SYSTEMATIC REVIEW: THE ASSOCIATION

OF ADVERSE CHILDHOOD EXPERIENCE

AND BIPOLAR DISORDER IN CHILDREN

AND ADOLESCENTS

Word Count: 10,692 words

Laurence S. Pe

14 August 2019

Supervisor: Athina Manoli

MSc Mental Health: Psychological Therapies

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Table of Content
Abstract……………………………………………………….….…………………...4

Introduction……………………………………………………….….………………5
Bipolar disorder……………………………………………………………...5
Clinical Characteristic of BD……………...……………………...…...5
BD in children and adolescents……………………………………….….….6
Prevalence Rate of BD in Youth……………………………….……...6
Symptoms of BD in Youth…………………………….………………7
Comorbidities of BD in Youth……………………….……….……….7
Adverse Childhood Experiences……………………….…………………....8
Adverse Childhood Experiences and Paediatric BD…….……..….……….9
ACE and Onset of BD…………………….…….…………….……….9
ACE and Symptoms and Duration of BD. ……………..….….…..…10
ACE and Comorbidities in BD………………..…….…………..…...10
1. Attention deficit/hyperactivity disorder….……….…………10
2. Conduct disorder………………………….………….………11
3. Post-traumatic stress disorder…………………....….……….11
ACE and Suicidality in BD………………….….………….….….….12
Aims and objectives………………………………….…..…………..…..….13

Methods………………………………………………………………………….…...13
Search Strategy.…………..………..…………………….……………..…...14
Search terms…...…………………………………………….……..…….….14
Study Selection.……………………….………………….………..…....…...15
Data extraction…………………………………….……………….….…….15
Assessment of quality…………………………………….…………..……...16
Synthesis of research………………………….……………………………..17

Results…….……………………………………………………………………..……17
Characteristics of participants………………………………………….….18
Demographic profile……………..…………………………………….……18
Gender…………………………………………………………….….18
Age…………………………………………………………………...25
Socioeconomic status………………………………………………...26
Association of ACE and Paediatric BD……………………………………26
Onset of BD……………………………………………………….….27
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Symptoms of BD………………………………………………….….29
Duration of BD……………………………………………………….30
Comorbidities in Paediatric BD with ACE………………………………..30
Attention-deficit/hyperactivity disorder……………………………...30
Conduct disorder………………………………………………….….31
Posttraumatic stress disorder…………………………………………32
Suicidality…………….…………………………….………………...33
Quality Assessment…………………………………………………...34

Discussion……………………………………………………………………………35
Association of ACE and Paediatric BD.…………………………………...36
Limitations………………...………………………………………………...40
Future Research…………………………………………………………….42
Conclusion……………………..…………………………….………………42

References…………………………………………………………………………...43

Appendix…………………………………………………………………………….55
Appendix A | Quality Assessment…………………………………..……...55

List of tables
Table 1 | Inclusion and Exclusion Criteria……………………….……......16
Table 2 | Summary of Studies………………………………………………20
Table 3 | Data Summary………………………………………….………...28

List of Figures
Figure 1 | Flowchart of selection process………………………………….19
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Abstract
Objective: Bipolar disorder has been examined extensively in adulthood. An earlier

onset, increased symptoms, longer duration and severe presentation of comorbidities were

found in adult BD with adversity during childhood. However, there are no reports of

review about the risk of childhood maltreatment in youth with BD. The aim of this review

is to examine the association between history of adverse childhood experiences and

diagnosis of bipolar disorder in children and adolescents.

Methods: Studies were generated electronically. From title, abstract and full paper,

studies were screened using the inclusion/exclusion criteria and synthesised findings of

individual studies regarding the association.

Result: Eight studies were included in this review and revealed that no direct association

can be firmly concluded between diagnosis of BD in children and adolescents and ACE.

History of ACE in BD youth contributed to an earlier onset, however, does not predict

onset of BD. Physical, sexual abuse and SUD were related to severe presentation of BD

symptoms and longer duration of BD, development of CD lifetime prevalence of PTSD

and suicidal attempts. However, ADHD did not show difference with non-BD or non-

ACE BD youth.

Conclusion: Across studies, direct association between BD diagnosis and adverse

experiences cannot be established. Therefore, association remain uncertain. Nonetheless,

adverse experiences of BD youth influence the presentation of clinical variables

(symptoms severity, duration of illness, CD, PTSD, and suicidality) in the manifestation

of BD.

Limitation: Outcomes were fluctuating throughout studies and onset of diagnosis was

not significantly indicated due to lack of studies. Additionally, some studies did not

mention the measurement of ACE. Finally, types and degree of adversity differs in BD

participants amongst included studies.

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Introduction

Bipolar disorder

Bipolar disorder (BD), formerly known as manic-depressive illness, is a severe chronic

mood disorder with episodes of mania or hypomania which intertwine or alternate with

episodes of depression (Grande et al., 2016). The episodic disturbance of mood by elation

or mania is called Bipolar I disorder while Bipolar II disorder is defined by presence of

major depression and hypomania (Goodwin, G., 2012). Otherwise, if the patient failed to

fulfil the diagnostic criteria of the disorder, either the episode includes manic or

hypomanic or when depressive symptoms did not meet full criteria, it is considered

“specified” or “unspecified” BD. There are also diagnosed BD which are induced by

substance use or medication (American Psychological Association: APA, 2013).

Clinical Characteristics of BD

Presentation of symptoms of BD may differ from patient to patient. Manifestation of

mania may include (but not limited to) unusual irritability, grandiose ideas, increased

sexual interest, inappropriate social behaviour or marked impairment in occupational

functioning which must have lasted for at least 1 week or resulted to hospitalisation. These

symptoms may vary in severity from severe psychotic exhaustion or harmful state of

elation channelled by poor judgement (APA, 2013; Mitchel et. al., 2008). Nonetheless, if

symptoms were less severe in form and lasted only for 4 consecutive days, it is considered

hypomania (Roberts, Sylvia & Reilly-Harrington, 2014). Moreover, presence of

depression in BD illustrates slow flowing of thoughts and actions, as well as psychotic

depression in younger population and hypersomnia – atypical feature of depression. A

mixed state may occur to BD patients and present a rapid alternating mania or depression

or severe depression with complete absence of euphoria, yet displaying extensive period

of pressured, irritability and paranoia (Mitchel et. al., 2008).

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BD (Type I and II) was traditionally labelled as an adult disorder which was presumed to

arise during late adolescence (≥ 18 years old) or early adulthood accompanied by

morbidity, mortality and some of the symptoms may manifest earlier, during childhood

(Goodwin & Jamison, 1990; Marangoni et. al., 2018). While it may be difficult to be

diagnosed at a very young age, it is acknowledged that BD may be evident during

childhood – paediatric bipolar disorder (Kraepelin, 1921).

BD in Children and Adolescents

BD can initiate during early childhood; however, it is rare for children to be diagnosed of

BD regardless of a prominent display of an extreme irritability and anger (Simon, 2016;

Walshaw & Bearden, 2016). One possible reason is that, it takes roughly 10 years in order

to properly diagnose an individual with bipolar disorder, which gives 10% lower chance

of recovery for youth (Singh, 2008). Similarly, difficulties in verbalising emotions in

children and adolescents may account for complexity of diagnosis (Kraepelin, 1921). One

approach that professionals use to assess BD in children is the DSM-IV BD “adult”

criteria as it can recognise mania for both children and adult (Leibenluft & Rich, 2008).

Prevalence Rate of BD in Youth

The prevalence rate of BD in youth have increased in the past decades, filling roughly

2% of the BD population (Merikanges et. al., 201l; Walshaw & Bearden 2016). In 11

countries (Brazil, Bulgaria, Colombia, India, Japan, Lebanon, Mexico, New Zealand,

Romania, Shenzhen, and United States) lifetime prevalence rate of Bipolar I (M= 0.6%),

Bipolar II (M=0.4%) and subthreshold BD (M=1.4%) were recorded and found that

United States had the highest lifetime prevalence rate of 4.4% as oppose to India with the

lowest life time prevalence rate of 0.1% (Merikanges et. al., 2011). In addition, one factor

that contributes to the increasing prevalence rate of BD were instances where some
 7
disorders also fall to BD criteria. For example, 30% of major depressive disorder cases

also fulfilled criteria for BD diagnosis (Angst et. al., 2002).

