Journal of Affective Disorders 170 (2015) 237–254

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Journal of Affective Disorders

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

Review

Risk factors for suicide in bipolar disorder: A systematic review

Lucas da Silva Costa a,n, Átila Pereira Alencar a, Pedro Januário Nascimento Neto a,
Maria do Socorro Vieira dos Santos a, Cláudio Gleidiston Lima da Silva b,
Sally de França Lacerda Pinheiro b, Regiane Teixeira Silveira b, Bianca Alves Vieira Bianco b,
Roberto Flávio Fontenelle Pinheiro Júnior c, Marcos Antonio Pereira de Lima c,
Alberto Olavo Advincula Reis d, Modesto Leite Rolim Neto e
a
Laboratório de Escrita Científica, Faculdade de Medicina, Universidade Federal do Cariri, UFCA, Barbalha, Ceará, Brazil
b
Programa de Pós-Graduação em Ciências da Saúde, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil
c
Faculdade de Medicina, Universidade Federal do Cariri, UFCA, Barbalha, Ceará, Brazil
d
Programa de Pós-Graduação em Saúde Pública, Faculdade de Saúde Pública, Universidade de São Paulo, USP, São Paulo, São Paulo, Brazil
e
Líder de Grupo de Pesquisa em Suicidologia, Universidade Federal do Ceará, UFC/Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq,
Faculdade de Medicina, Universidade Federal do Cariri, UFCA, Barbalha, Ceará, Brazil

art ic l e i nf o a b s t r a c t

Article history: Background: Bipolar disorder confers the highest risk of suicide among major psychological disorders.
Received 30 July 2014 The risk factors associated with bipolar disorder and suicide exist and are relevant to clinicians and
Received in revised form researchers.
18 August 2014
Objective: The aim of the present study was to conduct a systematic review of articles regarding the
Accepted 2 September 2014
Available online 16 September 2014
suicide risk factors in bipolar disorder.
Methods: A systematic review of articles on suicide risk factors in bipolar disorder, published from
Keywords: January 1, 2010 to April 05, 2014, on SCOPUS and PUBMED databases was carried out. Search terms were
Bipolar “Suicide” (medical subject headings [MeSH]), “Risk factors” (MeSH), and “Bipolar” (keyword). Of the 220
Suicide
retrieved studies, 42 met the eligibility criteria.
Risk factors
Results: Bipolar disorder is associated with an increased rate death by suicide which contributes to
overall mortality rates. Studies covered a wide range of aspects regarding suicide risk factors in bipolar
disorder, such as risk factors associated to Sociodemographic conditions, Biological characteristics, Drugs
Relationships, Psychological Factors, Genetic Compound, Religious and Spirituals conditions. Recent
scientific literature regarding the suicide risk factors in bipolar disorder converge to, directly or indirectly,
highlight the negative impacts of risk factors to the affected population quality of life.
Conclusion: This review demonstrated that Bipolar disorders commonly leads to other psychiatric
disorders and co-morbidities involving risk of suicide. Thus the risk factors are relevant to have a better
diagnosis and prognosis of BD cases involving risk of suicide.
& 2014 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
4.1. Risk factors associated with sociodemographic components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

n
Correspondence to: Laboratório de Escrita Científica, Faculdade de Medicina, Universidade Federal do Cariri, UFCA, Rua Divino Salvador, 284, 63180-000, Barbalha, Ceará,
Brazil. Tel.: þ 55 88 3312 5000; fax: þ 55 88 3312 5001.
E-mail address: lucas_10_00@hotmail.com (L.d.S. Costa).

http://dx.doi.org/10.1016/j.jad.2014.09.003
0165-0327/& 2014 Elsevier B.V. All rights reserved.
238 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

4.2. Risk factors associated with genetic components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

4.3. Risk factors associated with medicines and drugs in general that interfere with bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
4.4. Risk factors associated with biological components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
4.5. Risk factors associated with psychological causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
4.6. Risk factors associated with components of religious and spiritual components. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

