.70 ± 5.26 34.95 ± 5.20 34.65 ± 6.78 9.966 0.019*
CAPS
Hyper-arousal 34.20 ± 3.10 30.20 ± 4.61 31.40 ± 5.49 29.60 ± 4.09 12.477 0.006**
Total 103.70 ± 6.03 93.90 ± 10.89 95.30 ± 12.11 95.25 ± 12.66 10.331 0.016*
CAPS: The PTSD scale applied by a clinician:* p≤0.05, **: p≤0.01

Table 3: Paired comparison of the Beck Depression Inventory, Beck Anxiety Inventory, Dissociative Experiences Scale and CAPS according to types of trauma.
Sexual Trauma Sexual Trauma Sexual Trauma Work Accident Work Accident Traffic Accident
vs. vs. vs. vs. vs. vs.
Work Accident Traffic Accident Combat Trauma Traffic Accident Combat Trauma Combat Trauma
z p z p z p z p z p z p
Beck Anxiety
-1.572 0.116 -1.625 0.104 -1.381 0.167 -0.353 0.724 -0.881 0.378 -0.081 0.935
Inventory Score
Beck Depression
-2.472 0.013* -1.576 0.115 -0.992 0.321 -1.158 0.247 -0.885 0.376 -0.122 0.903
Inventory Score
Dissociative Experiences Scale Score -4.348 0.001** -3.729 <0.001** -3.575 <0.001** -0.746 0.456 -0.313 0.754 -1.193 0.233
Re-experiencing -0.777 0.437 -2.276 0.023* -0.885 0.376 -2.873 0.004** -1.338 0.181 -1.296 0.195
Avoidance/Blunting -2.322 0.020* -2.330 0.020* -2.514 0.012* -1.713 0.087 -0.707 0.480 -0.561 0.575
CAPS
Hyper-arousal -3.240 0.001** -3.042 0.002** -1.622 0.105 -0.435 0.664 -1.387 0.165 -0.696 0.487
Total -2.397 0.017* -3.278 0.001** -2.007 0.045* -0.149 0.881 -0.014 0.989 -0.691 0.489
p≤0.05, **: p≤0.01
138 Kul AT et al. / Arch Clin Psychiatry. 2020;47(5):135-139
and the severity of symptoms, anxiety, depression, and dissociative
experiences.
In line with the existing literature, our study showed that the
symptom severity of re-experiencing, avoidance/blunting, hyper-
arousal and dissociative experiences in PTSD patients with a history
of sexual trauma was higher than other types of trauma7,20,21. In a
recent study with a sample size of 2463, Jacop et al. found that sexual
trauma had a greater risk of PTSD and a higher symptom severity22.
Similarly, Kelley et al. and Smith et al. showed that PTSD following
a sexual trauma was associated with a higher symptom severity7,20.
On the other hand, Müller et al. concluded that remission took more
time and effort in PTSD patients with a history of sexual trauma23.
In Turkey, the study by Çoban et al. also shows that PTSD related
to sexual trauma displayed more severe symptoms10. The primary
reason for this higher severity in symptoms of PTSD induced by
sexual trauma might be that the trauma is directly related to the
person in such cases. This suggests a difference in terms of meaning
between a trauma experienced accidentally and a pre-meditated
one targeting a specific person. Moreover, it is perpetrated against
the sexual existence of the person which cannot be modified and/
or fortified. In other words, in another type of trauma it is possible
to change or control traumatic risk factors afterwards, whereas this
is not the case following a sexual trauma. Another possible cause
is the existence of a certain risk at all times in the circumstances
where other types of trauma (e.g. work accidents, traffic accidents,
etc.) develop. On the contrary, sexual trauma is unexpected and
unprepared for, regardless of the environment and this is a possible
factor contributing to a cognition of helplessness. This increases
the risk and severity of PTSD after a sexual trauma. Another
factor is the possibility of other types of trauma (e.g. physical
violence, restriction, humiliation) accompanying the sexual
trauma experienced, which would contribute to the cumulative
effect to increase the severity of the disorder24. Finally, it is shown
that peritraumatic reactions in sexual traumatic events play an
important role in the risk for development and worse response to
treatment. The peritraumatic reaction involving tonic immobility is
much more common in sexual trauma victims and could mediate
the association with greater severity of symptoms25. The fact that no
statistical difference in symptom severity was identified in patients
experiencing PTSD for reasons other than sexual trauma lends
more weight to the possible causes discussed above.
Another important finding in our study was that the time
without treatment was higher in PTSD patients with a history of
sexual trauma26. We suggest that the most probable cause is that
patients do not seek treatment for a long time out of fear of shaming
and stigmatization. However, factors such as threat and possible
harm should not be discarded. Moreover, as the age of sexual
trauma patients is relatively young may indicate a hesitation about
how to proceed in the search for treatment. Delay in treatment,
however, will make the disorder and its symptoms more resistant.
In addition, in our study, we found that PTSD patients with sexual
trauma were younger than other trauma types, in accordance with
the literature10. This may be a reason for patients having more severe
symptomatology. Because, even in mentally healthy individuals, the
effects of early traumas have been shown to leave deeper traces on
the individual27. Considering the fact that the group with sexual
trauma is young and the duration of without treatment is long, it
may suggest that it is associated with gruesome and associated with
worse symptomatology10,26.
The findings of our study should be evaluated with some
reservations. First of all, premorbid factors likely to affect
the development and severity of PTSD were not taken into
consideration. It should be noted that these factors can affect the
severity of trauma. Another limitation is that other possible traumas
accompanying the sexual trauma were not studied. Furthermore,
the fact that the types of trauma were not evaluated according to
being incidental or personal adds another limitation to the study
results. The study was sectional, cases were not controlled for
duration of treatment. It could be a confounding variable. Finally,
it is worth remembering that the sample size was limited and some
scales were based on self-reporting.
Conclusion
In conclusion, our study conducted with a group of PTSD patients
in Turkey showed that PTSD related to sexual trauma was more
severe and resistant. It also suggests that patients with sexual
trauma are younger and have longer treatment time. The findings
of the study were discussed in line with the existing literature on the
subject. We think that with our study, we draw attention to the type
of trauma and the importance of the time spent without treatment
in PTSD patients. The study have shown that these features may be
associated with worse symptomatology. We hope that our study will
contribute to the future studies aimed at reducing the long-term
non-treatment duration and related to the type of trauma, in PTSD
patients with sexual trauma.
Disclosure
The authors report no conflict of interest. The authors alone are
responsible for the content and writing of the paper.
Funding
The author received no financial support for the research,
authorship, and/or publication of this article.
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Review article

Lesion localization and performance on Theory of Mind tests in stroke survivors:

a systematic review
Ana Julia de Lima Bomfim1
https://orcid.org/0000-0003-3639-9626

Bianca Letícia Cavalmoretti Ferreira2

https://orcid.org/0000-0003-3639-9626

Guilherme Riccioppo Rodrigues3

https://orcid.org/0000-0003-1475-1908

Octavio Marques Pontes-Neto3

https://orcid.org/0000-0003-0317-843X

Marcos Hortes Nisihara Chagas1,2,3

https://orcid.org/0000-0003-3752-7984

1 Department of Psychology, Federal University of São Carlos, São Carlos, SP, Brazil.
2 Department of Gerontology, Federal University of São Carlos, São Carlos, SP, Brazil.
3 Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.

Received: 30/05/2019 – Accepted: 29/06/2020

DOI: 10.1590/0101-60830000000250

Abstract
Background: Theory of Mind (ToM) is the ability to attribute mental states to oneself and others. Individuals with a brain lesion following a stroke exhibit
a compromised ability to perform ToM tasks. Objective: To analyze studies that evaluated ToM in stroke survivors considering the lesion localization and
performance on ToM tests. Methods: The searches were carried out until November 28, 2018, using the following search terms: “social cognition” or “Theory
of Mind” and “stroke”. Searches were conducted in the PubMed, PsycInfo, Web of Science and Scopus data bases. The initial search led to the retrieval of 425
articles. After the exclusion of duplicates and the analysis of the titles, abstracts and full texts, 20 articles were selected for the present review. Results: The
studies showed that patients with lesion in the right hemisphere present lower performance on ToM tasks compared to those with lesion in the left hemisphere.
In addition, patients with lesion in the right hemisphere presented significant impairment in the performance on ToM tasks compared to healthy individuals.
Furthermore, the studies that evaluated lesions in specific regions such as temporal lobe, prefrontal cortex, posterior parietal cortex, and temporo-parietal
junction, indicated a significant deficit in ToM performance of these patients compared to healthy individuals. Discussion: This review showed that stroke
survivors have a poor performance on ToM tasks. The right hemisphere and prefrontal cortex seem to be associated with the deficit of this ability.

Bomfim AJL et al. / Arch Clin Psychiatry. 2020; 47(5):140-145

Keywords: Social cognition, Theory of Mind, stroke.

Introduction lesion in the left hemisphere3. According to Tompkins et al.7 right

The term “Theory of Mind” (ToM) emerged at the end of the
1970s with experimental studies on animal cognition. Premack
and Woodruff1 investigated the ability of chimpanzees to infer the
intentions of humans in a problem situation shown on video. The
results suggested that primates were able to understand and identify
options compatible with these intentions.
Abilities related to ToM emerge throughout the development
process2. ToM is the capacity to make inferences regarding the
thoughts, intentions, beliefs and emotions of others to predict and
explain their behavior1. The construct of ToM is comprised of affective
and cognitive components3. The cognitive component regards the
ability to distinguish the thoughts, beliefs and intentions of another
person, whereas understanding the feelings or others is attributed
to the affective component4.
Neuroimaging studies report a network of active brain regions
involved in the processing of ToM, including the anterior cingulate
cortex, posterior cingulate cortex, medial prefrontal cortex,
precuneus, inferior frontal gyrus, superior temporal sulcus and
temporoparietal junction2,5,6. Therefore, brain lesions that affect these
regions may result in an impaired ability of ToM.
Studies on stroke survivors commonly investigate the influence
of the cerebral lateralization in the ability of ToM. Evidence
indicates that individuals with the right hemisphere affected have
a deficit regarding the ability of ToM compared to patients with
hemisphere brain lesions can result in impaired communication
and social interactions. However, divergent results are found on the
lateralization of the function of ToM, indicating that stroke patients,
regardless of the location of the lesion, have significant impairment
in the ability of ToM compared to the control group8.
The aim of the present study was to perform a systematic review
of all studies published that have evaluated ToM in stroke survivors
considering the lesion localization and performance on ToM tests.
Methods
A systematic review was performed of studies conducted to evaluate
ToM in adult stroke survivors. The searches were carried out until
November 28, 2018 in the databases: Pubmed, PsycInfo, Web of
Science and Scopus, using the following search terms: (“social
cognition” or “Theory of Mind”) and stroke. The inclusion criteria
were studies published in English that evaluated post-stroke ToM
in individuals aged 18 years or older. No restriction was imposed
on the year of publication. Studies that evaluated ToM in specific
clinical samples (individuals with dementia, schizophrenia, autism,
Williams syndrome, Parkinson’s disease, epilepsy, etc.) in the absence
of stroke and post-stroke neuroimaging studies that did not evaluate
ToM were excluded from the review. Books, book chapters, opinions,
case studies, bibliographic/systematic reviews and meta-analyses
were also excluded.