Symptoms of BD in Youth

Irritability in mania is classified as quantitatively and qualitatively distinct, hence may be

utilised in distinguishing BD in youth (Biederman et. al., 2005; Woznak et. al., 2005).

Children and adolescents who were diagnosed of BD were found to report a moderate to

severe manic or hypomanic episodes or major depressive episodes within 12 months than

adults diagnosed at later age. Particularly, Bipolar I and Bipolar II disordered patients,

who were diagnosed at an earlier age (before 15 years old) displayed a more severe

presentation of symptoms over subthreshold BD patients (Merikanges et al., 2011).

Comorbidities of BD in Youth

Phenotype of paediatric BD may somewhat have similarities with other childhood-related

psychiatric disorder, and failure to distinguish these disorders may lead to wrong

diagnosis, hence wrong treatment (Spencer et al., 2001). Furthermore, these other

disorders may present as comorbid disorders in children and adolescents diagnosed of BD

which lead to a worse manifestation of BD (Frías, Palma and Farriols, 2015; Wilens et.

al., 2003). For example, youth who were diagnosed of BD and comorbid ADHD were

found to have longer and higher number of mood symptoms presentation compared to

BD youth without ADHD (Castilla et. al., 2013).

With all the findings in the previous studies, diagnosis of bipolar disorder during

childhood is essentially crucial as symptoms may be influenced by other clinical factors.

Furthermore, BD was known to be substantially biological and genetic psychiatric

disorder, yet, there are determinants which may affect the development of the disorder
 8
(Simon, 2016; Suotullo et. al., 2015), including psychosocial contributors – such as stress

and neglect – and childhood trauma (Etain et al., 2010; Larsson et al., 2013).

Adverse Childhood Experiences

Adverse childhood experiences (ACE) refer to various negative life events including

physical, sexual, emotional and verbal abuse, neglect, any form of domestic violence,

relational stress such as parental separation, and excessive substance use or criminal

behaviour of family members (Anda et. al., 2010). It was acknowledged to be usually first

experienced at home – familial violence (Xavier et al., 2016). ACE, though not specific

and limited, is a strong risk factor for earlier onset of psychiatric disorder – on children

or adolescents (Teicher et. al., 2014). These experiences also contribute to negative

outcomes of psychiatric disorders and induce the course of severe mental disorders, such

as schizophrenia and bipolar disorder (Danese et. al., 2009; Fisher & Hosang, 2010).

Furthermore, the rates of ACE were found to be twice in individuals diagnosed of BD,

particularly in bipolar I, triggering other psychiatric disorders which mostly co-occur with

BD (Gilbert et. al., 2009; Xavier et al., 2016).

Thus, it is feasible that adverse experiences during childhood may be associated with BD

diagnosis and contribute to a worse occurrence of comorbid disorders. It is necessary to

conduct this systematic review in order to address the gap in the literature of BD,

particularly, the association between traumatic experiences during childhood and the

earlier onset of BD considering that the emphasis of majority of the studies and reviews

were on adult BD.

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Adverse Childhood Experience and Paediatric BD

Childhood abuse was found to be associated with multiple aspects in adult BD –

suicidality, earlier onset of BD, rapid cycling pattern, and comorbid disorders such as

posttraumatic stress disorder (PTSD), conduct disorder (CD) and panic disorder (Brown

et. al., 2005; Carballo et. al., 2008; Garno et. al., 2005). Hence, these specific domains –

onset of BD, symptoms and duration of BD, ADHD, CD, PTSD, and suicidality – were

addressed in the current systematic review.

ACE and Onset of BD

First episodes of symptoms of bipolar disorder (BD) can approximately be present at the

age of 18 (APA, 2013). Nevertheless, onset of the disorder was found to be earlier in

patients who were exposed to maltreatment such as physical abuse, sexual abuse and

neglect. Particularly, physical abuse, as strongest predictor of BD, and sexual abuse were

independently found to be significantly associated with earlier onset of BD (<18 years)

(Leverich et. al., 2002). For instance, 92% of abused patients and neglected children had

the diagnosis of BD on or before that age of 14, as compared to 83% non-abused patients

with later diagnosis, 18 years and above (Dienes et. al., 2006; Leverich et. al., 2002).

However, it cannot be ascertained due to the presence of contradicting findings. McIntyre

et. al., (2008) found that child abuse did not predict the onset of the BD. However, it is

worth to note that McIntyre et. al., (2008) measurement of maltreatment history was only

based on psychiatric records, therefore, was not able to interview patients regarding

confirmation of maltreatments. Hence, BD patients with history of adverse childhood

experience (ACE) may be vulnerable to present an earlier mood disturbance compared to

non-ACE BD individuals.
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ACE and Symptoms and Duration of BD

Any form of adverse experiences was significantly associated with more depressive

episodes and increased manic/depressive symptoms severity (Garno et. al., 2005). In fact,

when childhood maltreatment (physical abuse, sexual abuse, emotional abuse and

neglect) and the polygenic risk were examined, BD patients who experienced

maltreatment had lower genetic risk with an increased presentation of symptoms,

depression and rapid cycling, but not on manic episodes. While, individuals with genetic

risk only had fewer mood episodes (Aas et. al., 2019). Thus, a severe form of BD needs

less genetic risk when already exposed to childhood maltreatment to demonstrate

increased symptoms of depression, but not mania. Aside from increased symptoms, after

experiencing number of different maltreatments during childhood, a longer duration of

BD was reported by abused patients when compared non-abused (Sala et. al., 2014).

Therefore, an increased presentation of BD symptoms may be seen in patients who were

exposed to maltreatment during childhood and may result to a longer duration of the

disorder.

Significant changes in the presentation of symptoms and duration of BD were revealed

in adult BD who experienced maltreatment (physical abuse, sexual abuse, emotional

abuse and neglect) during childhood. However, these were not extensively examined in

children and adolescents. Therefore, in this systematic review, it was assessed whether

there were significant changes in the symptom presentation and duration of BD in

children and adolescents who also had childhood maltreatment.

ACE and Comorbidities in BD

1. Attention deficit/hyperactivity disorder. ADHD is one of the most commonly

diagnosed co-occurring disorders in BD patients which are present in over half of

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the diagnosed bipolar I disordered patients (APA, 2013). Particularly, individuals

with bipolar I or bipolar II and history of abuse are 44% more often to develop

ADHD (Pinna et. al., 2018). Furthermore, individuals with history of ADHD had

earlier age onset of BD, greater risk of suicide attempts and substance misuse in

BD patients, which may be triggered by the impact of impulsivity during BD

development (Pinna et. al., 2018; Tamam et. al., 2008; Perugi et. al., 2013).

2. Conduct disorder. BD patients were also susceptible to misbehaviours or

criminal behaviours (Anda et. al., 2010). For instance, from 2 North Ohio

Counties in 2003-2006, it was found that maltreatment (abuse and neglect) and

lifetime diagnosis of depression and/or BD are predictors of later CD in youth,

although resulted to less delinquency (Mallett, Stoddard Dare and Seck, 2009).

While Olvera et al., 2014 found that BD youth with comorbid CD, as compared

to non-CD, were more likely to present a worse lifetime functioning, further mood

and attentional dysfunction, as well as more medication exposure. BD patients

with CD also had ADHD and MDD which differed significantly with non-BD CD

patient with absence of ADHD and MDD. Therefore, co-occurring presence of

ADHD may trigger a worse presentation of BD as it leads to impulsivity and

disruptive behaviours, as well as conduct disorder (APA, 2013).

3. Post-traumatic stress disorder. Correspondingly, adult patients diagnosed of

BD were more likely to acquire PTSD after surviving a trauma than those with

major depressive disorder (Dilsaver et. al., 2007) in contrast to Maguire et. al.,

(2008) who revealed no association between trauma in childhood and PTSD.