1. Introduction
Bipolar disorder confers the highest risk of suicide among
major psychological disorders (Goldstein et al., 2012; Goodwin
and Jamison, 2007). Suicide attempts and completed suicide are
significantly more common in patients with bipolar disorder when
compared with the general population (Eroglu et al., 2013; Simon
et al., 2007; Weissman et al., 1999).
Bipolar spectrum disorders, especially recurrent depressive epi-
sodes, is the major risk of repeated suicide attempt and co-morbidity
of another psychiatric disorders increase highly the risk of suicide
reattempt (Kheirabadi et al., 2012). In particular, among mental
disorders, bipolar disorder is one of the leading causes of suicidal
behaviors and this is a major issue in the management of the disease.
About 50% of patients with bipolar disorder will experience at least
one suicide attempt (Jamison, 2000) and 11–19% will commit suicide
(Goodwin and Jamison, 2007; Abreu et al., 2009; Angst et al., 2005;
Harris and Barraclough, 1997; Parmentier et al., 2012).
This study is based on the following research question: what is
the main suicide risk factors associated with bipolar disorder? This
issue has gained great impact in recent years with the establish-
ment of new risk factors for suicide and bipolar disorder. Thus, this
systematic review aims to present the main risk factors and
compares them, since the applicant was disagreement among
authors. Therefore, it is suggested, that further studies are needed
in order to establish a stronger relationship between bipolar
disorder and its risk factors that culminate in suicide.
2. Methods
We performed a qualitative systematic review of articles about
suicide risk factors in bipolar affective disorder in previously
chosen electronic databases.
A search of the literature was conducted via PubMed and
SCOPUS online databases in April 2014 and was limited to articles
published from January 1, 2010 to April 6, 2014. The reason for
limiting the search to 2010–2014 was that, during this period,
there was an expansion of research into new types of comorbid-
ities that influence the risk of suicide in Bipolar disorder, such as
hopelessness, altitude and religiosity. Therefore, the Bipolar Affec-
tive Disorder and its association with suicide had greater relevance
in the scientific community.
Initially, the search terms browsed in SCOPUS database were
with the theme object of the present review. The search strategy
and the retrieved articles were reviewed on two separate occa-
sions to ensure adequate sampling. A similar search strategy was
performed in the PubMed database, using the aforementioned
terms and their correspondent terms.
The article analysis followed previously determined eligibility
criteria. We adopted the following inclusion criteria: Goldstein
et al. (2012) references written in English; Goodwin and Jamison
(2007) studies pertaining suicide risk factors in bipolar affective
disorder; Eroglu et al., (2013) original articles with online acces-
sible full text available in database SCOPUS, PubMed or CAPES
(Higher Education Co-ordination Agency) Journal Portal
(Periodicos.capes.gov.br, 2014), a virtual library linked to Brazil's
Ministry of Education and subjected to content subscription;
(Simon et al., 2007) articles that included in the title at least one
combination of terms described in the search strategy; (Weissman
et al., 1999) case reports, cohort studies, controlled clinical trials
and case-control studies; Kheirabadi et al. (2012) articles that
appear in more than one database will be included only once,
giving priority to the SCOPUS database. Exclusion criteria were:
Goldstein et al. (2012) studies that did not include the proposed
topic; Goodwin and Jamison (2007) non-original studies, including
editorials, reviews, prefaces, brief communications and letters to
the editor.
Then, each paper in the sample was read in entirety, and data
elements were then extracted and entered into a matrix that
included authors, journal, description of the study sample, and
main findings. Some of the studies dealt not only with the risk
factors associated with bipolar disorder, but also to the risk factors
in other psychiatric disorders, such as schizophrenia and mood
disorder; because the focus of this study was the risk factors
associated with suicide in bipolar disorder, studies related to
psychiatric disorders in general were not recorded or analyzed
for this study.
To provide a better analysis, the next phase involved comparing
the studies and grouping. For heuristic reasons, the results regarding
the studied subject into six categories: Risk factors associated with
sociodemographic components; Risk factors associated with genetic
components; Risk factors associated with Medicines and Drugs in
general that interfere with bipolar disorder; Risk factors associated
with Biological components; Risk factors associated with Psycholo-
gical causes; and Risk factors associated with components of Reli-
gious and Spiritual components.

1. “bipolar” (keyword);
2. “suicide” (Medical Subject Headings [MeSH] term); and
3. “risk factors” (MeSH term). 3. Results

The following searches were performed: 1 AND 2 AND 3. Initially, the aforementioned search strategies resulted in 220
In addition to MeSH terms, we opted to add the keyword “bipolar” references. After browsing the title and abstract of the retrieved
to the search strategy, because, despite not being included in the citations for eligibility based on study inclusion criteria, 178 articles
MeSH thesaurus, it is frequently used to describe studies that deal were excluded and 42 articles were further retrieved and included
 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254
in the final sample Fig. 1). Articles from SCOPUS and PubMed
database matched the inclusion criteria of the present study.
Table 1 provides an overview of all studies included in the final
sample and of all data elements used during the data analysis
process. Study designs included one case report (Kerner et al.,
2013), seven transversal studies (Goldstein et al., 2012; Kheirabadi
et al., 2012; Undurraga et al., 2012; De Abreu et al., 2012; Algorta
et al., 2011; Evans et al., 2012; Gomes et al., 2010), nineteen cohort
studies (Parmentier et al., 2012; Huber et al., 2014; Ruengorn et al.,
2012; Etain et al., 2013; Cassidy, 2011; Baldessarini et al., 2012;
Bellivier et al., 2011; Sears et al., 2013; Jiménez et al., 2013; Leon
et al., 2012; Finseth et al., 2012; Oquendo et al., 2010; Kenneson
et al., 2013; Gilbert et al., 2011; Shabani et al., 2013; Pompili et al.,
2012; Acosta et al., 2012; Song et al., 2012; Suttajit et al., 2013), and
fifteen case-control studies (Eroglu et al., 2013; Antypa et al., 2013;
Ryu et al., 2010; Manchia et al., 2013; Neves et al., 2010; Magno
et al., 2011; Yoon et al., 2011; Arias et al., 2013; Clements et al.,
2013; Pawlak et al., 2013; Kamali et al., 2012; de Moraes et al.,
2013; Azorin et al., 2013; Dervic et al., 2011; Pawlak et al., 2013).
The 42 studies were distributed into the previously determined six
categories as follows:
Risk factors associated with sociodemographic components
(seven studies) (Huber et al., 2014; De Abreu et al., 2012;
Ruengorn et al., 2012; Algorta et al., 2011; Cassidy, 2011; Antypa
et al., 2013; Ryu et al., 2010); Risk factors associated with genetic
components (six studies) (Manchia et al., 2013; Sears et al., 2013;
Neves et al., 2010; Magno et al., 2011; Jiménez et al., 2013; Kerner
et al., 2013); Risk factors associated with Medicines and Drugs in
general that interfere with bipolar disorder (eight studies)
Fig. 1. Flow chart showing study selections for the review. Abbreviations MeSH, Medical Subject Headings.
239
(Bellivier et al., 2011; Yoon et al., 2011; Leon et al., 2012; Arias
et al., 2013; Clements et al., 2013; Finseth et al., 2012; Oquendo
et al., 2010; Kenneson et al., 2013); Risk factors associated with
Biological components (three studies) (Kamali et al., 2012; Evans
et al., 2012; Gomes et al., 2010); Risk factors associated with
Psychological causes (seven studies) (Parmentier et al., 2012;
Shabani et al., 2013; Pompili et al., 2012; Acosta et al., 2012;
Song et al., 2012; Suttajit et al., 2013; Stewart et al., 2009); and Risk
factors associated with components of Religious and Spiritual
(three studies) components (Azorin et al., 2013; Dervic et al.,
2011; Pawlak et al., 2013). Among the 42 studies, 8 discussed about
“suicide risk factors in Bipolar Affective disorder” — more broadly
(Goldstein et al., 2012; Eroglu et al., 2013; Kheirabadi et al., 2012;
Undurraga et al., 2012; Etain et al., 2013; Baldessarini et al., 2012;
Pawlak et al., 2013; Gilbert et al., 2011), being refered in more than
one category. The categorization of studies aims to a better
organizational quality systematic review and it is not compulsory
that each article must be referenced only in their respective
category.
4. Discussion
Bipolar disorder (BD) is a major public health concern worldwide,
and is associated with significant morbidity and mortality (Kupfer,
2005). In addition to an increased rate of death by suicide, community
and clinical studies indicate that bipolar patients usually present a
broadrange of comorbid general medical conditions, which contribute
240 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