Address for correspondence: Ana Julia de Lima Bomfim. Federal University of São Carlos, Department of Psychology. Rodovia Washington Luís, km 235 – 13565-905 – São Carlos, SP, Brazil.
Telephone +55 (16) 99721-2482. Fax: +55 (16) 3306-6675. E-mail: anaajullia@hotmail.com
 Bomfim AJL et al. / Arch Clin Psychiatry. 2020;47(5):140-145 141

Two independent researchers performed the data extraction and
documented the authors’ names, year of publication, sample size,
sex, age and schooling of the participants, time elapsed since the
stroke event, site of the brain lesion and instruments used to assess
ToM. Divergences of opinion between the reviewers were discussed
until a consensus was reached. The present systematic review was
conducted in accordance with the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA)9.
The initial search led to the retrieval of 425 articles. After the
removal of duplicates, the titles and abstracts of 268 articles were
analyzed for eligibility, 172 of which were preselected. Following the
full-text analysis, 152 articles were excluded and 20 were selected for the
present review. Figure 1 displays the flowchart of the selection process.
Records identified through
Identification
15 years of study19; five articles did not specify the schooling of the
participants20-24.
Regarding the affected region of the brain, six studies evaluated
patients with damage to both hemispheres3,4,8,13,17,18. Three studies
showed that patients with lesion in right hemisphere present
significant impairment in the performance on ToM tasks compared
to patients with lesion in the left hemisphere3,13,17 and control group17.
In contrast, Yeh and Tsai8 and Pluta et al.4 demonstrated that patients
with stroke showed impairment in the ToM abilities compared to
control group, regardless of the hemisphere of the lesion. The study
of Surian and Siegal18 found no association between the performance
on ToM tasks and post-stoke lesion.
In addition, seven studies evaluated patients with damage only
in the right hemisphere7,16,19,21,22,25,26 and only one study did not show
impairment in the ToM abilities in patients with lesion in the right
hemisphere compared to healthy patients7.

database searching
PubMed (n = 80)
Scopus (n = 85)
PsycInfo (n = 161)
Web of Science (n = 94)
Records after duplicates removed
Screening
Additional records identified
through other sources
(n = 5)
Seven studies evaluated specific regions of the brain, such as
the temporal lobe, prefrontal cortex, posterior parietal cortex and
temporoparietal junction15,20,23,24,27,28, and these patients showed
significant impairment on the performance on ToM tasks compared
to healthy individuals. Roca et al.14 did not specify the site of the
lesion. The time elapsed since the stroke event ranged from three
weeks24 to 23 years17. Four studies did not specify the time elapsed
since the stroke event6,14,19,23.

(n = 268) For the evaluation of ToM, the most frequently used tasks were:
The False Belief and True Belief task4,7,13,15-20,23,25-27, which is composed
of stories that require the attribution of false and true beliefs, with
the aim of verifying the participant’s ability to make inferences about
Records screened Records excluded
mental states, and these can be divided into false first-order beliefs,
(n = 268) (n = 96)
which concerns understanding the mental state of the other and
second order, which is ability to understand what someone thinks
Eligibility

about what someone else thinks; The FauxPas Detection test8,14,15,28

examine the individual’s ability to understand an embarrassing social
Full-text articles assessed Full-text articles
situation, such as when one individual says something to another
for eligibility excluded, with reasons
(n = 152)
without considering that he would not like to hear15; The Reading
(n = 172)
• Case study (n = 12) the Mind in the Eyes test3,24,28, which consists of presenting black and
• Sample < 18 years white photographs of the eye region, in which participants should
(n = 19) choose a word that best describes what the person in the image is
• FMRI with no thinking or feeling, with the intention of assess the ability to interpret
Included

evaluation of ToM the mental states of the other.

Studies included in (n = 29)
qualitative synthesis • Did not evaluate ToM
(n = 20) (n = 92)
Figure 1.
In addition, the studies selected in the present review were
evaluated for methodological quality based on the guidelines of
strengthening the reporting of observational studies in epidemiology
(STROBE). This instrument consists of 22 check items and aims
to provide greater transparency and improve the quality of the
description and presentation of observational study findings10. We
also used as a basis the Dictionary of STROBE, indicated by the
authors as an important theoretical framework for the critical analysis
of scientific articles11.
Regarding the score, studies with a score of 80 to 100% are
considered studies that have a strong methodological quality. Studies
with a score of 60%-79% are classified as moderate methodological
quality, and studies with lower than 60% scores are classified in
the STROBE checklist12.
Results
Table 1 displays the data extracted from the 20 articles selected for the
present review. The articles were published between 199613 and 20174.
The sample size ranged from 1114 to 804 participants, the majority of
whom was male (55.9%), and mean age ranged from 34.1215 to 73
years16,17. Educational level of the participants ranged from 7.318 to
In relation to the methodological quality of the studies, of the
20 studies evaluated according to STROBE, six studies14,19,20,23,27,28
obtained scores lower than 60% and were considered with poor
methodological quality and fourteen 3,4,7,8,13,15-18,21,22,24-26 studies
obtained a score of 60% to 79% and were classified with moderate
quality. None of the studies evaluated reached a score above 80%
and therefore no study was considered with strong methodological
quality. The main weaknesses identified according to STROBE were:
non-identification of the study’s design in the title or abstract (n =
20), absence of flow diagram (n = 19), absence of explanation of
how the study size was arrived at (n = 7), absence of explain how
missing data were addressed (n = 19) and the description of sensitivity
analyses (n = 17).
Discussion
The studies included in the present review generally indicate that
stroke survivors have a poorer performance on ToM tasks. Moreover,
the association between a lesion in the right hemisphere and the
performance on these tasks was a predominant characteristic of
this review.
In general, patients with lesion in the right hemisphere showed
lower performance on ToM tasks compared to those with lesion in the
left hemisphere. Furthermore, when compared to healthy individuals,
patients with lesion on the right hemisphere present impairment on
the performance on ToM tasks. Likewise, patients with lesions in
specific regions, such as temporal lobe, prefrontal cortex, posterior
parietal cortex and temporoparietal junction, presented deficit in
the performance on ToM tasks in relation to the healthy individuals.
142 Bomfim AJL et al. / Arch Clin Psychiatry. 2020;47(5):140-145

Table 1. Characteristics of the selected studies according to inclusion criteria

Authors/Year Sample Sex (M:F) Age Education (years) Lesion site Time post stroke ToM assessment Main findings
tool
Apperly et al., 12 SP: 10:2 SP: 55.2 (±13.5) - Frontal Parietal 8 (±4.2) years False Belief Lesions in the
200420 temporal lobes. Tasks temporoparietal region
impair the ability to
perform the False Beliefs
task.
Besharati et al., 45 AHP: 6:9 HP: AHP: 73.00 (±22.0) AHP: 12.00 (± 3.0) Right hemisphere - Adapted Stories Anosognosia group
201616 8:7 HC: 9:7 HP: 68.00 (±27.0) HC: HP: 12.00 (±3.0) inference performed worse than
71.00 (±7.0) HC: 13.00 (±6.0) of beliefs, both control groups when
intentions and having to perform tasks
emotions from a third versus a first
person perspective.
Champagne- 30 RHL: 6:9 RHL: 60.9 (±11.7) RHL: 11.7 (±3.1) Right hemisphere 1-4 months False belief task Patients with right frontal
Lavau et al., HC: 7:8 HC: 60.7 (±12.8) HC: 11.7(±3.2) and internal capsule
200926 lesions presented
pragmatic and ToM
deficits compared to HC
group.
Griffin et al., 31 RHL: 6:5 RHL: 61.0 RHL:14.0 Right hemisphere - A graded (first RHL patients differed
200619 HC: 7:13 HC: 66.0 HC: 15.0 order, second from non-brain-damaged
order) ToM controls in the ability to
task with non- attribute second order
mentalistic intentional states.
control questions
Hamilton et al., 70 RHL: 7:8 RHL: 67.80 (±14.1) RHL: 11.73 (±3.0) Left hemisphere RHL: RMET and Eyes The results showed that
20173 LHL: 7:8 LHL: 67.73 (±9.9) LHL:10.87 (±2.2) and Right 71.0 (±32.4) days control task stroke participants with
HC: 18:22 HC: 66.63 (±12.7) HC: 12.13(± 3.5) hemisphere LHL: RHL were significantly
77.47 (±32.4) days more impaired on the
visual RMET than those
with LHL, who performed
similarly to healthy
controls.
Happé et al., 38 RHL: 5:9 RHL: 64 RHL: 13.4 Right hemisphere RHL: ToM stories and RHL patients showed
199917 LHL: 4:1 LHL: 67 LHL: 12.6 and Left 4 months to 23 non- mental evidence of ToM
HC: 9:10 HC: 73 HC: 14.6 hemisphere years stories. impairment compared to
LHL: LHL patients and healthy
12 months to 21 controls.
years
Humphreys and 24 PPC/TP: PPC/TPJ: 68.33(±6.3) - Posterior parietal - Social Simon Patients with brain
Bedford, 201123 4:2FL: 6:0 FL: 63.5 (±14.2) LC: cortex and injuries present
LC: 6:0 HC: 56.16 (±14.2) HC: Temporoparietal impairment on ToM tasks
4:2 67.5 junction related to the capacity to
respond to social stimuli.
Mah et al., 200427 64 SP: 30:3 SP: 52.5 (±7.5) SP: 14.1 (±2.5) Prefrontal cortex - Interpersonal All patients showed
HC: 23:8 HC: 54.5 (±9.8) HC: 14.9 (±2.0) Perception Task poorer insight into their
deficits, relative to
healthy volunteers.
Martin and 42 RHL: 13:8 RHL: 69.2 (±14.8) - Right hemisphere 5.7 months Test of ToM and Patients with RHL
Mcdonald, 200621 HC: 6:15 HC: 68.5 (±14.7) Pragmatic Ability demonstrated significant
difficulty on tasks that
used the social context
to interpret pragmatic
inferences.
Pluta et al., 20174 80 RHL: 15:14 RHL: 57.7 (±13) RHL: <12: 18/ >12: Left hemisphere, RHL: 24.8 (±35.4) 18 short The results showed that
LHL: 12:12 LHL: 60.2 (±10) 9 LHL: <12: 10 / right hemisphere months vignettes (false there
BL: 5:0 BL: 45.5 (±19.8) >12: 14 BL: <12: 3 / and bilateral LHL: 28.4 (±28.1) beliefs, sarcasm, were no differences
HC: 9:13 HC: 55.4 (±10) >12: 2 HC: <12: 12 months white lie) between RHD, LHD, and
/ >12: 10 BL: 13 (±15.5) BD patients in any of the
months ToM tasks. Patient group
demonstrated impaired
performance on all ToM
tasks compared to a
control group.
Roca et al., 201314 11 9:2 50.6 (±12.1) 12.5 (±2.9) - - The Faux Pas Patients with cerebellar
task strokes did not show
impairment on the test.
 Bomfim AJL et al. / Arch Clin Psychiatry. 2020;47(5):140-145 143

Authors/Year Sample Sex (M:F) Age Education (years) Lesion site Time post stroke ToM assessment Main findings
tool
Shamay-Tsoory et 52 FL: 20:6 FL: 34.12 (±14.0) FL: 12.46 (±1.9) Prefrontal cortex 6 months, except false belief task, Lesions in the right
al., 200515 PL: 8:5 PL: 40.46 (±5.38) PL: 12.9 (±2.1) and posterior one patient who detection of irony ventromedial area were
HC: 10:3 HC: 34.12 (±12.59) HC: 14.4 (±3.4) lesions was assessed and identifying associated with more
3 months after social faux pas severe ToM deficit
trauma compared with patients
with posterior lesions
and normal control
subjects.
Siegal et al., 28 RHL: 7:10 RHL: 69.2 (±10.9) RHL: 8.6 Right hemisphere RHL: 1-24 months False belief Patients with RHL have
199613 LHL: 8:3 LHL: 70.3 (±9.7) LHL: 8.2 and Left LHL: 1-68 months and difficulties understanding
hemisphere True Belief task the false beliefs tasks.
Surian and 64 RHL: 9:7 RHL: 62.3 (±12.3) RHL: 7.3 (±3.1) Right hemisphere RHL: 9.9 months False Belief and The performances on the
Siegal, 200118 LHL: 8:8 LHL: 62.8 (±15.5) LHL: 7.6 (±2.5) and Left (±13.7) True Belief ToM tasks of the RHL
HC: 13:19 HC: 64.5 HC: 7.3 hemisphere LHL: 8.6 months stories. and LHL groups did not
(±8.1) differ significantly from
controls
Tompkins et al., 60 RHL: 3:9 RHL: 64.4 RHL: 14.6 (±3.2) Right hemisphere 65.7 (±52.2) months Narrative stimuli The group with RHL did
20087 HC: 9:19 HC: 60.4 HC: 13.9 (±2.2) that targeted not show impairment on
either a mental the test.
or a non-mental
causal inference.
Weed et al., 21 RHL: 8:3 RHL: 65.0 - Right hemisphere 3.09 (±1.7) months Animated films RHL group displayed
201022 HC: 4:6 HC: 65.0 with moving impaired ability to
geometric shapes discriminate between
film categories and
exhibited bias when
attributing mental states
to others.
Wilkos et al., 19 SP: 5:3 SP: 63.7 (±7.9) - Unilateral 3 weeks RMET Compared to healthy
201524 HC: 6:5 HC: 49.6 (±12.2) Thalamic controls, patients
showed significantly
worse performance on
RMET task.
Winner et al., 33 RHL: 6:7 RHL: 59.5 (±12.2) RHL: 14.5 (±2.6) Right hemisphere 5.6 (±5.2) years Sixteen short lie RHL patients performed
199825 HC: 14:6 HC: 66.5 (±8.2) HC: 14.2 (±2.4) or joke stories significantly worse than
control subjects on one
of two measures of
second-order belief.
Xi et al., 201328 39 TLCI: 16:3 TLCI: 55.16 (±14.0) SP: 10.11 (±3.3) Temporal lobe 36.42 days (±8.9) Recognition of TLCI group performed
HC: 13:7 HC: 56 (±6.7) HC: 10.95 (± 2.3) faux pas and significantly worse on
RMET tasks tasks compared to HC
group.
Yeh et al., 20148 74 LHL: 8:6 LHL: 57.79 (±10.8) LHL: 9.64 (±3.5) Left hemisphere LHL: The Faux Pas Patients with stroke were
RHL: 9:11 RHL: 63.85 (±11.5) RHL: 8.70 (±4.6) and Right 18.18 (±6.5) months task significantly impaired
HC: 22:18 HC: 60.20 (±11.87) HC: 9.10 (±3.5) hemisphere RHL: in both cognitive and
20.45 (±7.9) months affective ToM compared
to a control group.
M: male; F: female; HC: healthy control; SP: stroke participants; RHL: right hemisphere lesion; LHL: left hemisphere lesion; BL: bilateral lesions; FL: frontal lesions; LC: lesioned controls; PPC: posterior
parietal cortex; TPJ: temporoparietal junction; PL: posterior lesion; AHP: anosognosia for hemiplegia; HP: hemiplegic group; RMET: Reading the Mind in the Eyes Test; ToM: Theory of Mind; TLCI: temporal
lobe cerebral infarction.