However, Maguire et. al., (2008) utilised catchment-based samples and

convenient sampling, hence, a selection bias cannot be ruled out. Moreover, adult
 12
BD patients with PTSD had 4.5-fold increase in their suicide attempt. This may

be justified by BD patients being susceptible to post-trauma adjustment

difficulties. PTSD was found to be more prevalent in bipolar I disordered patients,

though, PTSD showed similar clinical presentation among all subtypes of BD

(Hernandez et al., 2013).

BD can almost always be misdiagnosed due to overlapping symptoms and co-occurring

psychiatric disorders (APA, 2013). Roughly 50%-81% of individuals who were

diagnosed of bipolar disorder were found to have comorbidities (Amiro et. al., 2014;

Leahy, 2007). Hence, comorbidities in adult BD was proven to significantly affect the

manifestation of BD. Specifically, it triggered an earlier onset of BD and contributed to

an increased number of symptoms with longer duration of the disorder. Since in adult

BD, it was found that more than half of the BD population have co-occurring psychiatric

disorders, it was examined whether similar changes was present in the diagnosis of BD

in children and adolescents.

ACE and Suicidality in BD

Aside from comorbidity, suicidality (both fatal and non-fatal behaviours) was known to

be predicted by various mental disorders, including BD (Malhi et al., 2013). BD was

considered to significantly predict first-onset of suicide after experiencing abuse,

accounting for the highest risk across 21 countries (Nock et. al., 2009). The association

was substantially reduced after controlling for comorbid disorders, albeit remained

significant. Depressed days of BD patients were associated with greater risk of suicidal

attempts and completion, where bipolar II disordered individuals were at a higher risk.

(APA, 2013). In fact, almost a quarter of completed suicide were committed by BD

patients (APA, 2013; Nock et. al., 2009).). Thus, suicidality in patients diagnosed of BD
 13
increases the risk of mortality rate of patients, emphasising the need for more extensive

care.

Reflecting upon the findings, adverse experiences during childhood impact the mental

health condition of an individual, specifically BD. Although reviews regarding

comorbidities of BD and different forms of childhood maltreatment were previously

conducted, they were particularly emphasized on adult BD. It is therefore worth to discern

the presentation and manifestation of comorbidities of BD in younger population,

particularly in children and adolescents.

Aims and objectives

Despite the limited studies concerning the significance of ACE in the presentation of BD

in youth, this systematic review was conducted to examine the association of history of

adverse childhood experience and presence of bipolar disorder in children and

adolescents. Moreover, the main objective was to assess the relationship of ACE in

clinical characteristics of BD in youth that were shared in previous studies, such as onset,

symptoms and duration of BD, ADHD, CD, PTSD, and suicidality.

Methods

Systematic review synthesises the collected studies with their individual findings

answering a specific question of interest. This systematic review used a narrative

synthesis which enclosed collation and summary of 8 included quantitative studies. It is

particularly useful to be conducted in order to critically evaluate and encapsulate the

findings of individual studies regarding the association of ACE and diagnosis of BD in

children and adolescents to see the consistency of result to be generalised in a wider

population.
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Search Strategy

Electronic searching was conducted in this review through PsycInfo via EBSCO,

PubMed, PsycArticles, and PsycBooks databases, or published articles between year

2000 and 2019. The search for studies was conducted from November 2018 to December

2018, then again in February 2019 to June 2019. Moreover, grey literature was

considered only if they met the criteria in the screening test. Grey literature articles may

contribute to the systematic review only with its academic papers such as dissertations,

theses, government papers, and some ongoing research, though not published. These

studies can be retrieved through PsycExtra, GLIN, UMI database, and ProQuest.

The search strategy was done by looking at the population of the studies within the age

criteria who were diagnosed of BD. For instance, searching for bipolar disorder in

children “and/or” adolescents, the results that usually appear are those studies which

examined the diagnosis of BD in children “and” adults since most study which relates to

BD and ACE are focused on adults with the disorder. In addition, all studies with benefit

and relevance to the topic and fit the inclusion and exclusion (table 1) were considered,

albeit was carefully assessed. Also, only studies with quantitative design were queued for

consideration. During the search, duplicated studies from a different database were

excluded. Finally, articles and studies recognised through the reference list and

bibliography will also be considered based on their title and whether or not they fulfil the

criteria provided.

Search terms

There are various initial key searches and Boolean operators that were used to identify

articles such as “paediatric bipolar disorder OR bipolar disorder AND children AND

adolescents OR youth AND maltreatment OR abuse OR adverse childhood experiences

 15
OR childhood maltreatment.” Additional key term search was carried out including

“bipolar disorder AND children AND adolescents OR bipolar disorder AND youth AND

physical OR emotional OR verbal OR sexual abuse OR substance abuse OR substance

misuse OR substance dependence OR child neglect OR parental divorce OR criminal

behaviours.” Aside from ACE in BD youth, objectives regarding clinical characteristics

of BD in children and adolescents with history of ACE were addressed with search terms

and Boolean operators such as “adverse childhood experiences AND bipolar disorder

AND children AND adolescents OR youth AND onset of BD OR symptoms of BD OR

duration of BD OR PTSD OR ADHD OR CD OR suicidality.”

Study selection

The articles that were used went through 4 stages of screening: 1. The titles were searched

using the databases and search terms, and gathered all related studies, 2. Read the

abstracts to see the relevance to the current systematic review based on the inclusion and

exclusion criteria, 3. The researcher run through full-copy articles and assessed content,

and; 4. Selected and included studies which were able to examine the aim of the

systematic review and the specific objectives.

Data Extraction

Through the pilot study, inclusion and exclusion criteria (table 2) was refined and applied

in order to gather data for the research question from included 8 quantitative studies which

examined association of ACE to BD in children and adolescents and the clinical

characteristics of BD (onset of BD, symptoms and duration of BD, ADHD, CD, PTSD,

suicidality).
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Table 1. Inclusion and Exclusion Criteria

Inclusion Exclusion
Population - Young people between birth - Participants with ACE but
and 18 years old adult-onset of bipolar
- Diagnosis of any Bipolar disorder
Disorder according to DSM
or ICD
Variables of - Adverse childhood - Schizophrenia diagnosis
Interest experience (physical, sexual, - Personality disorder
emotional, verbal abuse, - Neurodegenerative disease
neglect, substance misuse, and learning disabilities
relational stress, criminal
behaviour of family)
- Comorbid diagnosis of
ADHD, CD, or PTSD
- Present suicidality issue
Study - Any quantitative study - Studies with mixture of
Characteristics designs child-onset and adult-onset
- Published from year 2000 of bipolar disorder
and up - Published studies which are
not in English language
- Only discussed about
prevalence of bipolar
disorder
- Studies comparing youth-
onset of bipolar disorder with
another disorders

Assessment of quality

The quality of the selected studies was assessed using a tool by National Heart, Lung and

Blood Institute (Nhlbi.nih.gov, 2019). There were various tools provided for different

study design, and the tool that was used was specifically for cohort and cross-sectional

studies. It is used to check the quality of quantitative studies which involves synthesising

and appraising research evidence. The tool contains assessment of; 1. Research question,

whether they explicitly rationalised the goal of conducting the study; 2. Study

Participants, if they followed the criteria of recruitment, if the participants came from the

same group, and is the population enough to detect a possible association; 3. Exposure,
 17
to investigate if the exposure caused the outcomes, it is essential to allow enough time of

exposure prior to measurement and assessment at baseline for possible number of levels

of exposure, as well as repeated assessment to increase certainty of exposure status; 4.

Outcome measure, in order to produce a precise and detailed outcome, tools and

procedures were assessed on their reliability and accuracy. It would also be more effective

if the assessors were blinded in terms of whether the participants were exposed or not.

This is useful in developing recommendation for the study in order to produce high

quality literature in public health programs and policy. Hence, this was applied for the

quality check of the gathered studies.

Synthesis of Research

This systematic review utilised narrative synthesis as it helped to best to explain the

analysis within and between the gathered studies for the overall assessment of the

robustness of evidences through a textual presentation. It is important to be used in order

to fully analyse and interpret collected data in a more rigorous way and to be transparent

and reduce the likelihood of biases.