Table 1
Suicide risk factors in bipolar affective disorder: studies and main findings.

Authors Journal Sample Main findings

Goldstein et al. Archives of General A total of 413 youths (mean [SD] age, 12.6 [3.3] years) who received Of the 413 youths with bipolar disorder, 76 (18%)
(2012) Psychiatry a diagnosis of bipolar I disorder (n¼244), bipolar II disorder made at least 1 suicide attempt within 5 years of
(n¼ 28), or bipolar disorder not otherwise specified (n¼141). study intake; of these, 31 (8% of the entire sample
and 41% of attempters) made multiple attempts. Girls
had higher rates of attempts than did boys, but rates
were similar for bipolar subtypes. The most potent
past and intake predictors of prospectively examined
suicide attempts included severity of depressive
episode at study intake and family history of
depression. Follow-up data were aggregated over
8-week intervals; greater number of weeks spent
with threshold depression, substance use disorder,
and mixed mood symptoms and greater number of
weeks spent receiving outpatient psychosocial
services in the preceding 8-week period predicted
greater likelihood of a suicide attempt.

Eroglu et al. Dusunen Adam One hundred twenty two consecutive patients, from Bipolar The prevalence of suicide attempt was 19.7% in the
(2013) Disorder Unit of Çukurova University, Faculty of Medicine, outpatient group. Lifetime history of suicidal
Department of Psychiatry, are included in this study. behavior was significantly associated with following
characteristics: being a woman, depression as a first
episode and indicators of severity of bipolar disorder
including duration of illness, duration of untreated
illness (latency), number of hospitalization, number
of total mood episodes, number of depressive
episodes, number of mixed episodes, positive familial
psychiatric disorder history.

Kheirabadi Iranian Journal of Participants consisted of 703 individuals (424 of them were female) Bipolar spectrum disorders, unipolar depression and
et al. (2012) Epidemiology with mean age of 25.9 7 9.7. adjustment disorders were the more frequents
psychiatric disorders respectively. Age, family history
of suicide, kind of diagnosed psychiatric disorder and
method of attempted suicide were meaningfully
related to mean of attempt suicide frequency.

Parmentier European Psychiatry In a sample of 652 euthymic bipolar patients, we assessed clinical
et al. (2012) features with the Diagnostic Interview for Genetics Studies (DIGS)
and dimensional characteristics with questionnaires measuring
impulsivity/hostility and affective lability/intensity.
Of the 652 subjects, 42.9% had experienced at least
one suicide attempt. Lifetime history of suicidal
behavior was associated with being a woman, a
history of head injury, tobacco misuse and indicators
of severity of bipolar disorder including early age at
onset, high number of depressive episodes, positive
history of rapid cycling, alcohol misuse and social
phobia. Indirect hostility and irritability were
dimensional characteristics associated with suicidal
behavior in bipolar patients, whereas impulsivity and
affective lability/intensity were not associated with
suicidal behavior.

Huber et al. Medical Hypotheses Data were available for 16 states for the years 2005–2008, Altitude was a significant, independent predictor of
(2014) representing a total of 35,725 completed suicides in 922 U.S. the altitude at which suicides occurred (F¼ 8.28,
counties. p ¼ 0.004 and Wald chi-square.¼ 21.67, p o 0.0001).
Least squares means of altitude, independent of
other variables, indicated that individuals with BD
committed suicide at the greatest mean altitude.
Moreover, the mean altitude at which suicides
occurred in BD was significantly higher than in
decedents whose mental health diagnosis was major
depressive disorder (MDD), schizophrenia, or anxiety
disorder.

Undurraga Journal of Clinical Accordingly, we compared selected demographic and clinical
et al. (2012) Psychiatry factors for long-term association with nonlethal suicidal acts or
ideation in 290 DSM-IV bipolar I (n¼ 204) and II (n¼ 86) disorder
patients followed for a mean of 9.3 years at the University of
Barcelona, using preliminary bivariate comparisons followed by
multivariate logistic regression modeling.
Rates of suicidal ideation (41.5%) and acts (19.7%)
were similarly prevalent with bipolar I and II
disorders and somewhat more common among
women. Factors significantly and independently
associated with suicidal acts were determined by
multivariate modeling and ranked in order of their
strength of association: suicidal ideation, more
mixed episodes, Axis II comorbidity, female sex,
more antidepressant trials, rapid cycling,
predominant lifetime depression, having been
hospitalized, older onset, and longer delay of
diagnosis.