Studies that evaluated the cerebral location of the stroke event
found heterogeneous results regarding the lateralization of the
function of ToM. Stroke survivors with the right hemisphere affected
exhibited greater impairment on tasks that evaluate ToM than those
with lesions in the left hemisphere3,13,17 or healthy individuals19,21,22,25.
In contrast, Pluta et al.4 compared the performance on ToM tasks
among individuals with right hemisphere lesions, left hemisphere
lesions and bilateral lesions and found that stroke survivors exhibit
impairment on these tasks, but found no difference with regard to the
site of the lesion. Likewise, Surian and Siegal14 found no significant
difference in the performance on the False Belief and True Belief
test between two groups separated into right hemisphere and left
hemisphere lesions.
Tompkins et al.7 also found no difference on ToM tasks between
patients with a right hemisphere lesion and a control group. Happé
et al.17 found that eight out of 14 patients in the group with right
hemisphere lesions had a poorer performance on ToM tasks, whereas
only two out of 21 patients with left hemisphere lesions exhibited
a compromised ability on these tasks in the study by Tompkins
et al.7, indicating greater impairment on ToM tasks following a
stroke in the right hemisphere. However, it is important to stress
the methodological difference between the studies, as different tests
were used to assess ToM7. According to Happé et al.17 the association
between right hemisphere lesions and performance on ToM tasks
may stem from the characteristics of the lesion; stroke survivors with
the right hemisphere affected may have more or more severe lesions
in comparison to those with the left hemisphere affected.
In the study by Roca et al.14 patients with cerebellar strokes
demonstrated no impairment on the Faux Pas Detection task.
According to the authors, these tasks require other functions that
144 Bomfim AJL et al. / Arch Clin Psychiatry. 2020;47(5):140-145
may be related to the cerebellum, such as language, which may have
exerted an influence on the results.
In a study comparing abilities on pragmatic ToM tasks and
executive functions in stroke survivors with right hemisphere
lesions and healthy individuals, Champagne-Lavau et al.26 found
that the ability to understand pragmatic aspects of language is
closely associated with the ability to make inferences regarding
the intentions of others. The researchers also found an association
between an impaired ToM and executive dysfunction in subgroups
of individuals with damage in the right hemisphere.
Shamay-Tsoory et al.15 evaluated patients with lesions in the
prefrontal cortex, posterior lesions and participants without lesions
and found that those with prefrontal lesions, specifically ventromedial
prefrontal lesions, exhibited impairment on ToM tasks. Likewise,
Mah et al.27 compared patients with lesions in the prefrontal cortex to
healthy volunteers and found that the patients with lesions, especially
in the dorsolateral prefrontal cortex, demonstrated impaired abilities
regarding ToM. These findings support that notion that the prefrontal
cortex is associated with ToM skills and that the ventromedial
prefrontal cortex is essential to the regulation of emotions29.
According to Shamay-Tsoory et al.15, the difference between
sites and the asymmetry of the lesions may influence the results of
ToM tasks due to the involvement of different cognitive processes.
Stroke is associated with greater impairment in social cognition
assessments that require other cognitive processes, such as working
memory, language, executive function and attention, and which
may also be affected post-stroke3. In addition, it is expected that
the impairment after stroke is greater for more complex second-
order tasks compared to the first order tasks of the ToM and for the
classification of emotions26. Therefore, the choice of the task and
lesion site may influence the results of the studies.
It is known that patients with lesion in the right hemisphere seem
to perform worse in the ability to attribute intentional second-order
states compared to first-order mental states19,25. There is also evidence
that these tasks may not allow the distinction of effects in patients
with stroke and healthy controls7. For example, in the study by Griffin
et al.19, RHL patients differed from non-brain-damaged controls in
the ability to attribute second order intentional states, however, these
authors were not found differences between groups with regard to
attribute first order intentional states.
Another question considered as an influencing factor that can
influence in the performance in the of ToM tasks is the tool used.
Evidence indicates that this task RMET can have biased responses
and, consequently, limit its psychometric validity30. The study by
Hamilton et al.3 used the RMET task to assess the difference between
the performance of in ToM in of patients with RHL, LHL and healthy
controls, and the results showed that stroke participants with RHL
were significantly more impaired on the RMET than those with LHL,
who performed similarly to healthy controls. The authors present as
a limitation the use of RMET only for the assessment of ToM, since
the test involves the recognition of complex emotions and, therefore,
evaluates this ability restrictively.
Concerning to evaluation, the articles included in this review
used a wide variety of tools to evaluate ToM. In overall, the studies
found indicate that ToM evaluation has as purposes: (i) detect
mistakes and contextual information using, for instance, false beliefs
tasks4,7,13,15-20,23,25-27 e The Faux Pas Detection test8,14,15,28; (ii) analyze
the pragmatic understanding discourse21; (iii) verify the non-verbal
contents abstraction through The Reading the Mind in the Eyes
test3,24,28 and tasks composed of geometric elements22; in addition
to studies that integrate these different evaluation methods15,28. The
variability of measures of ToM assessment used by the selected
studies may be considered as limitation, as it made difficult the
systematization and the comparison between the results, invalidating
the meta-analysis accomplishment.
With regard to the time post stroke event, none of the articles
selected for the present review discussed the influence of this variable
on the results. Therefore, further studies are needed to investigate
this aspect. Another topic that could be explored by new studies
is the frequency of people post stroke with significant damage on
ToM ability.
The limitation of the present review resides in the inconsistency
of some of the data extracted for the construction of the table in
the results section, as some information considered pertinent for
a systematic evaluation of this topic was missing. Furthermore,
the absence of realization of cross-reference search, based on the
descriptors used, may have made it difficult to refinement the articles,
limiting the findings found. Finally, the general low quality of the
articles analyzed can also be considered as a limitation.
This review has important clinical implications, since an impaired
ability of ToM can affect the process of capturing and transmitting
information through social interaction. Therefore, accurate
identification of impaired ToM ability based on clinical evaluation
is essential to indicate the most appropriate treatment.
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 Review article

The impact of exercise in improving executive function impairments among children

and adolescents with ADHD, autism spectrum disorder, and fetal alcohol spectrum
disorder: a systematic review and meta-analysis
Anjali L. Varigonda1
https://orcid.org/0000-0001-5530-8262

Juliet B. Edgcomb1
https://orcid.org/0000-0002-5542-1879

Bonnie T. Zima1
https://orcid.org/0000-0001-5530-8262

University of California Los Angeles – Psychiatry, Los Angeles, California, United States.
1

Received: 15/03/2020 – Accepted: 18/04/2020

DOI: 10.1590/0101-60830000000251

Abstract
Objective: he goal of this work was to perform a systematic review and meta-analysis evaluating and comparing exercise related improvements in various
executive function (EF) domains among children and adolescents with attention-deficit hyperactivity disorder (ADHD), Autism Spectrum Disorders (ASD),
and Fetal Alcohol Spectrum Disorders (FASD). Methods: A systematic literature research was conducted in PubMed, CENTRAL, and PsycInfo from October
1st, 2018 through January 30th, 2019 for original peer-reviewed articles investigating the relationship between exercise interventions and improvements in
three domains of executive function (working memory, attention/set shifting, and response inhibition) among children and adolescents with ADHD, ASD,
and FASD. Effect sizes (ES) were extracted and combined with random-effects meta-analytic methods. Covariates and moderators were then analyzed using
meta-regression and subgroup analyses. Results: A total of 28 studies met inclusion criteria, containing information on 1,281 youth (N=1197 ADHD, N= 54
ASD, N=30 FASD). For ADHD, exercise interventions were associated with moderate improvements in attention/set-shifting (ES 0.38, 95% CI 0.01-0.75, k=14)
and approached significance for working memory (ES 0.35, 95%CI -0.17-0.88, k=5) and response inhibition (ES 0.39, 95%CI -0.02-0.80, k=12). For ASD and
FASD, exercise interventions were associated with large improvements in working memory (ES 1.36, 95%CI 1.08-1.64) and response inhibition (ES 0.78, 95%CI
0.21-1.35) and approached significance for attention/set-shifting (ES 0.69, 95% -0.28-1.66). There was evidence of substantial methodologic and substantive
heterogeneity among studies. Sample size, mean age, study design, and the number or duration of intervention sessions did not significantly moderate the
relationship between exercise and executive function. Conclusion: Exercise interventions among children and adolescents with neurodevelopmental disorders
were associated with moderate improvements in executive function domains. Of note, studies of youth with ASD and FASD tended to report higher effect sizes
compared to studies of youth with ADHD, albeit few existing studies. Exercise may be a potentially cost-effective and readily implementable intervention to
improve executive function in these populations.

Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156

Keywords: Epidemiology, depression, anxiety, prisoners, MINI.