Results

In attempt to supply the gap in the literature of bipolar disorder, studies retrieved were

filtered through different search-stages, which is presented in figure 1. Unfortunately,

there was limited full-access studies that were published, hence the researcher contacted

authors of various relevant studies (regarding duration, comorbidities and suicidality of

paediatric BD) in order to gain more relevant sources however, no response received.

Finally, a total of 8 studies were included in the present systematic research (Goldstein

et. al., 2008; Goldstein et. al., 2013; Heffner et. al., 2013; Marchand et. al., 2005; Romero

et. al., 2008; Schudlich et. al., 2014; Stephen et. al., 2014; Wilens et. al., 2007) and a
 18
summary of characteristics is presented in table 2 with significant values of the variables

included in the analyses in table 3.

Characteristics of the Participants

A total of 2,045 children and adolescents were included across 8 studies of this review.

The age was between 4 to 22 years old (M= 10.4 years to 17.0 years) Using either

Diagnostic Statistical Manual (DMS) (American Psychiatric Association, 2013) or

International Classification (ICD) (World Health Organization, 1992) (see table 2 for

specific screening tools), participants were diagnosed with different types of bipolar

disorder. Bipolar I disorder was found to be the most common diagnosis of the majority

of the participants followed by bipolar disorder-not otherwise specified (BD-NOS) and

finally. Bipolar II disorder. In the current systematic review, majority of the participants

were exposed to different adverse experiences such as physical abuse, sexual abuse, and

neglect, sent to foster care/adoption alcohol abuse/dependence, drug abuse/dependence,

heavy smoking and other substance use disorder (SUD). In addition, only small number

of ethnicities of participants were recorded – African-American, Caucasian, Hispanic,

and other ethnic minorities.

Demographic profile

Gender

According to the majority of studies, gender did not determine the diagnosis of BD in

children and adolescents nor differ in diagnosed youth. Goldstein et. al., (2008) revealed

no significant difference in the gender of BD youth with and without SUD (x2=1.6,

p=0.20). Goldstein et. al., (2013) also stated that youths with bipolar disorder who

experienced abuse did not differ significantly in their gender (p=0.97). While, physical

abuse, sexual abuse or both abuses were observed more in male youth, in 19 of 32
 19

Studies generated
Irrelevant studies
from search of
removed
databases
n=3,534
n=3,576

Relevant studies Duplicates

identified through removed/removed
title after review of
abstracts
n=42
n=23

Studies removed for

not meeting inclusion
Remaining studies and exclusion criteria
after review of
abstract
Did not meet age-
n=19 range for subjects
n=6

Discussed only the

prevalence of abuse
Manual bibliography n=5
search and grey
literature

n=1

Studies who met full

criteria

n=8

Figure 1. Flowchart of selection process and retrieved studies on each stage.

Table 2. Summary of Studies
Aim/Objective Population Outcome Measures Comparator Outcome
Measure of Bipolar Measure of ACE
Goldstein et. To examine the -249 adolescents Schedule for Life Event No SUD -No significant
al., 2008 prevalence and age 12-17 Affective Disorders Checklist subjects difference in sex, race,
correlates of SUD in and Schizophrenia SES, pubertal status.
adolescents with BD -139 females, 110 for School Age
males Children – Present -Participants are
Hypothesised the BD and Lifetime (K- significantly older at
youth with history of SADS-PL) first intake of SUD and
abuse (physical and less likely to be living
sexual) will have K-SAD-PL with both natural
higher rates of Depression Rating parents.
PTSD, CD, Scale
substance abuse and -increased SUD
suicide attempts. K-SAD-PL Mania prevalence in
Rating Scale adolescents with
adolescent-onset SUD
than childhood-onset.
Goldstein et. To examine -167 subjects Schedule for Schedule for No SUD -Adolescents who
al., 2013 predictors of first- age 12-17 years Affective Disorders Affective Disorders subjects developed SUD at
onset SUD among and 11 months and Schizophrenia and Schizophrenia follow-up were more
adolescents with BD. who did not have for School Age for School Age likely to develop
SUD at intake Children – Present Children – Present lifetime cigarette
To examine and had at least and Lifetime (K- and Lifetime (K- smoking, cannabis use,
predictors of SUD one follow-up SADS-PL) SADS-PL) and alcohol at intake
that occur during the assessment with lifetime comorbid
course of follow-up Kiddie Mania Rating K-SAD-PL ODD.
in BD. Scale (K-MRS) Lifetime Cigarette
Smoking, Lifetime

20
 K-SAD-PL Cannabis Use, and -Better overall
Depression Rating Lifetime Repeated functioning as to C-
Scale Alcohol Use GAS, lower
adolescent-reported
Longitudinal Interval Children’s Global familial cohesion and
Follow-Up Assessment Scale more negative life
Evaluation (LIFE) (C-GAS) events were observed
in adolescents who
Psychiatric Status developed SUD at
Rating (PSR) follow-up.
Heffner et. To examine the -80 adolescents Washington Child Semi- Adolescents -BD subjects with
al., (2013) prevalence and age 13-22. University at St. Structured without cannabis use disorder
correlates of heavy Louis Kiddie Assessment for the psychiatric appear to be in a
smoking and nicotine -38 females, 42 Schedule for Genetics of disorder significantly greater
dependence in males Affective Disorders Alcoholism- chance for progression
bipolar adolescents and Schizophrenia Adolescent version in patter of tobacco use
with co-occurring -Diagnosed of (WASH-U-KSADS) (C-SSAGA-A) than those without
cannabis use disorder Bipolar I psychiatric disorder.
disorder. Teen Addiction
Severity Index -Current heavy
(Teen ASI) smokers were
associated with older
Drug Use ages, lower diastolic
Screening blood pressure,
Inventory-Revised diagnoses of ADHD,
(DUSI-R) CD, and illicit drug use
disorder.
-Marijuana Craving
Questionnaire-
Short Form (MQC)

21
Marchand To determine the -66 patients age Clinical diagnosis Not mentioned -BD youth -There was a
et. al., (2005) frequency and effects 4-17 based on DSM-IV- without significant association
of adverse events in TR. abuse between adverse
the life of children -22 females, 44 events in the life of
and adolescents with males patients with BD and
BD treated in a -Diagnosed of measures related to
community mental BD according to symptoms severity and
health setting. DSM-IV-TR treatment outcomes.

Romero et. To examine the -446 youth age Schedule for K-SAD-PL abuse Non-abused -There is a significant
al., (2008) prevalence and 7-17 Affective Disorders questionnaire youth. association of history
correlates of physical and Schizophrenia of physical and/or
and sexual abuse. -Diagnosed of for School Age sexual abuse and older
either BD-I, BD- Children – Present age, longer duration of
II or BD-NOS. and Lifetime (K- illness, non-intact
SADS-PL) family, lifetime PTSD,
-From Psychosis, CD, and
Outpatient and Structural Clinical first-degree family
Inpatient units. Interview (SCID) history of mood
disorder and remained
significant after
regression analyses.
Schudlich To determine if -829 youth age 4Schedule for Child Abuse Youth -BD youth found to
et. al., (2014) physical and sexual years 11 Affective Disorders History (ABH) without the have correlation with
abuse showed months- 18 and Schizophrenia diagnosis of physical, sexual, and
relationship to early- years and 0 for School Age Achenbach System Bipolar both types of abuse.
onset bipolar month. Children – Present of Empirically Disorder
spectrum disorder. and Lifetime (K- Based Assessment -Though rate of the
-332 females, SADS-PL) (Child Behaviour overall abuse, physical
497 males Checklist 2001 for and sexual abuse were

22
 primary care givers not significantly
-152 subjects and Youth elf- different in both
were diagnosed report for subject groups.
of either BD- participants However, BD youth
NOS, were significantly
Cyclothymia, more likely to
BD-I, BD-II. experience both types
of abuse together.
Stephens et. To examine clinical -103 adolescents Washington Addiction Severity No SUD -There was no
al., (2013) and demographical age 12-20 years University at St. Index (ASI) during difference in terms of
characteristic of age Louis Kiddie follow-up demographic profile of
associated with Schedule for Structural Clinical Bd youth with and
SUDs in adolescents -Diagnosed of Affective Disorders Interview for DSM without SUD – sex,
with BD BD-I, and and Schizophrenia (SCID) race, SES, rates of
hospitalized for (WASH-U-KSADS) ADHD and PTSD.
To identify potential the first time for Urine drug screens
risk and resilience a manic or Structural Clinical -Association between
factors associated mixed episode Interview for DSM- lifetime SUD and
with the onset of IV Axis I Disorder – disruptive behavior
SUD following Patient Edition trended towards
hospitalization for a (SCID-I/P). significance.
first manic episode
-SUDs were
significantly
associated with later
age of index
hospitalization, later
age at onset of BD,
baseline psychotic
symptoms, physical or

23
 sexual abuse, and a
manic (vs mixed)
mood episodes at
baseline.