De Abreu et al. Comprehensive Psychiatry One hundred eight patients with Diagnostic and Statistical Manual Patients with BD and previous suicide attempts had
(2012) of Mental Disorders, Fourth Edition BD type I (44 with previous significantly lower scores in all the 4 domains of the
 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254 241

Table 1 (continued )

Authors Journal Sample Main findings

suicide attempts, 64 without previous suicide attempts) were World Health Organization's Quality of Life
studied. Instrument-Short Version scale than did patients
with BD but no previous suicide attempts (physical
domain P¼ 0.001; psychological domain Po 0.0001;
social domain P¼ 0.001, and environmental domain
P ¼0.039). In the euthymic subgroup (n¼ 70),
patients with previous suicide attempts had
significantly lower scores only in the psychological
and social domains (P¼ 0.020 and P ¼0.004).
Limitations: This was a cross-sectional study, and no
causal associations can be assumed.

Ruengorn et al. Psychology Research and Medical files of 489 patients diagnosed with BD at Suanprung Six statistically significant indicators associated with
(2012) Behavior Management Psychiatric Hospital between October 2006 and May 2009 were suicide attempts were included in the risk-scoring
reviewed. scheme: depression, psychotic symptom(s), number
of previous suicide attempts, stressful life event(s),
medication adherence, and BD treatment years. A
total risk score (possible range  1.5–11.5) explained
an 88.6% probability of suicide attempts based on the
receiver operating characteristic (ROC) analysis.
Likelihood ratios of suicide attempts with low risk
scores (below 2.5), moderate risk scores (2.5-8.0),
and high risk scores (above 8.0) were 0.11 (95% CI
0.04-0.32), 1.72 (95% CI 1.41–2.10), and 19.0 (95% CI
6.17-58.16), respectively.

Algorta et al. Bipolar Disorders Participants were 138 youths aged 5–18years presenting to
(2011) outpatient clinics with DSM-IV diagnoses of bipolar I disorder
(n¼ 27), bipolar II disorder (n¼ 18), cyclothymic disorder (n¼ 48),
and bipolar disorder not otherwise specified (n ¼45).
Twenty PBD patients had lifetime suicide attempts,
63 had past or current suicide ideation, and 55 were
free of suicide ideation and attempts. Attempters
were older than nonattempters. Suicide ideation and
attempts were linked to higher depressive
symptoms, and rates were even higher in youths
meeting criteria for the mixed specifier proposed for
DSM-5. Both suicide ideation and attempts were
associated with lower youth QoL and poorer family
functioning. Parent effects (with suicidality treated
as outcome) and child effects (where suicide was the
predictor of poor family functioning) showed equally
strong evidence in regression models, even after
adjusting for demographics.

Etain et al. Journal of Clinical 587 patients with DSM-IV-defined bipolar disorder were recruited Multivariate analyses investigating trauma variables
(2013) Psychiatry from France and Norway between 1996-2008 and 2007-2012, together showed that both emotional and sexual
respectively. abuse were independent predictors of lower age at
onset (P¼ 0.002 for each) and history of suicide
attempts (OR¼ 1.60 [95% CI, 1.07 to 2.39], P¼ 0.023;
OR ¼ 1.80 [95% CI, 1.14–2.86], P ¼0.012, respectively),
while sexual abuse was the strongest predictor of
rapid cycling (OR ¼2.04 [95% CI, 1.21–3.42],
P ¼0.007). Females reported overall higher childhood
trauma frequency and greater associations to clinical
expressions than males (P values o 0.05).

Cassidy (2011) Suicide and Life- The study cohort included 87 males and 70 females. Ninety-six Gender, nicotine use, medical comorbidity, and
Threatening Behavior were White and sixty-one were Black. history of alcohol and other drug abuse were not,
although a trend was noted for a history of
benzodiazepine abuse.

Blair-West Journal of Psychiatric Data was collected from the Systematic Treatment Enhancement The strongest predictor of a suicide event was a
et al. (1999) Research Program for Bipolar Disorder (STEP-BD) study. 3083 bipolar history of suicide attempt (hazard ratio¼ 2.60, p-
patients were included in this report, among these 140 (4.6%) had a value o 0.001) in line with prior literature. Additional
suicide event (8 died by suicide and 132 attempted suicide). predictors were: younger age, a high total score on
the personality disorder questionnaire and a high
percentage of days spent depressed in the year prior
to study entry.

Gould et al. Yonsei Med J. A total of 579 medical records were retrospectively reviewed. The prevalence of suicide attempt was 13.1% in our
(1996) patient group. The presence of a depressive first
episode was significantly different between
attempters and nonattempters. Logistic regression
analysis revealed that depressive first episodes and
bipolar II disorder were significantly associated with
suicide attempts in those patients.

Arató et al. Acta Psychiatrica We tested factors for association with predominantly (Z 2:1) Factors preliminarily associated with predominant-
(1988) Scandinavica depressive vs. mania-like episodes with 928 DSM-IV type-I BPD depression included: electroconvulsive treatment,
subjects from five international sites. longer latency-to-BPD diagnosis, first episode
depressive or mixed, more suicide attempts, more
Axis-II comorbidity, ever having mixed-states, ever
242 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

Table 1 (continued )

Authors Journal Sample Main findings

married, and female sex. Predominant-mania was

associated with: initial manic or psychotic episodes,
more drug abuse, more education, and more family
psychiatric history. Of the 47.3% of subjects without
polarity-predominance, risks for all factors
considered were intermediate. Expanding the
definition of polarity-predominance to Z 51% added
little, but shifting mixed-states to 'predominant-
depression' increased risk of suicidal acts from 2.4-
to 4.5-fold excess over predominant-mania-
hypomania, and suicidal risk was associated
continuously with increasing proportions of
depressive or mixed episodes.

Akiskal et al. Bipolar Disorders European Mania in Bipolar Longitudinal Evaluation of Medication
(1995) (EMBLEM) is a two-year, prospective, observational study that
enrolled 3,684 adult patients with bipolar disorder and initiated or
changed oral treatment for an acute manic/mixed episode.
Of the 2,219 patients who provided data on their
lifetime history of suicide attempts, 663 (29.9%) had
a history of suicidal behavior (at least one attempt).
Baseline factors associated with a history of suicidal
behavior included female gender, a history of alcohol
abuse, a history of substance abuse, young age at first
treatment for a mood episode, longer disease
duration, greater depressive symptom severity
(HAMD-5 total score), current benzodiazepine use,
higher overall symptom severity (CGI-BP: mania and
overall score), and poor compliance.