Introduction of prevalence rates ranging from 35% to 60%11. Therefore, new

Neurodevelopmental disorders, specifically attention-deficit/
hyperactivity disorder (ADHD), autism spectrum disorder (ASD),
and fetal alcohol spectrum disorders (FASD) affect approximately
1 out of 6 children in the United States1. ADHD has a high co-
occurrence in children and adolescents with FASD and ASD,
with prevalence estimates consistently over 50%-60%2,3. Executive
function (EF), which refers to higher order cognitive processes that
are responsible for purposeful goal-directed behavior4, is frequently
compromised in children with ADHD, ASD, and FASD and is
implicated in associated behavioral, socio-emotional, and cognitive
impairments5.
Although stimulants remain the gold standard for treatment
of EF deficits associated with ADHD, up to 30% of children do not
show a beneficial response to stimulants6-8. Response to stimulants
is even further reduced in children and adolescents with co-morbid
autism or prenatal alcohol exposure (PAE)6-8. Furthermore, there is
evidence that stimulants have a greater effect on certain EF measures
such as attentional performance, and less of an effect on measures
such as impulsivity9. Behavioral treatments are relatively difficult to
implement, costly, and effects are hard to maintain after termination
of treatment10. Research shows that as children with PAE mature,
they exhibit problems with the misuse of alcohol, with estimates
approaches to differentiate and treat the spectrum of EF impairments
in children with ADHD, FASD, and ASD are needed.
In recent years, a growing body of literature has supported the
growing role of exercise in improving cognition, notably EF12-14. Many
converging lines of research into the biological underpinnings of
exercise-based improvements in EF have been elucidated. Exercise
has been shown to increase levels of norepinephrine, dopamine,
and serotonin in the prefrontal cortex, hippocampus and striatum
to affect mood and cognition15,16. It is posited that, as a result of
exercise, increased levels of dopamine enhance attention, focus, and
learning, whereas increases in norepinephrine improve executive
function, reduce distractibility, modulate arousal, and enhance
memory to assist in learning17,18. In animal models, exercise has
been shown to reduce oxidative stress and improve neuroendocrine
auto-regulation which has been shown to counteract stress and
age-related neuronal degeneration19. Exercise has also been shown
to directly cause morphological changes in the brain by increasing
blood flow, and has also been shown to result in upregulation of brain-
derived neurotrophic factor (BDNF), which plays an integral role in
hippocampal functioning and long term potentiation for learning and
memory, synaptic plasticity, neurogenesis, and neuroprotection20.
Exercise appears to improve EF in children and adolescents
with attention-deficit/hyperactivity disorder (ADHD)14,21,22. Aerobic

Address for correspondence: Anjali L. Varigonda. University of California Los Angeles – Psychiatry. 760 Westwood Plaza, 90095, Los Angeles, California, United States.
E-mail: avarigonda@caps.ucla.edu
 Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156
exercise interventions of at least 30 minutes show the most promise
in improving EF deficits associated with ADHD22. Research provides
further evidence that exercise induces improvements in executive
function (EF) in children and adolescents with ADHD, more so than
in typically developing children14,21,22. Although studies suggest that
exercise induces similar improvements in EF in animal models exposed
prenatally to alcohol, research evaluating the impact of exercise in EF in
children and adolescents with prenatal alcohol exposure is lacking. To
this date, there is only one study evaluating effectiveness of an exercise
intervention on EF in children and adolescents with prenatal alcohol
exposure23. Furthermore, research investigating whether exercise
interventions have beneficial effects on some EF domains in children
with neurodevelopmental disorders is lacking24.
The purpose of this systematic review and meta-analysis is to
1) examine potential differences in exercise related improvement in
EF outcomes in different neurodevelopmental disorders, specifically
ADHD, FASD, and ASD; 2) evaluate whether certain EF domains are
more sensitive to the effects of exercise in children and adolescents
with ADHD, FASD, and ASD; and 3) explore whether specific
characteristics of participants or the exercise interventions can
predict the magnitude of EF improvement in children and adolescents
with ADHD, FASD, and ASD. To our knowledge, this is the first
meta-analysis of existing studies investigating and comparing the
effects of exercise on EF subdomains in children and adolescents
with ADHD, FASD, and ASD.
Methods
Search strategy
A systematic literature review was performed using PubMed,
CENTRAL, the Cochrane Collaboration database of controlled
trials (in the Cochrane Library), and PsycInfo from October 1st,
2018 through January 30th, 2019. Keywords used in the search
included (autism OR ADHD OR fetal alcohol exposure OR Fetal
Alcohol Spectrum Disorders) AND (exercise OR physical activity
OR physical fitness) AND (executive function tests OR executive
function OR common neuropsychological measures of executive
function). Search strategy was based on previous systematic reviews
looking at executive function deficits in FASD and ADHD and can
be found in the supplemental materials5. Reference lists of included
manuscripts and related prior review articles were reviewed for
additional studies13,22,24-30.
Study selection
The meta-analysis followed the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) statement
guidelines and adhered to protocol defined prior to data extraction.
Only peer-reviewed English-language journal articles were included.
The following additional inclusion criteria were applied: study
participants 0-18 years old, the study participants were diagnosed
with ADHD, ASD, or FASD, the study tested the effect of an exercise
intervention on EF, the study used individual neuropsychological
assessment tasks as an outcome measure. Studies were excluded
if the study did not report an effect size, or statistic from which an
effect size could be computed (i.e. book chapters, qualitative reviews).
The following exclusion criteria were applied: the study measured
domains of cognition other than executive function, the study did
not report a measure of executive function directly obtained by
assessment of the child (i.e. studies that relied on parent or teacher
report), the study did not test the effect of an exercise intervention
(i.e. observational studies). The literature search, title, and abstract
screening, and evaluation of inclusion and exclusion criteria were
performed independently by two of the study’s authors, with
disagreements resolved via consensus ratings.
147
Data extraction
Effect sizes were extracted when the effect size measured the
relationship between exercise intervention and executive function.
If an effect size was not reported, data from which an effect size could
be calculated (e.g. means and standard deviations) was extracted.
Measures of executive function were divided into the following
domains: working memory, attention/set-shifting, and response
inhibition. When more than one domain was reported, a separate
effect size was extracted (or calculated) for each domain.
Measures of attention/set shifting included the following:
Wisconsin Card Sorting Test, Cognitive Battery Test (a mixed
measure of Paced serial addition, size ordering, listening span, digit
span backwards, and visual coding), the Color Trails Test Part 1, the
Trail Making Test, Eriksen Flanker Test, Test of Everyday Attention,
Connor’s Continuous Performance Test, the Visual Pursuit Test, Task
Switching Paradigm, and the Auditory Oddball Test. Measures of
working memory included the following: Digit Span, Digit Symbol
Test, Visual Sequential Memory Test, Corsi Block Tapping Test, and
Automated Working Memory Assessment Test. Measures of response
inhibition included the following: Stroop Color and Word Test, Go/
No Go Test, Determination Test, Stop Signal Task, STOPIT Task, and
Children’s Color Trails Test Part 2. The following data were extracted
from each study when reported: participant characteristics including
diagnosis, mean age, and stimulant medication use; sample size;
study year; study design (crossover, parallel, or single-group pretest-
posttest); duration of exercise intervention (i.e. one-time exercise
vs weekly exercise); exercise intensity (low vs moderate or high
intensity); and type of exercise (running, cycling, mixed exercises, or
other). Moderate or High intensity exercise was defined by exercise
that reaches at least 50% of the maximal heart rate as defined by the
American College of Sports Medicine (ACSM) guidelines31.
Data analysis
As studies reported different measurement methods, standardized
mean different estimates of difference in executive function
domain scores were used as effect size (ES) estimates. ES estimates
were converted to Hedges’ g to provide an unbiased ES adjusted
for small sample sizes. An ES of 0.2 is considered to be low, 0.5
moderate, and 0.8 large32. The 95% Confidence Interval for each
ES was also calculated. The ES of each executive function domain
represents the average ES estimate derived from each of its relevant
neuropsychological measures. At least three independent datasets
had to be available to calculate a summary ES. The DerSimonian-
Laird (D-L)33 random effects method of meta-analyses was used
to pool effect size estimates. This method accounts for variability
between studies and allows for generalization of results beyond
the sample population34. Each domain of EF (attention/set shifting,
working memory, and response inhibition) was pooled separately.
Between-study heterogeneity was assessed with the I2 statistic and
Cochran’s Q. Confidence intervals were inspected for each pooled
SMD and regression coefficient to evaluate the interval estimate
of each population parameter. To assess for possible impact of
continuous covariates on effect measures, meta-regression was
performed on effect size estimates on sample size N, mean age, and
year of study publication. A covariate was investigated using meta-
regression when at least three independent datasets provided data on
the potential moderator. Begg’s and Egger’s tests35,36, were conducted
to assess for publication bias and funnel plots were visually inspected.
Statistical Analyses were carried out in STATA Version 15.1 (College
Station, TX: StataCorp, LLC). P-values were two-tailed, and an alpha
level of 0.05 conferred statistical significance. The study did not meet
criteria for IRB review.
148 Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156

Subgroup analyses
To ascertain potential sources of heterogeneity between studies,
subgroup meta-analyses were performed to further evaluate sources
of variability. Between-study heterogeneity within subgroups was
assessed using the I2 statistic. Subgroup analyses were conducted
for categories for which sufficient data was reported (k > or equal to
2). The following subgroups were assessed: (1) duration (single vs
multiple session intervention), (2) intensity (moderate or high vs low),
(3) type of exercise intervention (running, cycling, mixed, and other),
and (4) study design (repeated measures vs intervention/control).
Records identified through
Identification
exercise (refer to Table 1). Detailed characteristics on the included
studies are presented in Table 1.
Attention and set-shifting
Fourteen studies investigated the relationship between exercise
interventions and attention and set-shifting scores. Of these, 5 studies
reported scores pre- and post-exercise intervention and pre- and
post-control intervention21,39-42, three studies reported post-exercise
intervention and post-control intervention scores only43-45, and 1
study reported pre- and post-exercise intervention scores only46.
Five studies included a healthy (non-ADHD) control group38,43,47-50.
The overall pooled ES was 0.38 (95% CI 0.01-0.75, k = 14)
(Figure 2). The I2 test of heterogeneity was statistically significant (I2 =
99.7%, df = 13, p < 0.01), and thus subgroup analyses were conducted

database searching
(n = 256); to identify substantive and methodological sources of heterogeneity.
PubMed: 107 Additional records identified Type of exercise was a significant moderator of ES, wherein studies
CENTRAL: 33 through other sources that involved running as the exercise intervention tended to find
PsycInfo: 107 (n = 21) more robust ES (g = 0.49, 95% CI 0.12-0.86, k = 5) compared to other
types of exercise (cycling: g = 0.16, 95% CI -0.41-0.72, k = 3; mixed
exercises: g = 0.19, 95% CI -0.17-0.55, k = 2; other: g = 0.50, 95% CI
Records after duplicates removed
-0.34-1.33, k = 4). Meta-regression analyses suggested that participant
Screening

(n = 22)
age and year of study publication were not significant predictors of
ES. Subgroups analyses found that presence of healthy control group,
study design, duration, intensity, and comorbid medication were not
Records excluded significant moderators of ES. Egger’s test demonstrated evidence of
Records screened (n = 79), with reasons: publication bias (t(13) = -2.43, p = 0.032), wherein smaller studies
(n = 255) -wrong target population tended to report stronger associations between exercise intervention
-wrong diagnosis and improvement in attention and set-shifting scores.
Eligibility

Full-text articles Working memory

Full-text articles assessed excluded, with reasons
for eligibility (n = 148) Five studies investigated the relationship between exercise
(n = 176) 7- predoctoral interventions and working memory scores. Of these, four studies
dissertations reported scores pre- and post-exercise intervention and pre- and
74-did not use executive post-control intervention39,40,51,52. One study reported post-exercise
function as outcome and post-control scores only53. The overall pooled ES was 0.35 (95%
Included

8- did not measure
executive function with
Studies included in neuropsychological
quantitative synthesis assessment task
(meta-analysis) 59- observational
(n = 28) (non-intervention) studies
CI -0.17-0.88, k = 5) (Figure 2). The I2 test of heterogeneity was
statistically significant (I2 = 99.5%, df = 4, p < 0.01). Meta-regression
analyses suggested that study size, participant age and year of
study publication were not significant predictors of ES. Subgroup
analyses were limited due to small number of total studies. Begg’s
and Egger’s tests, as well as visual inspection of the funnel plot, did
not demonstrate evidence of publication bias.

Figure 1. PRISMA Flowchart depicting study search and selection process.