-Psychosis was the

strongest predictor of
SUD.
Willens et. -To re-examine the -203 participants DSM-IV Schedule Structured Non-mood -No significant
al., (2007) association between age 10-18 years for Affective interview: Kiddie disorder difference in terms of
BD and SUD in old. Disorders- KSADS-E. adolescents. sex, family intactness,
adolescents. Epidemiology between subjects with
-105 diagnosed version (KSADS-E) BD and the control
-Examine findings of Bipolar group.
from an ongoing, Disorder and
controlled, their first-degree -BD subjects had
longitudinal family- family. significantly higher
based study of rate of age-adjusted of
adolescents with BD -Excluded youth any SUD with a higher
and Psychiatric with major rate of alcohol abuse
Comorbidities. sensorimotor and dependence
handicaps, compared to non-
autism, mood disorder
inadequate subjects.
command of
English
language or a
full-scale IQ less
than 70.

24
 25

participants who are currently heavy smokers (p=0.66) and in 29 of 56 nicotine dependent

youths (p=0.99), there was no significant difference depicted (Heffner et. al., 2013).

Romero tet. al., (2009) revealed that there is no significant difference in gender of BD

youth with abuse, albeit female participants in sexually abused group were greater

compared to non-abused group (p=0.05). Conversely, Manchard et. al., (2005) illustrated

that among 35 abused youth 40.9% participants were male and 77.3% were female, thus,

a significant difference in gender was presented (x2= 6.395, df=1, p=0.011).

Age

Older age or adolescents were considered to be more exposed to adverse experiences.

However, possible under-reporting of children should be taken into consideration. Two

studies showed that older age was associated with more adverse experiences in BD youth

(Heffner et. al., 2013; Romero et. al., 2008). Romero et. al., (2009) reported in their study

that BD youth with older age were more exposed to abuse (p=0.02) with a higher rate

(p=0.04) compared to participants ≤12 years of age (16% vs. 24%, respectively). Adjusted

odd ratio showed that older age remained significantly associated with physical or sexual

abuse, or both type of abuse (OR=1.15, 95% CI 1.03-1.2, p=0.015). Furthermore, after

adjusting for differences in demographic of the participants, age was particularly

associated with history of combined abuse (p=0.05), specifically older age (p=0.03).

Correspondingly, BD youth who are currently heavy smokers were found to have older

age (p=0.03) compared to non-users or light-users in the study of Heffner et. al., (2013).

However, BD youth who are nicotine dependents found to have no significant difference

in terms of age (p=0.83) compared to non-nicotine dependents. Goldstein et. al., (2008)

also described BD participants with substance use disorder to be significantly older at

intake than the non-SUD BD youth (p<0.001). On the other hand, Marchand et. al.,

(2005), as well as Wilens at al., (2008) (p=0.83), revealed no significant difference in the
 26
age of BD youth with ACE and the control group. Nevertheless, Wilens at al., (2008)

illustrated that BD participants had significantly higher age-adjusted rates of SUD than

the control group (4% vs. 34%, p=0.001). Finally, Goldstein et al., (2013) found no

significant difference in the age of BD youth with Substance use disorder and the control

group (p=0.97).

Socioeconomic status

Majority of their participants who were exposed to any form of adverse experiences

during childhood were predominantly from a lower socioeconomic status (SES). Romero

et. al., (2009) stated that the abused BD group, compared to non-abused BD youth, was

significantly from lower SES backgrounds (p=0.05). Wilens et. al., (2008) revealed that

BD youth participants also had significantly lower SES that the control group (p=0.02).

Although Schudlich et. al., (2014) noted that SES may be associated with particular

dependent variables such as GFES and P-GBI Hypomanic/Biphasic variables, it was

found to have no relation with the rest of the variables and did not influence pattern of

findings. One possible reason for this finding is that majority of their participants were

drawn from low-income community mental health setting. Meanwhile, no significant

difference between the SES of BD participant with and without substance use disorder

was found in the study of Goldstein et. al., (2008), Goldstein et. al., (2013) and Stephens

et. al., (2014) (p=0.85, p=0.22, p=0.62, respectively).

Association of ACE and Paediatric BD

Due to different forms of methodology and measurements, results found various

outcomes. Nevertheless, included studies were able to address the research question.

Furthermore, a summary of data in the association of ACE and BD in children and

adolescents was depicted in table 3.

 27
Onset of bipolar disorder

Some studies emphasised the age of onset, while some were focused on the number of

years after ACE until BD onset. Nonetheless, in youth with history of ACE, onset of BD

was found mostly during adolescence (12 years of age and above). Goldstein et. al.,

(2008) discovered that diagnosis of BD was antecedent to SUD among 60% of the

participants while SUD was antecedent of BD among 30%. A simultaneous onset of BD

and SUD was found in the remaining 10% of the sample. Furthermore, an increased trend

of SUD was found in adolescent-onset (≥12 years old) of BD as compared to childhood-

onset (x2=3.3, df=1, p=0.07). One study (Wilens et. al., 2008) reported that 22 of 33 BD

participant with SUD had onset of BD before SUD while 3 subjects was exposed to SUD

before BD diagnosis. Moreover, eight subjects experienced both onset on the same year.

Manchard et. al., (2005) found that after the first presentation of mood symptoms was

recorded, 8 was the median number of years until diagnosis of BD in participants who

were exposed to physical abuse, 3 years for those without abuse which was a significant

difference (p=0.010). Moreover, the onset of BD in youth with any physical or sexual

abuse did not significantly differ (p=0.06) in the study of Romero et. al., (2009). On the

other hand, Schudlich et. al., (2014) found that physical and sexual abuse did not

significantly predict age of onset for bipolar disorder, depression spectrum, depression or

hypomanic episodes. Whereas, Stephens et. al., (2014) found a significant difference in

the age of onset of BD youth with and without SUD (p<0.01).

Table 3. Data Summary of Bipolar Youth with Adverse Childhood Experience
Study Various Age Age of Symptom Duration AHDH CD PTSD Suicidality
ACE onset Severity of Illness
Ideation Attempt
Goldstein et. - p=0.01 p=0.01 p>0.05 - p=0.35 p<0.001 P=0.02 - p=0.07
al., 2008
Goldstein et. - p<0.05 - p=0.03 - p>0.4 - - - -
al., 2013
Heffner et. al., - p = 0.83 p = 0.69 p = 0.79 - p=0.04 p = 0.09 - p = 0.82 p = 0.98
2013
Manchard p = 0.011 * * ** - ** - p =0.026 - -
et.al., 2005
Romero et. p >0.05 p ≤0.03 p = 0.06 - p ≤0.03 p=0.09 p ≤0.03 p ≤0.03 - p = 0.01
al., 2008
Schudlich et. p = 0.02 - - p <0.05 - - - p <0.050 p = 0.0066 p<0.005
al., 2014
Stephens et. - - p<0.01 - - p=0.39 - p≤0.20 - -
al., (2013)
Wilens et. al., p = 0.1 p = 0.9 - * - p=0.09 * - - -
2008
Note: (*) significant, (**) not significant with no value presented, (-) not applicable

28
 29

Symptoms of bipolar disorder

Similar to adult BD, findings in the symptoms of BD children and adolescents with ACE

were inconsistent. Heffner et. al., (2013) illustrated that both current heavy smokers and

nicotine dependent youths indicated severe symptoms of mania, yet nicotine dependent

youths had significantly higher rates (no values depicted). Another study (Schudlich et.

al., 2014) showed a strong relationship between increased depressive symptoms and

independent physical abuse (p≤0.05). On the other hand, sexual abuse was correlated with

reports of mood changes within the same day (no values depicted). However, neither of

the associations was found to have significant relationship with number mood episodes

(no values depicted).