McIntyre et al. Bipolar disorders We studied 737 families of probands with MAD with 4919 first- The estimated lifetime prevalence of suicidal
(2008) degree relatives (818 affected, 3948 unaffected, and 153 subjects behavior (attempted and completed suicides) in 737
with no information available). probands was 38.4 7 3.0%. Lithium treatment
decreased suicide risk in probands (p ¼0.007). In
first-degree relatives, a family history of suicidal
behavior contributed significantly to the joint risk of
MAD and suicidal behavior (p ¼0.0006).

Vaccari et al., Journal of Affective We used family-based association testing in a cohort of 130
(1978) Disorders multiplex bipolar pedigrees, comprising 795 individuals, to look for
associations between suicidal behavior and 32 single nucleotide
polymorphisms (SNPs) from across the genes brain-derived
neurotrophic factor (BDNF), cholecystokinin (CCK) and the
cholecystokinin beta-receptor (CCKBR).
We found associations (p r 0.05) between suicide
attempt and 12 SNPs of CCKBR and five SNPs of
BDNF. After correction for multiple testing, seven
SNPs of CCKBR remained significantly associated. No
association was found between CCK and suicidal
behavior.

WHO (2011) Journal of Affective We evaluated 198 bipolar patients and 103 health controls, using a We found that 26.77% and 16.67% had a lifetime
Disorders structured interview according to DSM-IV criteria. history of non violent suicide attempt and violent
suicide attempt, respectively. The clinical factors
associated with violent and non violent suicide
attempt had several differences. Violent suicide
attempters had an earlier illness onset and had a
higher number of psychiatric comorbidities
(borderline personality disorder, panic disorder and
alcoholism). The frequency of S allele carriers was
higher only in those patients who had made a violent
suicide attempt in their lifetime (x2 ¼16.969;
p ¼ 0.0001). In a logistic regression model including
these factors, S allele carrier (5-HTTLPR) was the only
factor associated with violent suicide attempt.

Baldessarini Journal of Affective TaqMan genotyping was used to detect FOXO3A SNPs in 273 BD Three SNPs (rs1536057, rs2802292 and rs1935952)
et al. (2006) Disorders patients and 264 control subjects. were associated with BD, but none was positively
linked with suicidal behavior.

Dwivedi et al. European Polymorphisms at the IMPA1 (rs915, rs1058401 and rs2268432)
(2003) Neuropsychopharmacology and IMPA2 (rs66938, rs1020294, rs1250171 and rs630110), INPP1
(rs3791809, rs4853694 and 909270), GSK3α (rs3745233) and GSK3β
(rs334558, rs1732170 and rs11921360) genes were genotyped.
Single SNP analyses showed that suicide attempters
had higher frequencies of AA genotype of the
rs669838-IMPA2 and GG genotype of the rs4853694-
INPP1gene compared to non-attempters. Results also
revealed that T-allele carriers of the rs1732170-
GSK3β gene and A-allele carriers of the rs11921360-
GSK3β gene had a higher risk for attempting suicide.
Haplotype analysis showed that attempters had
lower frequencies of A:A haplotype (rs4853694:
rs909270) at the INPP1 gene. Higher frequencies of
the C:A haplotype and lower frequencies of the A:C
haplotype at the GSK-3β gene (rs1732170:
rs11921360) were also found to be associated to SB in
BP. Therefore, our results suggest that genetic
variability at IMPA2, INPP1 and GSK3β genes is
associated with the emergence of SB in BP.
 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254 243

Table 1 (continued )

Authors Journal Sample Main findings

Polter et al. Front Psychiatry Here, we describe a family with four siblings, three affected females Our results support a new model for psychiatric
(2009) and one unaffected male disorders, in which multiple rare, damaging
mutations in genes functionally related to a common
signaling pathway contribute to the manifestation of
bipolar disorder.

Kerner et al. Compr Psychiatry. This study is based on the US Multiple Cause of Death public-use
(2013) data files for 1999 to 2006. Secondary data analysis was conducted
comparing decedents with unipolar/bipolar disorders and
decedents with all other causes of death, based on the death
records of 19,052,468 decedents in the Multiple Cause of Death
data files who died at 15 years and older
Prevalence of comorbid SUDs was higher among
unipolar and bipolar disorder deaths than that
among all other deaths. Among unipolar and bipolar
disorder deaths, comorbid SUDs were associated
with elevated risks for suicide and other unnatural
death in both men and women (prevalence ratios
ranging 1.49–9.46, P o0.05). They also were
associated with reductions in mean ages at death
(ranging 11.7–33.8 years, Po 0.05). In general, these
effects were much stronger for drug use disorders
than for alcohol use disorders. Both SUDs had
stronger effects on suicide among women, whereas
their effects on other unnatural deaths were stronger
among men.

Nilsson et al., American Journal of Analyses included 199 participants with bipolar disorder for whom Participants who had more severe manic symptoms
(2002) Psychiatry 1077 time intervals were classified as either exposed to an were more likely to receive antiepileptic drugs.
antiepileptic (carbamazepine, lamotrigine, or valproate) or not Mixed-effects grouped-time survival models
exposed to an antiepileptic, an antidepressant, or lithium during revealed no elevation in risk of suicide attempt or
30 years of follow-up. suicide during periods when participants were
receiving antiepileptics relative to periods when they
were not (hazard ratio¼0.93, 95% CI ¼0.45–1.92),
controlling for demographic and clinical variables
through propensity score matching.