Adapted from: Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group.
Preferred reporting items for systematic reviews and meta-analyses: the
PRISMA statement. PLoS Med. 2009;6(7):e1000097.
. reported scores pre- and post-exercise intervention and pre- and
Results
A total of 256 potentially relevant studies were retrieved, including
107 from PubMed, 39 from CENTRAL, and 110 from PsycInfo. After
duplicates were removed, the titles and abstracts of 255 references
were assessed for eligibility. Of these, 79 were excluded, and 176 full-
text articles were screened. Finally, 28 studies met eligibility criteria,
of which 23 assessed children with ADHD, four studies assessed ASD,
and one study assessed FASD. Due to the relatively small number
of ASD and FASD studies, these studies were combined. The study
inclusion (PRISMA) flow chart is displayed in Figure 1.
ADHD and exercise
The total number of participants in the selected studies was 1,197. The
number of participants per study varied from 1237 to 55238. Exercise
interventions varied in terms of frequency, intensity, and type of
Response inhibition
Twelve studies investigated the relationship between exercise
interventions and response-inhibition scores. Of these, nine studies
post-control intervention, two studies reported post-exercise
intervention and post-control intervention scores only54,55 and one
study reported pre- and post- exercise scores only46. Only one study
included a healthy (non-ADHD) control group49.
The overall pooled ES was 0.39 (95% CI -0.02-0.80, k = 12)
(Figure 2). The I2 test of heterogeneity was statistically significant
(I2 = 99.5%, df = 11, p < 0.01), and thus subgroup analyses were
conducted to identify substantive and methodological sources of
heterogeneity. Meta-regression analyses suggested that study size,
participant age and year of study publication were not significant
predictors of ES. Subgroup analyses suggested that studies including
participants taking co-morbid ADHD medication tended to report
higher ES of the relationship between exercise interventions and
response inhibition scores (with comorbid medications: ES 0.50,
95% CI 0.17-0.82; without comorbid medication ES 0.28, 95% CI
-0.46-1.03). Presence of healthy control group, study design, duration,
intensity, and type of exercise were not significant moderators of ES.
Begg’s and Egger’s tests, as well as visual inspection of the funnel plot,
did not demonstrate evidence of publication bias.
Table 1.
Study Sample characteristics Intervention Findings
Author Pub Study design Co-morbid Sample Size Age range Diagnosis Type Intensity Duration EF Measure EF Domain Key Result
Year stimulant (M+\- SD)
medication
Chang 2012 Parallel group Yes 40 (3 female, 10.43+/-0.90 ADHD Running Moderate-high 30 minutes on Stroop Test, Stroop Test: Greater improvement
37 male) intensity treadmill (5 min Wisonsin Card response Inhibition; in non perseverative
warmup, 5 minute sorting Test (WCST) WCST: attention/set errors of WCST and
cooldown, 20 minute shifting Stroop Color-Word
run) Test in exercise
group compared to
controls
Pritchard 2018 Crossover Not reported 30 (14 boys, 16 10.2 (+/- 0.4 FASD Mixed Unreported 8 week duration Children’s Color CCTT 1: attention/ Greater improvement
wait-list girls) years) (FAST club (two 1.5 hr sessions Trails Test (CCTT) set shifting; CCTT 2: in exercise group
control study intervention per week) response inhibition post-intervention vs
program) pre-intervention
Chang 2014 Crossover Yes 27 (23 male, 4 age 5-10 ADHD Aquatic Moderate-high 8 week duration Go/No go Task Response inhibition Greater improvement
wait-list female) exercise intensity (two 1.5 hr sessions in accuracy on No/
control study per week) go task scores in
exercise group
compared to controls
Hill 2011 Crossover Not reported 552 (295 male, age 8-12 ADHD Mixed (jogging Moderate-high I:exercise Paced Serial Paced Serial Exercise group
wait-list 257 female) and jumping) intensity intervention for Addition, Size Addition, Size outperformed non
control study week 1; C: no Ordering, Listening Ordering, Listening exercise group by
exercise for week 1. Span, Visual Coding, Span, Visual Coding: week 2
Exercise was 10-15 Digit Span attention/set
minutes daily shifting; Digit Span:
working memory
Kang 2011 Parallel group Yes 28 ages 7-9 ADHD Running Moderate-high 6 week duration (2 Digit Symbol Test Digit Symbol Test: Greater improvement
intensity 1.5 hr sessions per and Trail Making working memory; in Digit Symbol
week) Test Part B and Trail Making Test, and TMT-Part
Test: attention/set B scores in exercise
shifting group compared to
controls
Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156

Pontifex 2012 Crossover No 20 (14 male, 6 ages 8-10 ADHD Running Moderate-high 20 minute session Eriksen Flanker Test Attention/set Greater improvement
female) intensity shifting in response accuracy
and improvement in
post-error slowing
in exercise group
compared to controls
Verret 2012 Parallel group Yes 21 (19 male, 2 9.1 (+/- 1.1) ADHD Mixed Moderate-high 10 week duration (3 Test of Everyday Attention /set Improvements
female) (basketball, intensity 45 minute sessions Attention for shifting in attention and
soccer) per week) children informational
processing in
exercise group
compared to controls
149
Study Sample characteristics Intervention Findings
150

Author Pub Study design Co-morbid Sample Size Age range Diagnosis Type Intensity Duration EF Measure EF Domain Key Result
Year stimulant (M+\- SD)
medication
Medina 2010 Single group Yes 25 (all males) 9.33 +/-2.87 ADHD Running Moderate-high 30 minute session Conner’s Continuous Attention/set Improvement in
intensity Performance Test-II shifting attention measures
in exercise group
compared to controls
Mahon 2013 Parallel group Yes 43 (30 male,13 age 8-14 ADHD Cycling Moderate-high 10 minute session Conner’s Continuous Attention/set No significant
female) intensity Performance Test-II shifting improvement in
(CCPT II) CCPT II scores in
either ADHD or
healthy control group
following exercise
Craft 1983 Single group No 31 (all males) ages 7-10 ADHD Cycling Unreported 10 minute session Digit Span, visual Working memory No improvement in
sequential memory working memory
post-intervention vs
pre-intervention
Anderson-Hanley 2011 Single group Not reported 12 (8 boys, 4 14.8 +/-2.7 ASD Other (dance) Unreported 20 minute session Digit Span, Color Digit span: working Improvement in 1
girls) Trails Test, Stroop memory; Color Trails measure of digit span
Task Test: inhibition (digit backwards)
and attention/set post-intervention vs
shifting; Stroop Task: pre-intervention
response inhibition
Anderson-Hanley 2011 Single group Not reported 10 (all males) 13.2 +/- 3.8 ASD Cycling Unreported 20 minute session Digit Span, Color Digit span: working Improvement in 1
Trails Test, Stroop memory; Color Trails measure of digit span
Task Test: inhibition (digit backwards)
and attention/set post-intervention vs
shifting; Stroop Task: pre-intervention
response inhibition
Choi 2014 Parallel group Yes 30 (all males) 15.9 +/-1.2 ADHD Mixed Moderate-high 6 week duration (3 Wisconsin Card Attention/set Greater improvement
(running, intensity 90 minute sessions Sorting Test (WCST) shifting in perseverative
jumping, per week) errors of WCST
basketball) in exercise group
Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156

compared to controls
Gawrilow 2016 Single group Yes 47 (all males) 14.37+/-1.88 ADHD Other Unreported 5 minutes Go no task Response inhibition Improvement in
(trampoline) response inhibition
in exercise group
compared to controls
Ziereis 2014 Crossover No 43 9.45 +/-1.43 ADHD Mixed Unreported 12 week duration (60 Digit span, letter Working memory ignificant
wait-list (acrobatics, minute sessions) number sequencing improvement in all
control study balance task of HAWIK-IV, working memory
training, Corsi blocking measures seen after
coordinative tapping test 12 weeks in exercise
exercises, etc) groups, though no
effects were seen
after one week in
either group
Chou 2017 Parallel group No 49 (38 males, age 8-12 ADHD Other (yoga) Moderate-high 8 week duration (2 Visual pursuit test Visual pursuit Improvements seen
11 females) intensity 40 min sessions per of the vienna test test: attention/ in both EF measures
week) system set shifting in yoga group
determination test: compared to controls
response inhibition
Study Sample characteristics Intervention Findings
Author Pub Study design Co-morbid Sample Size Age range Diagnosis Type Intensity Duration EF Measure EF Domain Key Result
Year stimulant (M+\- SD)
medication
Memarmoghaddam 2016 Parallel group No 40 (all males) 8.31+/-1.29 ADHD Mixed (table Moderate-high 8 week duration (3 Go/no Go Task, Response inhibition Significant
tennis, intensity 90 min sessions per Stroop Task improvement seen
football, week) in exercise group
basketball, post-intervention vs
etc) pre-intervention
Hung 2016 Single group No 34 (33 males, 10.24+/-1.78 ADHD Running Moderate-high 30 minute session Task switching Attention/set Improvement in task
1 female) intensity paradigm (Dai et al shifting switching in exercise
2013) group compare to
controls
Gelade 2017 Parallel group No 37 (28 male, 9 9.8 +/-1.96 ADHD Other (not Moderate-high 10-12 week duration auditory oddball AOT:attention/ Improvement found
female) mentioned) intensity (3 sessions per task, SST, visual set shifting; SST: for working memory
week ) spatial working response inhibition; in exercise group
memory task visual spatial WM compared to controls
task: working
memory
Pan 2017 Crossover Not reported 22 (all boys) age 6-12 ASD Other (table Unreported 12 week duration (2 Wisconsin card Attention/set Significant
wait-list tennis) 70 min sessions per sorting test (WCST) shifting improvement in total
control study week) correct, perseverative
response, and
conceptual -level
response subscores
of WCST post-
intervention vs pre-
intervention
Pan 2016 Crossover Yes 32 (all males) 8.93+/-1.49 ADHD Other (racket Moderate-high 12 week duration (2 Stroop Test Response inhibition Significant
study sport) intensity 70 min sessions per improvements seen
week) in response inhibition
post-intervention vs
pre-intervention
Bustamente 2016 Parallel group Yes 19 age 6-12 ADHD Mixed Unreported 10 week duration (5 STOPIT task, and STOPIT: response Improvement in
Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156

(modified 60 min sessions per automated working inhibition; AWMA: working memory
sports, week) memory assessment working memory but not in response
jumprope, etc) (AWMA-S) inhibition post-
intervention vs pre-
intervention
Shema-Shiratzky 2018 Single group- No 14 (11 male, 3 9.3+/-1.2 ADHD Other Low 6 week duration (3 Stroop Test, Go- Stroop and : Improvement in
pilot study female) (walking) sessions ranging NoGO Task, color response inhibition; attention /set
from 30 min- 1 hr trails test CTT: attention/ shifting and response
per week) set shifting and inhibition post-
response inhibition intervention vs pre-
intervention
Ringenbach 2015 Crossover Not reported 10 12.3+/-2.2 ASD Cycling Low 20 minute session Stroop Task, Trail ST: Inhibition; All three improved
study Making Test TMT: attention/set significantly post-
shifting intervention vs pre-
intervention
151
Study Sample characteristics Intervention Findings
152

Author Pub Study design Co-morbid Sample Size Age range Diagnosis Type Intensity Duration EF Measure EF Domain Key Result
Year stimulant (M+\- SD)
medication
Ludyga 2017 Crossover Yes 16 (11 male, 5 12.8+/-1.8 ADHD Cycling Moderate-high 20 min session Flanker Test Attention/set Greater improvement
study female) intensity shifting in reaction time not
accuracy in exercise
group compared to
control group
Lee 2017 Parallel group No 12 (all males) 8.83 +/-0.98 ADHD Mixed Moderate-high 12 week duration (3 Stroop Color and Response inhibition Improvement
(jumprope, intensity 60 minute sessions word test in inhibition in
jogging, etc) per week) exercise group post-
intervention vs pre-
intervention
Piepmeier 2015 Parallel group Yes 14 (five 10.14+/-1.96 ADHD Cycling Moderate-high 20 minute session Trail Making Test, TMT: attention/set Improvement in
females, 9 intensity Stroop shifting; Stroop: inhibition, not in
males) response inhibition attention/set shifting
in exercise group
compared to controls.
Chuang 2015 Crossover No 19 (16 males, 9.42+/-1.38 ADHD Running Moderate-high 30 minute session Go/No go Task Response inhibition Greater improvement
study 3 females) intensity in attention/set
shifting and response
inhibition in exercise
group compared to
controls
Pan 2017 Crossover Not reported 22 (all males) age 6-12 ASD Other (table Unreported 12 week duration (2 Wisconsin card Attention/set Greater improvement
wait-list tennis) 70 min sessions per sorting test (WCST) shifting in total correct,
control study week) perseverative
response, and
conceptual -level
response subscores
of WCST after
exercise
Ringenbach 2015 Crossover Not reported 10 (5 male, 5 12.3+/-2.2 ASD Cycling Low 20 minute session Stroop Task, Trail ST: Inhibition; Greater
Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156