According to Goldstein et. al., (2008), symptoms of BD in youth may have increased after

sexual abuse, however, changes were not significant regardless of the exposure to ACE

(physical abuse, sexual abuse and substance misuse). However, symptoms of BD were

found to precipitate the development of substance use disorder (SUD). SUD was not a

significant predictor of baseline manic (x2=0.0, df=1, p=0.97) and depressive (x2=0.1,

df=1, p=0.74) symptoms (and vice versa) and did not impact the significance of other

predictors. Goldstein et. al., (2013) stated that greater hypo/manic symptoms in the

follow-up, preceding 12-week period, were associated with considerable likelihood of

developing SUD (HR: 1.26, 95% CI 1.03-1.56, p=0.03). Furthermore, Wilens et. al.,

(2008), although no values reported, found that substance use disorder (SUD) has no

significant effect on the likelihood of occurrence of rapid cycling or mean annual number

of manias prior to diagnosis of any depressive disorder. No significant difference was

found in the number of manic symptoms or episodes in BD youth either with or without

SUD. Also, number of major depressive disorder (MDD) symptoms or lifetime number
 30

of depressive episodes on BD with and without SUD subjects with both BD and MDD

did not differ.

Duration of bipolar disorder

Only physical and sexual abuse were found to initiate a longer duration of BD in children

and adolescents. The study of Romero et. al., (2009) revealed that abused group, either

physically or physically and sexually abused, had greater duration of illness (p=0.01)

compared to non-abused group with a significant association to adjusted OR of abused

BD youth (x2=6.27, p=0.01). Also, physical abuse, independently, and both abuses were

found to be associated with a longer duration of BD (p≤0.04, p≤0.03, respectively). On

the other hand, Schudlich et. al., (2014) found neither physical nor sexual abuse had

significant association with duration of mood episode (no values were presented). Wilens

et. al., (2008) found no significant difference in the duration of BD in either with or

without substance use disorder, even after the age-adjusted model (p>0.5).

Comorbidities in Paediatric BD with ACE

Attention-deficit/hyperactivity disorder

Although there is a higher number of ADHD children and adolescent with BD, ADHD

was not significantly associated with diagnosis of BD in children and adolescents. In the

study of Goldstein et. al., (2008), Attention-deficit/hyperactivity disorder (ADHD)

diagnosis were found to not have a significant difference in terms of prevalence between

BD youth with and without SUD (x2=0.09, p=0.35). Goldstein et al., (2013) also found

that diagnosis of ADHD in children and adolescent with BD at intake of first-onset SUD

did not significantly differ with non-SUD group (x2=0.64, p=0.42). Also, at follow-up of

first-onset SUD where a small number of BD youth developed SUD (12 weeks prior to

onset and earlier 23-week interval) BD youth with SUD did not differ significantly with
 31

non-SUD (x2=0.40, p=0.53). Although ADHD was diagnosed in the majority of the

participants in the study of Marchand et. al., (2005), it was not revealed to be significantly

associated with BD diagnosis in youth with history of any adverse childhood experience.

Likewise, Stephens et. al (2009) illustrated that the number of participants diagnosed with

ADHD did not significantly differ to the control group (p=0.82) and ADHD showed no

significant association with BD in youth (95% CI 0.4-1.4, p=0.39). Wilens et. al., (2008)

stated that when ADHD was included in the significant association of BD in youth and

ACE, specifically substance use, there was no significant risk found and the effect on the

association was not significant (x2=1.45, p=0.09). Nevertheless, there is a higher number

of BD participants diagnosed with ADHD compared to non-mood disordered control

(x2=40.45, p<0.001). Romero et. al, (2009) revealed a non-significant difference between

BD participants with and without history of ACE in terms of ADHD diagnosis (p=0.09).

Furthermore, only Heffner et. al., (2013) found an association between ADHD and heavy

smoking participants (p=0.04), albeit the association was weak.

Conduct disorder

In all studies, CD was revealed to be significantly associated with BD in youth with

history of ACE, specifically physical abuse, sexual abuse and substance misuse.

Goldstein et. al., (2008) revealed that there is a significantly greater lifetime prevalence

of conduct disorder (CD) in BD youth diagnosed with SUD than those without (p<0.001).

In the study of Goldstein et. al., (2013), out of 167 participants, 54 BD youth developed

first-onset of SUD while 113 did not (HR=1.03, x2=6.52, p=0.01). Heffner et. al., (2013)

illustrated that there are more BD youth who are current-heavy smokers with conduct

disorder (CD) than light/non-current heavy smokers (p=0.01). While the number of

nicotine dependents and not-nicotine dependent BD youth showed no significant

difference (p=0.09). Romero et. al., (2008) found a considerable correlation of abuse on
 32

BD youth and conduct disorder (CD) (OR=2.3, 95% CI 1.1-4.8, p=0.03) with a greater

lifetime prevalence compared to non-abused BD youth (p<0.01). Although CD was not

significantly associated with either physical or sexual abuse (p>0.05), combined abuse

was specifically significantly associated with CD (p<0.05) in BD youth. In addition, first-

degree family history of CD was also found to be greater in abused BD youth than non-

abused (p≤0.01), while second-degree family history did not significantly differ.

Moreover, Wilens et. al., (2008) revealed CD to have influenced the significant effects of

BD on age-adjusted risk for any SUD (x2=6.22, p=0.01) and the effect was significant

(p=0.05). When CD was accounted in the analyses, BD status had significant effects on

the age-adjusted risk of alcohol abuse (x2=4.5, p=0.03), drug abuse (x2=4.38, p=0.04) and

smoking (x2=4.67, p=0.03) and the effects of CD was also significant (x2=4.16, p=0.04;

x2=4.3, p=0.04; x2=7.03, p=0.008, respectively).

Post-traumatic stress disorder

Consistent with adult BD findings, PTSD was significantly associated with BD children

and adolescents who had ACE. Goldstein et. al., (2008) found that BD youth with

substance use disorder (SUD) had a significantly greater lifetime prevalence of post-

traumatic stress disorder (PTSD) compared to non-SD BD youth (p<0.02). A robust

correlation (OR=8.8, 95% CI 3.1-25.1, p<0.001) of abuse and children and adolescents

with BD and a greater lifetime prevalence of PTSD (p<0.01) were noted in the

participants of Romero et. al., (2008). Specifically, PTSD was significantly associated

with physical abuse (p<0.001), sexual abuse (p<0.01) and combined abuse (p<0.03) in

BD youth. Likewise, Schudlich et. al., (2014) found that 20 % of the participants with

history of physical abuse had PTSD, 7% in sexually abused, 19% with both abuse and

4% in youth without any abuse. Hence, illustrated PTSD to be significantly associated

with physical abuse or combined physical and sexual abuse in youth with BD (p<0.050).
 33

Marchand et. al., (2005), who indicated gender differences, revealed that out of 35 BD

participants who experienced any abuse or neglect 13 had diagnosis of PTSD (23.1%

male vs. 76.9% female, p<0.001). Thirty-eight per cent of those diagnosed are from foster

care or adaption while only 11% are not in foster care (p=0.018). Although Stephens et.

al., (2014) found no difference between PTSD of BD youth with and without substance

abuse disorder (SUD) at baseline, after entering into univariate proportional hazards (PH),

PTSD significantly increased the risk for having a lifetime SUD diagnosis (HR=2.8, 95%

CI1.206.7, p=0.02).