Ratcliffe et al., Mental Health and The sample consisted of 837 outpatients from Madrid, Spain. We It was considered that 76.1% of the alcohol addicts
(2008) Substance Use: Dual compared 528 subjects with a lifetime diagnosis of alcohol abuse or had a current dual diagnosis, the most prevalent
Diagnosis dependence and 182 with other substance use disorders (SUDs) not being mood and anxiety disorders. Fifty-two percent
involving alcohol. had a personality disorder and most of them (81.6%)
had other SUDs. There was a greater prevalence of
dual pathology in the alcohol addict subgroup than
in the subgroup without problems of alcohol abuse
or dependence. Alcohol addicts were associated with
diagnoses of several types of personality disorder
and bipolar disorder and presented a greater suicide
risk than the subgroup of other SUDs.

Tsai et al. Psychological Medicine During the study period 1489 individuals with BD died by suicide, Compared to other primary diagnosis suicides, those
(2002) an average of 116 cases/year. with BD were more likely to be female, more than
5 years post-diagnosis, current/recent in-patients, to
have more than five in-patient admissions, and to
have depressive symptoms. In BD suicides the most
common co-morbid diagnoses were personality
disorder and alcohol dependence. Approximately
40% were not prescribed mood stabilizers at the time
of death. More than 60% of BD suicides were in
contact with services the week prior to suicide but
were assessed as low risk.

Clements et al. General Hospital The aim of the study was to look for suicide risk factors among
(2013) Psychiatry sociodemographic and clinical factors, family history and stressful
life events in patients with diagnosis of unipolar and bipolar
affective disorder (597 patients, 563 controls).
In the bipolar and unipolar affective disorders
sample, we observed an association between suicidal
attempts and the following: family history of
psychiatric disorders, affective disorders and
psychoactive substance abuse/dependence;
inappropriate guilt in depression; chronic insomnia
and early onset of unipolar disorder. The risk of
suicide attempt differs in separate age brackets (it is
greater in patients under 45 years old). No difference
in family history of suicide and suicide attempts;
marital status; offspring; living with family;
psychotic symptoms and irritability; and coexistence
of personality disorder, anxiety disorder or substance
abuse/dependence with affective disorder was
observed in the groups of patients with and without
suicide attempt in lifetime history.

Pawlak et al. Bipolar Disorders A total of 206 consecutive patients (mean age 42 715years; 54.9%
(2013) women) with DSM-IV diagnosed BD-I (n¼140) and BD-II (n¼ 66)
acutely admitted to a single psychiatric hospital department from
November 2002 through June 2009 were included.
Ninety-three patients (45.1%) had a history of one or
more serious suicide attempts. These constituted 60
(42.9%) of the BD-I patients and 33 (50%) of the BD-II
patients (no significant difference). Lifetime suicide
attempt was associated with a higher number of
hospitalizations due to depression (po 0.0001),
244 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

Table 1 (continued )

Authors Journal Sample Main findings

antidepressant (AD)-induced hypomania/mania

(p ¼0.033), AD- and/or alcohol-induced affective
episodes (p ¼ 0.009), alcohol and/or substance use
(p ¼0.002), and a family history of alcohol abuse and/
or affective disorder (p ¼ 0.01). Suicide attempt was
negatively associated with a higher Positive and
Negative Syndrome Scale for Schizophrenia (PANSS)
Positive Subscale score (p¼ 0.022) and more
hospitalizations due to mania (p ¼0.006).

Sublette et al. Journal of Clinical 1,643 individuals with a DSM-IV lifetime diagnosis of bipolar More than half of the respondents (54%) who met
(2009) Psychiatry disorder were identified from 43,093 general-population criteria for bipolar disorder also reported alcohol use
respondents who were interviewed in the 2001-2002 National disorder. Bipolar individuals with comorbid alcohol
Epidemiologic Survey on Alcohol and Related Conditions. use disorder were at greater risk for suicide attempt
than those individuals without alcohol use disorder
(adjusted odds ratio¼ 2.25; 95% CI, 1.61–3.14) and
were more likely to have comorbid nicotine
dependence and drug use disorders.

Lopez et al., Comprehensive Psychiatry Using data collected from the National Comorbidity Survey
(2001) Replication study, we identified 158 individuals with childhood-
onset ( o13 years) or adolescent-onset (13-18 years) primary
bipolar disorder (I, II or subthreshold).
Compared to adolescent-onset, people with
childhood-onset bipolar disorder had increased
likelihoods of attention deficit hyperactivity disorder
(ADHD) (adjusted odds ratio¼2.81) and suicide
attempt (aOR ¼3.61). Males were more likely than
females to develop SUD, and did so at a faster rate.
Hazard ratios of risk factors for SUD were: lifetime
oppositional defiant disorder (2.048), any lifetime
anxiety disorder (3.077), adolescent-onset bipolar
disorder (1.653), and suicide attempt (15.424). SUD
was not predicted by bipolar disorder type, family
history of bipolar disorder, hospitalization for a mood
episode, ADHD or conduct disorder.

Oquendo et al. Journal of Clinical Participants included 67 adult inpatients and outpatients aged We found that nonattempters reported significantly
(2010) Psychiatry 18-60 years meeting DSM-IV criteria for bipolar disorder (bipolar I higher trait impulsivity scores on the Barratt
and II disorders, bipolar disorder not otherwise specified). Impulsiveness Scale compared to attempters (t
57 ¼ 2.2, P ¼ 0.03) and that, among attempters, lower
trait impulsivity score was associated with higher
scores of lethality of prior attempts (r25 ¼  0.53,
P ¼0.01). Analyses revealed no other group
differences on demographic, clinical, or
neurocognitive variables when comparing
attempters versus nonattempters. Regression models
failed to identify any significant predictors of past
suicide attempt.