study female) Making Test TMT: attention/set improvements in

shifting exercise group
compared to controls
 Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156
Figure 2.
ASD/FASD and exercise
Five studies conducted exercise interventions for children with
ASD/FASD (total N of participants was 84). Studies were small: the
sample size of persons with ASD/FASD ranged from 1056 to 3023.
All studies used a within-subjects randomized crossover design,
with the exception one study57 which used an A-B sequential design
(control then intervention). No studies included a healthy control
group. Exercise interventions varied in terms of frequency, intensity,
and type of exercise. Detailed characteristics on the included studies
are presented in Table 1.
Attention and set-shifting
The overall pooled ES was 0.69 (95% CI -0.28-1.66, k = 4) (Figure 3).
The I2 test of heterogeneity was statistically significant (I2 = 98.5%,
df = 3, p < 0.01). Meta-regressions of sample size N, mean age of
study participants, and year of study publication on ES were not
153
significant. Begg’s and Egger’s tests did not demonstrate evidence
of publication bias.
Working memory
Only two pilot studies (reporting data from 22 children) investigated
the relationship between exercise interventions and working memory
(Anderson-Hanley, 2011). Both studies reported a significant
improvement of working memory following exercise intervention,
using an A-B sequential control design. The overall pooled ES was
1.36 (95% CI 1.08-1.64, k = 2).
Response inhibition
The overall pooled ES was 0.78 (95% CI 0.21-1.35, k = 4) (Figure 3).
The I2 test of heterogeneity was statistically significant (I2 = 92.7%,
df = 3, p < 0.01). Meta-regressions of sample size N, mean age of
154 Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156
Figure 3.
study participants, and year of study publication on ES were not
significant. Begg’s and Egger’s tests did not demonstrate evidence
of publication bias.
Discussion
Exercise interventions among children and adolescents with
neurodevelopmental disorders were associated with moderate
improvements in executive function domains. Of note, studies
of youth with ASD and FASD tended to report higher effect sizes
compared to studies of youth with ADHD, albeit few existing
studies. Exercise may be a potentially cost-effective and readily
implementable intervention to improve executive function in
these populations.
For ADHD, exercise interventions were associated with
moderate improvements in attention/set-shifting and approached
significance for working memory and response inhibition. Although
this meta-analysis supports previous research13,26 indicating exercise
is associated with moderate improvements in EF in ADHD, it
challenges a previous meta-analysis’s findings that exercise has
specific beneficial effects on response inhibition and working
memory relative to attention or set shifting in children and adults
with ADHD24. Nevertheless, it supports the notion that exercise may
have specific beneficial effects in certain EF domains depending
on the diagnosis. For ASD and FASD, exercise interventions were
associated with large improvements in EF, notably response inhibition
and working memory. This was a surprising result given the relative
dearth of exercise intervention studies in ASD and FASD compared
to ADHD. Sample size, mean age, study design, and the number
or duration of intervention sessions did not significantly moderate
the relationship between exercise and EF. Running interventions,
compared to other forms of exercise, trended toward significance
in moderating the effect of exercise on attention and set shifting in
children and adolescents with ADHD. Only in the ADHD subgroup
did stimulant medication use seem to moderate the relationship of
exercise on improvement in response-inhibition but not in attention/
set shifting or working memory.
Given the potential clinical implications of this meta-analysis, it is
important to discuss the study’s potential limitations. Heterogeneity
in outcome measures made comparisons across studies difficult
and resultant heterogeneity of ES estimates was high. As studies
varied with regard to randomization and control of confounding
variables, causal inferences must be limited. It also impeded attempts
to explore predictors of better response to exercise. We sought to
explore possible sources of heterogeneity using subgroup and meta-
regression analyses. Results of meta-regressions should be interpreted
with some caution due to the possibility of Type I errors, a known
limitation of meta-regression35. Study bias was also evident in the
existing literature, with a positive Egger’s test for the association
of exercise interventions and attention/set-shifting, wherein small
studies tended to demonstrate larger effects than studies, suggesting
that small negative studies are less likely to be published, and thus not
included in the meta-analysis. Although exercise interventions were
associated with large improvements in working memory in ASD and
FASD (ES 1.36, 95% CI 1.08-1.64), conclusions are limited given the
availability of only 2 studies.
Moving forward, studies using more standardized and robust
methodologies, including larger sample sizes across a diverse
range of comorbidities, are needed before recommendations can
be made with regard to the dose, intensity, duration, and type
of exercise. Further understanding of the effects of particular
exercises on specific executive functioning domains (attention, set
shifting, response inhibition, working memory) could be helpful
in tailoring individualized exercise programs for children with
different neurodevelopmental disorders. Research investigating the
effect of co-morbid stimulant use to augment benefits of exercise
in neurodevelopmental disorders is needed. Finally, research
investigating the putative mechanisms for those improvements
(i.e. BDNF or dopamine receptor upregulation) could be helpful
in identifying additional treatments for children with executive
functioning impairments.
 Varigonda AL et al. / Arch Clin Psychiatry. 2020;47(5):146-156
Conclusions
Exercise interventions among children and adolescents with
neurodevelopmental disorders are associated with moderate
improvements in executive function, particularly in children and
adolescents with ASD and FASD. Exercise may improve some EF
domains more than others depending on the diagnosis. This meta-
analysis finds that exercise has a moderate effect on EF in children
and adolescents with ADHD and a large effect on EF in children and
adolescents with FASD and ASD. There is a need to further investigate
the relationship between exercise interventions and different
domains of EF in children and adolescents with neurodevelopmental
disorders, especially in ASD and FASD.
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54. Gawrilow C, Stadler G, Langguth N, Naumann A, Boeck A. Physical
Activity, Affect, and Cognition in Children With Symptoms of ADHD.
J Atten Disord. 2016;20(2):151-62.
55. Chuang LY. Effects of acute aerobic exercise on response preparation in
a Go/No Go Task in children with ADHD: an ERP study. J Sport Health
Sci. 2015;4:82-8.
56. Ringenbach SDR. Assisted Cycling Therapy (ACT) improves inhibition
in adolescents with autism spectrum disorder J Intellect Dev Disabil.
2015;40(4):376-87.
57. Anderson-Hanley C, Tureck K, Schneiderman RL. Autism and exerga-
ming: effects on repetitive behaviors and cognition. Psychol Res Behav
Manag. 2011;4:129-37.

Supplemental Figure 1
Search Strategy
((autism) or (autism spectrum disorders) OR (adhd) OR (Attention Deficit Disorder with Hyperactivity) OR (attention-deficit hyperactivity disorder) OR (fetal
alcohol exposure) OR (fetal alcohol spectrum disorders)) AND ((exercise) OR (physical activity) OR (physical fitness)) AND ((executive function tests) OR
(executive function) OR (executive dysfunction) OR (Attention Capacity Test) OR (CANTAB) OR (COWAT) OR (CPT) OR (CCST) OR (D-KEFS) OR (IVA) OR
(K-ABC) OR (NEPSY) OR (SOC) OR (SWM) OR (TEA-Ch) OR (TOVA) OR (TMT) OR (WCST) OR (WISC) OR (WMS) OR (WMTB-C))

Treatment of insomnia with repetitive transcranial magnetic stimulation (rTMS) in a
patient with posttraumatic stress disorder (PTSD)
Abdullah Bolu1
https://orcid.org/0000-0002-5687-7181
Ibrahim Gündoğmuş1
https://orcid.org/0000-0002-1921-1495
Taner Öznur1
https://orcid.org/0000-0002-3936-419
Cemil Çelik1
https://orcid.org/0000-0002-1021-8762
1 Department of Psychiatry, Gülhane Training and Research Hospital, Ankara, Turkey.
Received: 09/10/2019 – Accepted: 26/02/2020
DOI: 10.1590/0101-60830000000252
Bolu A et al. / Arch Clin Psychiatry. 2020;47(5):157-158
Dear Editor,
Posttraumatic stress disorder (PTSD) is a psychiatric disorder
that develops after a traumatic event, characterized by specific
symptoms such as re-experiencing, avoidance, blunting, hyperarousal
symptoms, and non-specific symptoms such as nightmares, sleep
disturbances, and impaired functioning. Sleep disorders are a very
significant problem in PTSD patients and are generally resistant to
treatment. Impaired sleep quality has been shown to be associated
with increased PTSD symptom severity and suicidal ideation1.
Although medications and psychotherapy are at the top of the list for
the treatment of PTSD, repetitive Transcranial magnetic stimulation
(rTMS) has recently emerged as an important treatment option in
treatment-resistant PTSD cases2. In this article, treatment of insomnia
with rTMS in a patient with PTSD is described.
A 45-year-old male patient was followed up for 20 years with a
diagnosis of PTSD. The patient presented with a three-month history
of insomnia while in remission, with treatment of lithium 1200 mg/d
and sertraline 100 mg/d. No pathology was found when this patient
was studied with diagnostic tests such as an MRI of the brain and
an EEG applied for the exclusion of organicity, and the laboratory
findings of the patient were within normal limits. No pathology
was found in the patient’s internal medicine, neurology, and chest
consultations. The patient underwent a one-night polysomnographic
measure (PSG). Sleep-apnea syndrome, snoring, and periodic
leg-movement disturbances were not observed during PSG. The
PSG findings supported insomnia consistent with the patient’s
complaints. Although the patient was treated with agomelatine,
ramelteon, clonazepam, lorazepam, trazodone, herbal preparations,
and quetiapine in sufficient doses and time, his complaints did not
regress. It was thought that the patient would benefit from rTMS,
and it was decided that rTMS should be applied.
The patient received 1500 high-frequency (10Hz) repetitive
sessions with 40 pulses (four seconds each) on his left dorsolateral
prefrontal cortex for 26-second pulse intervals (20 consecutive
sessions/30 minutes each weekday) at 120% of motor threshold
for four weeks. rTMS was performed using the Dantec magnetic
stimulator (Dantec Medical A/S, Skovlunde, Denmark) for magnetic
stimulation, and the Dantec MC-125 circular structure coil (Dantec
Medical A/S, Skovlunde, Denmark) with an internal diameter of 90
mm was used as the stimulus coil. After rTMS, the patient’s CAPS
scale “difficulty falling asleep and maintaining sleep” item decreased
Address for correspondence: Ibrahim Gündoğmuş. Department of Psychiatry, Gülhane Training and Research Hospital. Emrah, Gen. Dr. Tevfik Sağlam Cd No:11 – 06010 – Keçiören, Ankara, Turkey.
Telephone: +905455870575. Fax: +9003123042000. E-mail: dribrahim06@gmail.com
Letter to the editor
from 3 points to 0 points. The patient did not have any additional
immediate complaints, and his complaints did not recur during the
first and sixth month follow-up examinations.
As with all psychiatric disorders, sleep disorders are one of the
symptoms closely related to quality of life for people who have PTSD.
Moreover, sleep disorders are also closely related to the severity of
PTSD. Treatment of sleep disorders is therefore very important in
patient management. Although medical treatment and/or behavioral
changes take the first place in the treatment of sleep disorders, our
case should be taken into consideration, as it shows that rTMS
treatment can be used as an alternative in treatment-resistant cases.
The effect of rTMS on the treatment of insomnia is unknown.
However, there are two possible mechanisms. The first of these,
noradrenaline, which has neuromodulator functions in the brain,
also has an effect on sleep regulation3. It is possible that the
regulation disorder that occurs in the noradrenergic system in
the pathophysiology of PTSD is the cause of insomnia symptoms
in our patient.1 The effect of rTMS on the noradrenergic system,
as well as serotonin, may have been effective in relieving our
patient’s complaints4. Another possible mechanism may be that the
deterioration of neuroplasticity and hippocampal function, which
is shown to be the cause of sleep disorders in PTSD patients, is
corrected by rTMS4,5. In addition, although the findings in our case
support PTSD-related insomnia, it should be noted that depression
or another psychiatric cause-related insomnia may have been treated.
rTMS can be considered as an alternative treatment for possible
treatment-resistant sleep disorders in PTSD patients. However,
randomized blind-controlled trials with PSG are needed to evaluate
the efficacy of rTMS on sleep disorders.
Author contribution
Conception and design of the study: A.B. and C.Ç.; acquisition and
analysis of data: I.G. and T.Ö.; drafting the manuscript: I.G. and A.B.,
critical review: T.Ö. and C.Ç.; literature review: A.B. and I.G.
References
1. Ribeiro JD, Pease JL, Gutierrez PM, Silva C, Bernert RA, Rudd MD, et
al. Sleep problems outperform depression and hopelessness as cross-
sectional and longitudinal predictors of suicidal ideation and behavior
in young adults in the military. J Affect Disord. 2012;136:743-50.
158 Bolu A et al. / Arch Clin Psychiatry. 2020;47(5):157-158

2. Oznur T, Akarsu S, Celik C, Bolu A, Ozdemir B, Akcay BD, et al. Is
transcranial magnetic stimulation effective in treatment-resistant
combat related posttraumatic stress disorder. Neurosciences (Riyadh).
2014;19:29-32.
3. Gottesmann C. Noradrenaline involvement in basic and higher integrated
REM sleep processes. Progr Neurobiol. 2008;85:237-72.
4. Chervyakov AV, Chernyavsky AY, Sinitsyn DO, Piradov MA. Possible
mechanisms underlying the therapeutic effects of transcranial magnetic
stimulation. Front Hum Neurosci. 2015;9:303.
5. van Liempt S, Arends J, Cluitmans PJ, Westenberg HG, Kahn RS, Ver-
metten E. Sympathetic activity and hypothalamo-pituitary-adrenal axis
activity during sleep in post-traumatic stress disorder: A study assessing
polysomnography with simultaneous blood sampling. Psychoneuroen-
docrinology. 2013;38:155-65.