Suicidality

There was inconsistency in terms of suicidality, one reason is that it was split into ideation

and attempts in some studies, resulting to various outcomes. Nevertheless, BD children

and adolescents with history of ACE had a higher lifetime prevalence of suicide when

compared to non-ACE Bd youth. Goldstein et. al., (2013) revealed that suicidality (self-

injurious behaviour, attempts and ideation) was not significantly associated with the

intake variables on the first-onset SUD in adolescents diagnosed with bipolar spectrum

disorder (p>0.05). Likewise, Heffner et. al., (2013) exposed no correlations on suicidality

– attempts and ideation – of BD adolescents both current heavy smokers (p>0.05) and

nicotine dependents (p>0.05), although, significantly high rates of lifetime suicidality was

observed. On the other hand, Goldstein et. al., (2008) depicted that BD youth with SUD

exhibited a significantly greater lifetime prevalence of suicide attempts (p=0.007).

Romero et. al., (2008) found children and adolescents diagnosed with BD who had history

of physical and/or sexual abuse to have significantly greater lifetime prevalence of suicide

attempts compared to non-abused BD youth (p=0.004), but not in suicide ideation

(p=0.08). Similarly, Schudlich et. al., (2014) specified that physical abuse in BD youth

tends to triple the probabilities of ideation (p=0.06) and quadruple the attempts (p=0.019).
 34

Also, in their full sample, physical abuse doubles suicidal ideation (p=0.001), while both

physical and sexual abuse together triple the attempts (p<0.001). Thus, a significant

association (x2[6 df] =42.45, p<0.001) between history of abuse and suicidality in BD

youth was depicted. Furthermore, no significant difference was noted on the effect of

adverse experience in BD youth and full sample.

Quality assessment

Most of the papers (Goldstein et. al., 2008; Heffner et. al., 2013; Manchard et. al., 2005;

Romero et. al., 2009; Schudlich et. al., 2014; Wilens et. al., 2008) received a rating of

“fair” while 2 studies (Goldstein et. al., 2013; Stephens et. al., 2013) were marked “good.”

All of the studies were not able to justify the sample size used in their paper. A reason

could be that some studies did not pay much attention whether the number of participants

is sufficient enough to provide a statistical power to answer the research question as it is

not applicable to their study design – retrospective studies, analyses of the association of

the exposure and the outcome are exploratory and was examined on the same timeframe.

Thus, the study design did not allow studies to measure the exposure prior to the outcome.

One study (Manchard et. al., 2005) was not able to perform a follow-up of the exposure

of their participants as the measurement of the exposure was not specified. Though this

is not a fatal flaw, it may still have affected the outcome. Nonetheless, Goldstein et. al.,

(2013) and Stephens et. al., (2013), which involved follow-up of current exposure as part

of the procedure, were not able to validate the reason of using the sample size as well.

Hence, lowers the degree of generalisability of the findings of the systematic review.

Manchard et. al., (2005) did not present adjusted variables such as age and gender of their

participants which could have influenced the association of BD in children and

adolescents and ACE exposure. It is also important to note that blinding of the assessor

to the exposure does not apply to the study design of the selected studies .
 35

Discussion

This systematic review examined the association between history of adverse childhood

experience (ACE) and paediatric bipolar disorder (BD), as well as the relationship of

clinical characteristic of BD to ACE in BD children and adolescents. Eight studies

(Goldstein et. al., 2008; Goldstein et. al., 2013; Heffner et. al., 2013; Marchand et. al.,

2005; Romero et. al., 2008; Schudlich et. al., 2014; Stephen et. al., 2014; Wilens et. al.,

2007) were included after comprehensive searching and screening were done. These

studies were then utilised to examine the association between ACE and BD in children

and adolescents, to identify the relationship of ACE in BD youth to clinical variables of

BD and which of those variables was found to be the most common among all participants

across studies.

The results showed that BD in children and adolescents were indirectly associated with

adverse childhood experiences. Also, not all BD youth who had history of adverse

experiences had the same modifications in the manifestation of the disorder. Nonetheless,

history of ACE (physical abuse, sexual abuse and substance misuse) contributed in an

earlier onset of BD, specifically, adolescent-onset (from 12 years old and above).

Symptoms of BD were found to increase with presence of ACE. However, a strong

relationship was only found between physical and sexual abuse and increased depressive

symptoms and mood changes within the same day, respectively. Moreover, Attention

deficit/hyperactivity disorder (ADHD) showed no difference with non-ACE BD youth

and did not postulate risk to BD presentation in children and adolescents. While, a greater

lifetime prevalence was only found in conduct disorder (CD) and post-traumatic stress

disorder (PTSD) in BD children and adolescents with physical and sexual abuse or

substance use disorder (SUD), which increased the risk for developing lifetime SUD.

Finally, a higher rate of suicidality was found in BD youth with history of physical and
 36

sexual abuse and SUD, but only physical and sexual abuse were significantly associated

with suicidality in BD youth, and not SUD.

Association of ACE and Paediatric BD

There was an indirect association observed between BD in children and adolescents and

history of ACE, specifically, physical and sexual abuse, neglect, heavy smoking, nicotine

dependence, and substance use disorder (SUD). It can be presumed that the changes

observed in the presentation of BD in youth are influenced by various factors which are

led by adverse experiences of children and adolescents but not caused by ACE itself.

However, it should be considered that other young people (less than 12 years old) may

not be able to distinguish abusive treatment (e.g. physical abuse, sexual assault and

neglect) which increases the likelihood for under-reporting and bias (Downs & Harrison,

1998; Cawson et. al., 2000). Consistent with Curell, E., (2016), childhood maltreatment

was not found to be a cause or associated with BD in adult, however, it is an additive to

a severe psychopathology presentation in adult, such as in BD. Additionally, this

systematic review included number of adverse experiences, where some did not

specifically report the degree of ACE in BD youth. Feasibly, this yielded to false positive

results. Future research should substantially regard the measurement for adverse

experiences for more accurate ratings, results and to avoid biases.

Furthermore, causal relationship between emergence of BD during childhood and

adolescent and history of ACE could not be ascertained to be precipitated directly. This

is because the focus of the systematic review is just the association and the included

studies did not extensively examine the causal relationship. Hence, ACE cannot be

accounted as an indicator of the diagnosis with this systematic review, but rather a

prevalent life stressor. In fact, maltreatment was considered as one of the leading social
 37

problems with approximately 20% pervasiveness on adolescents in general population

(Diaz et. al., 2002; May-Chalhal & Cawson, 2005). Taken as a whole, this systematic

suggest that paediatric bipolar disorder could be considered as an antecedent than a

consequence of trauma (Bierderman et. al., 1990) or could be both an outcome to and a

risk factor for adverse experience (Wozniak et. al., 1999). However, association remains

unclear (Fisher & Hosang, 2010). ACE, in the course of the disorder, in youth was found

to be linked to common clinical variability present in the diagnosis of BD with an increase

in the risk of the disorder.

Similar to the findings of McIntyre et. al., (2008) and Brown et. al., (2005), ACE did not

predict the onset of BD in children and adolescent. Although BD children and adolescents

with history of adversity (such as abuse, neglect, relational stress, and substance misuse)

had an earlier onset when compared to non-ACE paediatric BD, the difference did not

show significance since both groups had adolescent-onset (12 years and above).

However, Brown et. al., (2005) only based their conclusion on male adult population,

therefore, findings cannot be generalised. Moreover, consistent with Carballo et. al.,

(2012), although episodes of symptoms present at an earlier age in BD with suicidal

behaviour and history of abuse, the onset of BD did not differ significantly with BD

patient with history of abuse or suicidal, or neither. However, history of abuse was

measured mainly through semi-structured interview and did not validate answers with

other informants. It can be assumed that since the diagnosis of BD in children is not

always clear (Simon, D., 2016) there is a higher chance of being undiagnosed or

misdiagnosed at an earlier pace. Additionally, majority of the included studies (Goldstein

et. al., 2008; Goldstein et. al., 2013; Heffner et. al., 2013; Stephen et. al., 2013) have

early-adolescent participants and did not include children (≤11 years old), contributing to

the findings regarding adolescent-onset.