Pfennig et al., Journal of Affective Salivary cortisol was collected for three consecutive days in 29 A past history of suicide was associated with a 7.4%
(2005) Disorders controls, 80 bipolar individuals without a history of suicide and higher bedtime salivary cortisol level in bipolar
56 bipolar individuals with a past history of suicide. Clinical factors individuals. There was no statistical difference
that affect salivary cortisol were also examined. between non-suicidal bipolar individuals and
controls in bedtime salivary cortisol and awakening
salivary cortisol was not different between the three
groups.

Yerevanian PLoS ONE We studied 27 bipolar subjects using the NEO-PI We found positive associations between personality
et al., (2004) factors and ratios of n-3 PUFA, suggesting that
conversion of short chain to long chain n-3s and the
activity of enzymes in this pathway may associate
with measures of personality. Thus, ratios of
docosahexaenoic acid (DHA) to alpha linolenic acid
(ALA) and the activity of fatty acid desaturase 2
(FADS2) involved in the conversion of ALA to DHA
were positively associated with openness factor
scores. Ratios of eicosapentaenoic acid (EPA) to ALA
and ratios of EPA to DHA were positively associated
with agreeableness factor scores. Finally, serum
concentrations of the n-6, arachidonic acid (AA),
were significantly lower in subjects with a history of
suicide attempt compared to non-attempters.

Evans et al. Acta Neuropsychiatrica Two hundred fifty-five DSM-IV out-patients with bipolar disorder
(2012) were consecutively recruited from the Bipolar Disorder Program at
Hospital das Clínicas de Porto Alegre and the University Hospital at
the Universidade Federal de Santa Maria, Brazil.
Over 30% of the sample was obese and over 50% had
a history of suicide attempt. In the multivariate
model, obese patients were nearly twice (OR ¼1.97,
95% CI: 1.06–3.69, p ¼ 0.03) as likely to have a history
of suicide attempt(s).

Azorin et al. Iranian Journal of One hundred patients were followed for 2–42 months (mean: Only one patient attempted suicide during the
(2009) Psychiatry and Behavioral 20.6 7 12.5 months). follow-up period. 33% of the patients had history of
Sciences previous suicide attempts. Female gender, divorce,
 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254 245

Table 1 (continued )

Authors Journal Sample Main findings

and early age at onset of the disease were

independently correlated with suicide attempt.

Undurraga Comprehensive Psychiatry Participants were 216 consecutive inpatients (97 men and 119
et al. (2011) women) with a Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision (DSM-IV-TR), BD who were
admitted to the Sant'Andrea Hospital's psychiatric ward in Rome
(Italy).
Patients with BD-II had higher scores on the BHS
(9.78 7 5.37 vs. 6.87 7 4.69; t143.59 ¼  3.94; P
o 0.001) than patients with BD-I. Hopelessness was
associated with the individual pattern of
temperament traits (i.e., the relative balance of
hyperthymic vs. cyclothymic-irritable-anxious-
dysthmic). Furthermore, patients with higher
hopelessness (compared with those with lower
levels of hopelessness) reported more frequently
moderate to severe depression (87.1% vs. 38.9%;
P o 0.001) and higher MINI suicidal risk.

Shabani et al. Comprehensive Psychiatry A sample of 102 outpatients with a diagnosis of bipolar disorder As compared with the nonsuicidal group, female sex,
(2013) according to International Classification of Diseases, 10th Revision combined psychopharmacologic treatment, and
criteria during nonsyndromal stage were evaluated. hopelessness were independently associated with
suicide attempt. Hopelessness and insight into
having a mental disorder were independently
associated with history of suicidal ideation.

Akiskal (2007) Journal of Nervous and Among 212 patients with bipolar disorder, 44 (21.2%) patients had The variables that differentiated those who did from
Mental Disease histories of suicide attempts. those who did not attempt suicide included age at
first contact, lifetime history of antidepressant use,
major depressive episode, mixed episode, auditory
hallucinations, rapid cycling, the number of previous
mood episodes, age of first depressive episode, and
age of first psychotic symptoms.

Weinstock and Neuropsychiatric Disease
Miller (2008) and Treatment
The data of 383 bipolar I disorder patients were included in the
analyses.
The demographic/clinical variables significantly
associated with the MINI suicide risk scores included
age, number of overall previous episodes, the Young
Mania Rating Scale score, the Montgomery Asberg
Depression Rating Scale scores, and the Clinical
Global Impression Severity of Illness Scale for Bipolar
Disorder mania score, depression score, and overall
score. The variables affecting the differences of
suicide risk scores between or among groups were
type of first mood episode, a history of rapid cycling,
anxiety disorders, and alcohol use disorders.

Pompili et al. Psicologia: Reflexao e The Iowa Gambling Task and the Conner's Continuous Performance A factorial analysis evaluated the adequacy of the
(2012) Critica Test evaluated impulsivity in 95 euthymic bipolar patients -42 instruments. Furthermore, a multiple regression
suicide attempters and 115 normal control participants. analysis was done in order to develop a model to
predict suicide attempts. Our results point to a
specific type of impulsivity related to making
decisions, lack of planning and borderline
personality disorder comorbidity. This type of
impulsivity is a risk factor for suicide attempts in
patients with bipolar disorder.

American Journal of Affective As part of the EPIDEP National Multisite French Study of 493 Compared to LRl, HRl patients did not differ with
Psychiatric Disorders consecutive DSM-IV major depressive patients evaluated in at least respect to their religious affiliation but had a later
Association two semi-structured interviews 1 month apart, 234 (55.2%) could age at onset of their affective illness with more
(2003) be classified as with high religious involvement (HRl), and 190 hospitalizations, suicide attempts, associated
(44.8%) as with low religious involvement (LRl), on the basis of hypomanic features, switches under antidepressant
their ratings on the Duke Religious lndex (DRl). treatment, prescription of tricyclics, comorbid
obsessive compulsive disorder, and family history of
affective disorder in first-degree relatives.