Excessive consumption of tianeptine by a person with former alcohol problem
Jakub Grabowski1
https://orcid.org/0000-0002-0638-4565
Leszek Bidzan1
https://orcid.org/0000-0002-4373-5459
1 Department of Developmental, Psychotic and Geriatric Psychiatry, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland.
Received: 24/11/2019 – Accepted: 29/01/2020
DOI: 10.1590/0101-60830000000253
Grabowski J, Bidzan L / Arch Clin Psychiatry. 2020;47(5):159
Dear Editor,
Tianeptine is used to treat symptoms of depression with coexisting
anxiety. It is thought that, contrary to SSRIs, it reduces stress-
induced behavioral and physical effects through the hypothalamo-
hypophysial axis1,2. Cases of excessive consumption of tianeptine were
described, suggesting its addictive potential. The mechanism of this
process remains unknown, while withdrawal is difficult3.
A 53-year old female was frequently hospitalized because of
alcohol addiction secondary to anxiety and depression symptoms.
However, during two years, when the patient was taking tianeptine,
she maintained alcohol abstinence. After a change in therapy,
lack of the drug evoked a strong need to drink again, and further
hospitalizations were needed. Tianeptine was again administered
during the last hospitalization. Since then the patient has not been
abusing alcohol, neither was she hospitalized anywhere in the region.
Three years after her last hospital stay, the patient came to our
out-patient clinic asking to begin treatment. She claimed that due to
depression she took tianeptine with positive results and suggested the
need to increase the dosage significantly above the recommended one.
It soon turned out that the police had been leading an
investigation against the patient on forging prescriptions for
tianeptine. After having left the hospital for the last time, she was
systematically increasing the dosage of tianeptine, due to intensifying
anxiety. According to the patient, the maximum dosage equaled
three pills three times a day (112.5 mg). She asked various specialists
to prescribe it, but having difficulties to obtain a satisfying amount
legally, she forged the prescriptions. Information provided by the
police state that only during eleven months, 158 prescriptions were
gathered, both legal and forged, out of which 143 were accepted,
which stands for the total number of 9,180 pills. Therefore, it may
be estimated that the patient was taking in that period at least 347
mg of tianeptine per day.
She declared a will to stop taking tianeptine. During the
examination a subjective feeling of anxiety, tension and increased
tiredness, difficulties with concentration, sleeping and mood
disorders were reported. The Hamilton Anxiety Rating Scale
was performed (14-item version) with a score of 18 points with
insignificant somatic component. Life parameters were normal.
Address for correspondence: Jakub Grabowski. Department of Developmental, Psychotic and Geriatric Psychiatry, Faculty of Medicine, Medical University of Gdansk. Srebrniki, 17, 80-282, Gdansk,
Poland. Telephone/Fax: +48583446085. E-mail: jgrabowski@gumed.edu.pl
Letter to the editor
She claimed she did not take tianeptine for a week, because other
physicians, aware of the whole situation, refused to prescribe her the
medicine. Ambulatory treatment with sertraline and buspirone was
administered with good effect. A stable dosage was maintained with
patient demonstrating a significant resistance against any suggestions
down-titrate the drugs. At the same time, she negated the necessity
to undertake a psychotherapeutic treatment.
Case reports revealed that the most common reason of
dependence is the psychostimulant and euphorising effect 3,4.
However, in the presented case tianeptine was first prescribed in order
to reduce anxiety and mood disorders, and later it was substituted
by a combined treatment of buspirone with sertraline, both of them
having anti-anxiety influence. During the period when tianeptine
was withdrawn, she developed a psychological expression of anxiety,
lacking any intense vegetative symptoms. Also, intensified anxiety
was present before alcohol problems began. These elements make
tianeptine dependence diagnosis doubtful and indicate rather a
personality predisposition to substance misuse, than a special
addictive mechanism of tianeptine itself, as suggested in other
publications5,6.
References
1. Malka R, Lôo H, Ganry H, Souche A, Marey C, Kamoun A. Long-term
administration of tianeptine in depressed patients after alcohol withdra-
wal. Br J Psychiatry Suppl. 1992;(15):66-71.
2. Wilde MI, Benfield P. Tianeptine. A review of its pharmacodynamic and
pharmacokinetic properties, and therapeutic efficacy in depression and
coexisting anxiety and depression. Drugs. 1995;49(3):411-39.
3. Vandel P, Regina W, Bonin B, Sechter D, Bizouard P. [Abuse of tianeptine.
A case report]. Encephale. 1999;25(6):672-3.
4. Saatçioğlu O, Erim R, Cakmak D. [A case of tianeptine abuse]. Turk
Psikiyatri Derg. 2006;17(1):72-5.
5. Lauhan R, Hsu A, Alam A, Beizai K. Tianeptine Abuse and Dependence:
Case Report and Literature Review. Psychosomatics. 2018;59(6):547-53.
6. Springer J, Cubała WJ. Tianeptine Abuse and Dependence in Psychiatric
Patients: A Review of 18 Case Reports in the Literature. J Psychoactive
Drugs. 2018;50(3):275-80.
 Case Report

Vortioxetine-induced nausea and its treatment: a case report

Calogero Crapanzano1
https://orcid.org/0001-6006-1268

Andrea Politano2
https://orcid.org/0003-1004-9337

Chiara Amendola3
https://orcid.org/0002-0522-3022

Despoina Koukouna4
https://orcid.org/ 0002-6263-3642

Ilaria Casolaro3
https://orcid.org/0002-6276-1732

1ASPAG, CSM Licata, Licata, Italy

2Clinica S. Croce, Orselina, Switzerland
3ASST Lariana, Como, Italy

4U.O. Psichiatrica MANTOVA 1, MANTOVA, Italy

Received: 14/12/2019 – Accepted: 29/01/2020

DOI: 10.1590/0101-60830000000254

Crapanzano C et al. / Arch Clin Psychiatry. 2020;47(5):160-161

Vortioxetine is a multimodal antidepressant that binds with high
affinity the serotonin transporter (SERT) > (serotonin receptor)
5-HT3 > 5-HT1A > 5-HT7 > 5-HT1B > 5-HT1D. It acts by inhibiting
the SERT, with antagonism activity on the 5-HT1D, 5-HT7 and
5-HT3 receptors, partial agonism activity on the 5-HT1B receptor,
agonism activity at 5HT1A receptor1. Vortioxetine is a compound
approved by the FDA for major depressive disorder. Its efficacy
and tolerability are widely proven2. Regarding tolerability, both
in short and long-term studies, nausea was the most common
treatment emergent adverse event (TEAE) and the primary TEAE
that caused discontinuation after vortioxetine treatment2-4. Nausea
is one of the most frequently reported adverse effects after SSRI and
SNRI treatment. This can be attributed to their action on serotonin
levels and on receptor 5-HT35. Nausea management includes:
splitting daily dosage, taking medication after a meal, using drugs
like 5-HT2 antagonists, proton pump inhibitors, promethazine,
prochlorperazine, or ondansetron6. It is well established how the
antidepressant tolerability influences quality of life and adherence
to pharmacological treatment7. In this study we describe a case of
nausea induced by vortioxetine along with its following treatment
in a 32-year-old Italian patient with a diagnosis of bipolar disorder
type 2, most recent depressive episode. At the time of our evaluation
the patient was treated with lurasidone 37 mg/day and lithium
carbonate 600 mg/day. In the past, trials with SSRIs and SNRIs
have been conducted with improvement of depressive symptoms
but the onset of sexual dysfunction led to drug discontinuation.
A trial with bupropion was reported to have induced the onset of
anxious symptoms. A trial was then started with vortioxetine 10
mg, increased to 20 mg after 8 days, then nausea occurred. It was
decided to introduce mirtazapine 15 mg in the evening. After 2 days
of mirtazapine augmentation the patient reported improvement in
the nausea that was maintained at follow up; in addition, 2 weeks
later an improvement in mood, anxiety, sleep regularity was observed,
as well as the absence of sexual dysfunctions. In our case report
we used mirtazapine in augmentation to vortioxetine following a
pharmacodynamic and clinical reasoning. Mirtazapine, thanks to its
5-HT3 antagonism, has antiemetic properties already recognized in
the literature8. Although the same 5-HT3 antagonism is universally
accepted for vortioxetine as well, a recent study has shown a different
behavior of vortioxetine on 5-HT3 receptors than that hypothesized
so far: it can have, in fact, a significative agonist activity. Quoting:
“[…] the mechanism of vortioxetine differs from classical 5-HT3A
orthosteric ligands with inhibitory activity […] vortioxetine binding
induces a brief agonistic response followed by a rapid transition
into a desensitized state from which vortioxetine has an extremely
slow unbinding rate”9. Our case report suggests the possible role of
mirtazapine against antidepressant-induced nausea. Further studies
are needed to investigate how these data could be useful to explain
and manipulate the clinical effects in terms of efficacy and tolerability.
Conflict of interests
The authors declare no conflict of interest.
Acknowledgements
The research did not receive any specific grant from funding agencies
in the public, commercial or not-for-profit sectors.
References
1. D’Agostino A, English CD, Rey JA. Vortioxetine (brintellix): a new
serotonergic antidepressant. P T. 2015;40(1):36-40.
2. Pae CU, Wang SM, Han C, Lee SJ, Patkar AA, Masand PS, et al. Vortio-
xetine: a meta-analysis of 12 short-term, randomized, placebo-controlled
clinical trials for the treatment of major depressive disorder. J Psychiatry
Neurosci. 2015;40(3):174-86.
3. Nomikos GG, Tomori D, Zhong W, Affinito J, Palo W. Efficacy, safety, and
tolerability of vortioxetine for the treatment of major depressive disorder
in patients aged 55 years or older. CNS Spectr. 2017;22(4):348-62.
4. Inoue T, Nishimura A, Sasai K, Kitagawa T. Randomized, 8-week, double-
-blind, placebo-controlled trial of vortioxetine in Japanese adults with
major depressive disorder, followed by a 52-week open-label extension
trial. Psychiatry Clin Neurosci. 2018;72(2):103-15.
5. Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The Safety,
Tolerability and Risks Associated with the Use of Newer Generation
Antidepressant Drugs: A Critical Review of the Literature. Psychother
Psychosom. 2016;85(5):270-88.