 38

Paediatric BD shows significantly greater symptoms when exposed to adversity during

childhood. Specifically, physical abuse increases depressive symptoms while sexual

abuse correlates with mood changes within the same day. In line with previous findings,

there was an increase of severity in the symptoms of BD with the presence of childhood

maltreatment than BD without maltreatment (Garno et. al., 2005). However, in previous

study childhood maltreatment was not specified whether each has contribution to the

observed changes or rather just general findings of maltreatment. Moreover, SUD is not

a significant predictor of manic symptoms, depressive symptoms, and occurrence of rapid

cycling in paediatric BD. Nonetheless, a considerable likelihood of developing SUD is

precipitated by a significant increase in hypomanic/manic symptoms. One possible reason

that SUD may not have shown relationship to increased symptoms is because other

studies provided the needed treatment for children and adolescents with SUD, which

could have affected any possible relationship.

A longer duration of BD was found in children and adolescents with history of physical

abuse or physical and sexual abuse, which is consistent to previous findings (Garno et.

al., 2005). However, the systematic review did not have enough data to confirm this.

Nevertheless, it could be that, physical and sexual abuse were found to contribute to a

significant increase in the presentation of symptoms in BD which could initiate a greater

duration of BD in children and adolescents. Future research should examine whether the

duration of BD in children and adolescents is influenced by increased severity symptoms

BD (in mania, hypomania, or depression).

ADHD was found to be the most prevalent comorbid disorder in BD children and

adolescents, in general; surprisingly, it was not significantly associated with paediatric

BD and SUD and does not contribute to a risk in ACE and BD youth. In contrast with
 39

Perroud et al., (2014), ADHD was associated with earlier onset of BD, increased

depressive symptoms and greater number of comorbid disorders and SUD. However,

association was not specified whether it applies to a specific population (children,

adolescents or adult) and the number of participants (n=24) was too low for

generalisation. It could be that in this systematic review, all studies assessed the difference

in prevalence of ADHD between BD youth with and without ACE and only half of the

studies (Heffner et. al., 2013; Manchard et. al., 2005; Stephens et. al., 2009; Wilens et.

al., 2008) examined the association of ADHD and paediatric BD with ACE.

Unlike ADHD, CD and PTSD in BD youth proved a strong association with physical

and/or sexual abuse. CD is significantly associated to paediatric BD with ACE, physical

and sexual abuse and SUD contributes to the development and severe presentation of BD.

Comparably, Docherty et al., (2018) found that youth who experienced any maltreatment

before the age of 14 is associated with development of CD. It can be assumed that abused

youth are vulnerable in terms of emotional development acquiring callous-unemotional

trait, such as lack of guilt. Hence, initiating a higher risk of developing CD (Frick, 2012).

SUD is prevalent more in BD youth with CD than CD but non-BD youth, however, with

the presence of ADHD diagnosis the generalisation of findings is limited (Masi et al.,

2008). Yet, although CD does not confer to an elevated risk of SUD in BD adolescence,

it can be assumed to be associated with more complex presentation of SUD in BD

adolescence (Wilens et. al., (2009)

Moreover, physical abuse and/or sexual abuse or SUD initiates a greater lifetime

prevalence of PTSD in BD children and adolescent, inducing a severe manifestation of

BD. Similarly, traumatic experiences, childhood sexual abuse, adult sexual assault as well

as survival of suicide and accident or death of loved ones increases the risk or the
 40

likelihood of developing PTSD in children and adolescents with BD (Goldberg & Garno,

2005). It could be that children and adolescents may have a hampered recovery due to

self-blame or guilt, which exacerbate symptoms of PTSD (Foa, Steke- tee, & Rothbaum,

1989; Janov-Bulman, 1979). Furthermore, substance abuse interferes with coping skills

of individuals putting them in a higher risk of involvement in accidents, crimes or

violence as well as trauma (Jacobsen, Southwick and Kosten, 2001). Thus, SUD is one

of the significant factors contributing to the development of PTSD, otherwise, onset of

PTSD precedes development of SUD (Back et al., 2006).

As an indicator of suicidality, an expected pattern of increased rate was influenced by

ACE, specifically abuse, in BD youth. A tripled suicide ideation and quadrupled suicide

attempt in physically abused BD youth (Schudlich et. al., 2014) matched with previous

finding that physical abuse, sexual abuse, or neglect initiates 3 to 5 times higher attempted

suicide in youth (Hadland et. al., 2019) with 8% of US high school students attempted

suicide within a year (Kann et. al., 2017). Consistently, SUD was not found to be linked

with suicidality in youth (Waxmonsky et. al., 2005). However, previous studies had

mixed population of adult and adolescents and used binary indicator (yes/no) of substance

misuse which could have biased the results. Nonetheless, ACE, regardless of type,

contributes to the high rates of suicidality in youth, especially to BD children and

adolescents.

Limitation

There are number of limitations that were identified in the current systematic review

which could have influenced the association between the history of ACE and diagnosis

of BD in children and adolescents. Some studies did not specify the measurement of

adverse experiences and some was based exclusively on direct interviews with subjects
 41

and/or parents which may result recall bias. Degree of adversity was also not identified,

which may influence the changes observed in the manifestation of the disorder due to

variation of adversities. Some studies did not have control group leaving no comparison

analyses which could have over-presented BD in youth with history of ACE.

Additionally, some participants are on medication, lowering the positive result of the

findings which may have affected the association; therefore, results may not be

generalised, or limited to treatment-seeking BD patients. Also, there were a lot of ACE

included in the systematic review, but only 4 (physical abuse, sexual abuse, SUD, and

some neglect) were examined.

Moreover, the researcher found a very low number of studies which could examine the

research question. Hence, gathered papers were inadequate for the review to provide more

certain inferences, leading conclusions and assumptions to be easily contested.

Furthermore, it is worth to note that since there were few studies included, one study was

still utilised after failing on one criterion. Specifically, Heffner et. al., (2013) defined

adolescent up to 22 years, but ideally it is limited to 18 years of age which resulted to bias

during the screening process. Finally, the current systematic review only focused on the

association between history of ACE and diagnosis of BD in children and adolescents and

some specific clinical variables that were common to other studies. Therefore, causality

cannot be inferred from the present systematic review.

It is therefore important to narrow down and strictly imply inclusion and exclusion criteria

for the future research. This could also help to reduce inconsistency and contradicting

propositions of some studies. A more focused approached on particular ACE (maybe one

type of ACE) would be beneficial in order to come up with a more specific and precise

synthesis. It is also worth to add more papers to increase reliability and validity of claims.
 42

Overall, the review needs more studies, be reviewed again by another rater and assess the

quality of the selected studies, more rigorously.

Future Research

Considering that findings of this systematic review is greatly influenced by limitations,

future studies should; 1. Imply strictly the inclusion and exclusion criteria; 2. Focus on a

fewer ACE, or one; 3. Include more studies and; 4. Have a second rater on the quality

assessment. Furthermore, specific symptoms increase and severity were related to

specific ACE and the duration of BD in children and adolescents were found to be longer

in abused youth, future research should consider how increased symptoms of BD

influence duration in children and adolescents.

Conclusion

In conclusion, albeit it is not plausible to corroborate direct association between the

diagnosis of BD during childhood or adolescents and history of any ACE, the findings of

the present review validate the significance of investigating the research question

systematically. Influence of adversity during childhood was observed in some clinical

variance in the manifestation of BD. Particularly, earlier onset of BD, increased

symptoms and longer duration of BD was documented in youth with history of physical

and sexual abuse and SUD. However, the onset of BD either with or without history of

adversity during childhood was both on adolescent-onset. Furthermore, physical and

sexual abuse were the strongest predictor of lifetime prevalence of PTSD and CD in BD

youth, while any abuse or SUD indicates lifetime prevalence of suicidality in BD youth.

Nonetheless, further research is needed in order to rigorously examine the association,

probably with longitudinal studies.

 43

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Appendices

Appendix A | Quality Assessment

56