Address for correspondence: Ilaria Casolaro. ASST Lariana. Via Ravona 20, 22010, San Fermo della Battaglia, Como, Italy. Telephone: 0039-0315859598. E-mail: casolaro.ilaria@gmail.com
 Crapanzano C et al. / Arch Clin Psychiatry. 2020;47(5):160-161
161

6. Kelly K, Posternak M, Alpert JE. Toward achieving optimal response:
understanding and managing antidepressant side effects. Dialogues Clin
Neurosci. 2008;10(4):409-18.
7. Cleare A, Pariante CM, Young AH, Anderson IM, Christmas D, Cowen
PJ, et al. Evidence-based guidelines for treating depressive disorders
with antidepressants: A revision of the 2008 British Association for
Psychopharmacology guidelines. J Psychopharmacol. 2015;29:459-525.
8. Kim SW, Shin IS, Kim JM, Kim YC, Kim KS, Kim KM, et al. Effectiveness
of mirtazapine for nausea and insomnia in cancer patients with depres-
sion. Psychiatry Clin Neurosci. 2008;62(1):75-83.
9. Ladefoged LK, Munro L, Pedersen AJ, Lummis SCR, Bang-Andersen B,
Balle T, et al. Modeling and Mutational Analysis of the Binding Mode
for the Multimodal Antidepressant Drug Vortioxetine to the Human
5-HT3A Receptor. Mol Pharmacol. 2018;94(6):1421-34.
Letter to the editor

Huntington’s disease presenting as mixed state episode

Laiane Tábata Souza Corgosinho1
https://orcid.org/0000-0002-7895-0917

João Antônio Bomfim Silva1

https://orcid.org/0000-0002-9399-4328

Rogério Gomes Beato1,2

https://orcid.org/0000-0002-6775-8022

Vinicius Sousa Pietra Pedroso1,3

https://orcid.org/0000-0001-8882-8176

1 Psychiatry Residency Program, Raul Soares Institute, Hospital Foundation of Minas Gerais State (FHEMIG), Belo Horizonte, MG, Brazil.
2 Department of Internal Medicine, School of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG Brazil.
3 Department of Medicine, Pontifical Catholic University of Minas Gerais (PUC-Minas), Betim, MG, Brazil.

Received: 10/02/2020 – Accepted: 15/04/2020

DOI: 10.1590/0101-60830000000255

Corgosinho LTS et al. / Arch Clin Psychiatry. 2020;47(5):162

Dear Editor, manifestations are mood disorders, especially depressive symptoms,

A 49-year-old woman presents with depressive symptoms
characterized by depressed mood, diminished interest, aggressive
behavior and recurrent suicide attempt. Symptoms had begun four
years before, involving irritability, impulsive behavior, fatigue at work
and persecutory delusions. Two months before, symptoms became
more intense and she was diagnosed with bipolar disorder. She was
referred to a psychiatric hospital due to the persistence of symptoms
after irregular use of haloperidol, risperidone and valproate. There
was no previous psychiatric history.
During hospitalization, mixed mood symptoms were observed:
dysphoric mood, psychomotor agitation, suicidal ideation and
delusions of persecution and ruin. Olanzapine and fluoxetine
were started and the patient’s mood improved. It was possible to
distinguish the persistence of sluggish and impoverished thinking,
spatial disorientation, increased response latency and apathy.
Neurological examination revealed involuntary choreiform body
movements imperceptible to the patient, which had started seven
years before, and vocal tics that had appeared six months earlier. The
patient had a family history of chorea. Clock drawing test exhibited
visual spatial impairment; Mini-Mental State Exam revealed general
cognitive decline (10 points; schooling: 8 years).
Laboratory (CBC, VDRL, HIV test, vitamin B12 levels, ionized
calcium levels, blood glucose, thyroid, liver and renal function tests)
was unremarkable. Computed tomography of the brain showed mild
frontal lobe atrophy associated with dilation of the anterior horns of
the lateral ventricles and decreased caudate nuclei heads (Figure 1).
Genetic testing was performed due to suspected Huntington’s disease
(HD) and yielded 42 cytosine-adenine-guanine (CAG) repeats.
After discharge, patient maintained mood stability and significant
reduction of choreiform movements, with the prescription of
fluoxetine 40 mg/day and olanzapine 10 mg/day.
HD is a rare inherited neurodegenerative disorder caused by
the repeated expansion of a CAG trinucleotide, characterized by
progressive motor, cognitive and psychiatric symptoms. Clinical
manifestations and disease onset depend on the number of CAG
repetitions. Symptoms present when there are more than 36
repetitions. Clinical manifestation is more common between 35 and
45 years, but can occur at any age. The course is chronic, slow and
progressive, with an average survival of 10 to 20 years.1,2
Psychiatric manifestations are varied and can occur even in the
prodromal phase, making diagnosis challenging. Neuropsychiatric
symptoms occur in 35% to 73% of cases2,3. The most frequent
and an increased risk of suicide. Episodes of mania or hypomania
may be present in 10% of cases. Studies show that up to 4.8% of HD
patients develop bipolar disorder3-5.
Here, we present the case of a patient diagnosed with HD,
presenting as mixed state episode in the context of behavioral
manifestations of a neurodegenerative disease. The patient met DSM
5 criteria for manic episode with mixed symptoms, due to dysphoric
mood, psychomotor agitation, aggressive behavior, lack of interest
and pleasure, delusions of ruin and recurrent thoughts of death. We
could not find any reports of mixed state episodes in HD. This report
may help the clinician to consider differential diagnoses regarding
the onset of psychiatric symptoms associated with neurological
manifestations.
Figure 1. Computed Tomography of the brain showing mild frontal lobe
atrophy associated with dilation of the anterior horns of the lateral ventricles
and decreased caudate nuclei heads.
References
1. Jauhar S, Ritchie S. Psychiatric and behavioural manifestations of Hun-
tington’s disease. Adv Psychiatr Treat. 2010;16:168-75.
2. McColgan P, Tabrizi SJ. Huntington’s disease: a clinical review. Eur J
Neurol. 2018;25:24-34.
3. Paoli RA, Botturi A, Ciammola A, Silani V, Prunas C, Lucchiari C, et al.
Neuropsychiatric burden in Huntington’s disease. Brain Sci. 2017;7:67.
4. Husain M, Schott JM (eds.). Oxford Textbook of Cognitive Neurology
and Dementia. 1st ed. Oxford: Oxford University Press; 2016.
5. Miller BL, Cummings JL (eds.). The Human Frontal Lobes Functions and
Disorders. 3rd ed. New York: The Guilford Press; 2017.

Address for correspondence: Vinicius Sousa Pietra Pedroso. E-mail: viniciuspietra@yahoo.com.br

 Letter to the editor

Treatment of food addiction: preliminary results

Edgar Luis Lima de Oliveira1
https://orcid.org/0000-0003-2507-7592

Emilie Lacroix2
https://orcid.org/0000-0001-9716-9504

Andrea Lorena Costa Stravogiannis1

https://orcid.org/0000-0003-2378-0102

Maria de Fátima Vasques1

https://orcid.org/0000-0003-3819-6494

Cristiane Ruiz Durante1

https://orcid.org/0000-0003-3937-7115

Érica Panzani Duran1

https://orcid.org/0000-0003-3005-9057

Daniela Pereira1
https://orcid.org/0000-0003-0501-0083

Janice Rico Cabral1

https://orcid.org/0000-0002-7765-6548

Hermano Tavares1
https://orcid.org/0000-0002-6632-2745

1 Department of Psychiatry, Psychiatry Institute, University of São Paulo (USP), SP, Brazil.
2 Department of Psychology, University of Calgary, AB, Canada.

Institution where the study was conducted: Instituto de Psiquiatria do Hospital de Clínicas da Universidade de São Paulo, São Paulo, SP, Brasil.

Received: 27/08/2019 – Accepted: 18/04/2020

DOI: 10.1590/0101-60830000000256

Oliveira ELL et al. / Arch Clin Psychiatry. 2020;47(5):163-164

Dear Editor, Table 1. Description of Food Addiction Group Treatment Program

SESSION THEME OBJECTIVES
There has been an increase in the number of publications using
Motivational Interviewing Phase
the term food addiction (FA), with many animal and humans
neuroimaging studies demonstrating similarities between food 1 Orientation, motivation levels, Group integration;
and drugs of abuse1,2. FA is most often assessed with the Yale Food and stages of change psychoeducation on food
Addiction Scale (YFAS), a questionnaire which directly applies DSM- addiction; participants identify
their motivation levels and stages
IV-TR substance dependence criteria to food and eating2. Although
of change; baseline assessment.
FA is not an official diagnosis, YFAS scores are associated with eating
disorders, depression, emotion dysregulation and lower self-esteem3, 2 Stages of change, cognitive Explore cognitive distortions
suggesting a need to target these symptoms in treatment. distortions, and ambivalence about behaviour change;
increase motivation and resolve
There is a scarcity of research investigating treatments designed
ambivalence surrounding change.
specifically for FA. Schema therapy (ST) is an approach which
emphasizes the therapeutic relationship, the emotional and life 3 Discrepancies and obstacles to Investigate psychosocial
experiences. Group ST treatments have demonstrated efficacy in behaviour change obstacles and facilitate problem
treating both eating disorders and substance abuse3. solving.
The aim of the present pilot study was to examine the feasability Behavioural Nutrition Phase
and efficacy of a group treatment program for FA which included 1 Presentation, Food Pyramid, Describe the food pyramid;
components of nutritional orientation, motivational interviewing Food Diary (FD) introduce FD.
(MI) and ST. Participants were referred, in 2016, through the 2 Food groups Explain the food groups and
outpatient impulse control disorders unit at the Institute of Psychiatry the importance of nutritional
of the University of São Paulo. The program comprised 21 weekly awareness.
sessions divided into two phases, presented in Table 1. Patients 3 Behavioural nutrition Review the FD; investigate
completed self-report questionnaires pre- and post-treatment to dysfunctional eating behaviour
assess eating behaviour, maladaptive schemas, depression and and identify alternative
anxiety symptoms. Weight and height were measured to assess behaviours. Education surrounding
BMI. We administered the portuguese versions of the YFAS2, the physiology of nutrition and its
Bulimic Investigatory Test of Edinburgh (BITE), Beck Depression consequences on behaviour.
Inventory (BDI), Beck Anxiety Inventory (BAI), and the Young 4 Nutrition, diet and low-cal Information about diet, low-cal
Schemas Questionnaire (YSQ-S35), a measure of early maladaptive food products, and fad diets. food products, fad diets, and
schemas (EMS). Saciating foods. saciating foods.

Address for correspondence: Edgar Luis Lima de Oliveira. Rua Dr. Ovídio Pires de Campos, 785, São Paulo/SP – Brasil – CEP 05403-903. Telephone: +55 (11) 2661-7805.
Email: dredgaroliveirapq@gmail.com
164 Oliveira ELL et al. / Arch Clin Psychiatry. 2020;47(5):163-164

SESSION THEME OBJECTIVES in BITE severity (from 4,83 to 5,67) or symptom count (from 17,67
to 17,83), depressive symptoms (BDI) (from 20 to 17,17), anxiety
5 Nutrition planning Discuss the importance of
organization and nutritional
symptoms (BAI) (from 15,14 to 14,42), EMS (from 3,71 to 0,29) or
planning and how to put it into BMI (from 40,22 to 38,65). At post-treatment, six of seven patients
practice. (85.71%) no longer met YFAS diagnostic criteria for FA.
Our reductions in symptom count and proportion meeting FA
6 Concluding session Review. Discuss how to set
criteria exceed those found by Hilker et al.8. Taken together, our
achievable goals. Termination.
findings suggest that the proposed model of ST, accompanied by
Schema Therapy (ST) Phase behavioural nutrition and MI, may represent a promising avenue
1 Psychoeducation about ST 1 Discuss ST and the results of for the treatment of FA. Additional research is needed to investigate
and questionnaire results Young’s questionnaires. the efficacy of this treatment in larger samples, employing control
2 Psychoeducation about ST 2 Reading about schemas and groups and randomization. Furthermore, continued investigation of
and Thought Diary (TD) completing TD. the validity of the FA construct is needed.
3 Revision and schema diary Revise schemas and complete
schema diary.
Acknowledgements
4 Role of schemas and principal Understand the relationship
modes between schemas and modes. No funding was received for support of this research work.
Work with images.
5 Images and the origin of Understand the relationships Disclosure
schemas. among schemas, modes, and
attachment bonds. HT receives research support from Conselho Nacional de
6 Avoidant Protector mode Avoidant Protector mode: Desenvolvimento Científico e Tecnológico – CNPq – (National
empathic confrontation. Council for Scientific and Technological Development), grants
7 Demanding/punitive Parent Demanding/punitive Parent mode: #465550/2014-2 and #425716/2018-0, and from Fundação de
mode limited reparenting. Amparo a Pesquisa do Estado de São Paulo – FAPESP – (São Paulo
Research Foundation), grant #2014/ 50917-0. The other authors
8 Impulsive and vulnerable child Impulsive and vulnerable child
mode mode: empty chair technique.
declare no conflict of interest.
9 Healthy Adult Strengthening the healthy adult
through mental imagery and References
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