World Health Journal of Clinical A retrospective case control study of 149 depressed bipolar patients
Organization Psychiatry (DSM-III-R criteria) in a tertiary care university research clinic was
(WHO) conducted. Patients who reported religious affiliation were
(2003) compared with 51 patients without religious affiliation in terms of
sociodemographic and clinical characteristics and history of
suicidal behavior.
Religiously affiliated patients had more children and
more family-oriented social networks than
nonaffiliated patients. As for clinical variables,
religiously affiliated patients had fewer past suicide
attempts, had fewer suicides in first-degree relatives,
and were older at the time of first suicide attempt
than unaffiliated patients. Furthermore, patients
with religious affiliation had comparatively higher
scores on the moral or religious objections to suicide
subscale of the RFLI, lower lifetime aggression, and
less comorbid alcohol and substance abuse and
childhood abuse experience. After controlling for
confounders, higher aggression scores (P¼ 0.001)
and lower score on the moral or religious objections
246 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254
Table 1 (continued )
Authors Journal Sample
Suttajit et al. General Hospital The aim of the study was looking for suicide risk factors among
(2013) Psychiatry personality dimensions and value system in patients with diagnosis
of unipolar and bipolar affective disorder (n¼ 189 patients, n¼ 101
controls).
to overall mortality rates (Angst et al., 2002; Roshanaei-Moghaddam
and Katon, 2009).
The risk of suicide for individuals with BD is approximately 60
times greater than that of the general population (Simon et al.,
2007). Fifteen to twenty percent of individuals with BD complete
suicide and up to 40% report at least one suicide attempt during
their lifetime (Simon et al., 2007).
The ratio of suicide attempts to completed suicides for the
general population is 35:1, but for individuals with BD, the same
ratio is 3:1 (Simon et al., 2007). In fact, it is estimated that BD may
account for one-quarter of all completed suicides (American
Psychiatric Association, 2013; Huber et al., 2014).
However, unlike other authors included in this review,
Undurraga et al., (2012) concluded that suicidal risk-factors found
to be independent of bipolar disorder. This fact, as well as the
different conclusions reached by the authors, which will be
demonstrated below, exposes the need for further research.
4.1. Risk factors associated with sociodemographic components
Quality of life seems to be associated with suicidal behaviors
(i.e., suicidal ideation, suicide attempts, and complete suicide) in
the general population and in psychiatric patients (De Abreu et al.,
2012).
A recent review showed that Quality of Life (QoL) is markedly
impaired in patients with BD, even when they are clinically
euthymic (De Abreu et al., 2012; Michalak et al., 2005). Also,
stressful life event(s) was another preponderant factor predicting
suicide attempts, and has played an important role in predicting
suicide attempts among BD patients in many studies, particularly
during depressive phases (Azorin et al., 2009; Ruengorn et al.,
2012).
De Abreu et al. (2012) hypothesized that patients with BD and
previous suicide attempts would have worse QoL than patients
with BD but no previous suicide attempts . It is possible that low
QoL may reflect the existence of poor coping skills and inadequate
social support, which in turn may increase the risk for suicide
attempts (De Abreu et al., 2012). Further prospective studies are
needed to clarify the causal and temporal relationships between
low QoL and suicide attempts (De Abreu et al., 2012).
Pediatric Bipolar Disorder (PBD), for example, is associated
with substantially lower average QoL than found with many other
major medical illnesses, and worse than other mental illnesses in
youth except for major depression (Freeman et al., 2009; Algorta
et al., 2011). Suicidality and lower youth QoL both were signifi-
cantly associated with worse family functioning (Algorta et al.,
2011). Poor family functioning, poor youth QoL, and mixed
features will each make unique contributions to suicidality as an
outcome variable (Algorta et al., 2011). Also, Etain et al. (2013)
Main findings
to suicide subscale of the RFLI (Po 0.001) were
significantly associated with suicidal behavior in
depressed bipolar patients. Moral or religious
objections to suicide mediated the effects of religious
affiliation on suicidal behavior in this sample.
The main limitations of the study are number of
participants, lack of data about stressful life events
and treatment with lithium. Novelty seeking and
harm avoidance dimensions constituted suicide
attempt risk factors in the group of patients with
affective disorders. Protective role of cooperativeness
was discovered. Patients with and without suicide
attempt in lifetime history varied in self-esteem
position in Value Survey.
demonstrated consistent associations between childhood trauma
and more severe clinical characteristics in bipolar disorder .
Moreover, family history of completed suicide had the highest
odds ratio of significant findings. In previous reports in bipolar
cohorts (Galfavy et al., 2006; Valtonen et al., 2006), family history
of suicide was no different between bipolar patients with and
without histories of attempts, although one study reported family
history was predictive of earlier attempts (Galfavy et al., 2006;
Cassidy, 2011). Also, the higher frequency of bipolar disorder
family history in agitated depression suggests that a bipolar
vulnerability may be required to obtain such clustering of hypo-
manic symptoms (Akiskal et al., 2005). Overall, findings support an
association between family functioning and suicidality within
families where youths have bipolar disorder (Miklowitz and
Chang, 2008). Results suggest that it is plausible that the youth's
illness may play an active role in disrupting family processes.
Bipolar disorder may involve a potent combination of mood
dysregulation and interpersonal processes where threats of harm
— against oneself or another — may occur both impulsively and/or
instrumentally (Algorta et al., 2011). In fact, bipolar disorder
imparts the greatest risk for completed suicide among youth
(Goldstein et al., 2012).
With regard to age groups at risk for suicidal behavior, prior
literature suggests that young-aged patients are at higher risk of
suicide compared to older patients, in line with the finding of this
report. Studies with depressed patients have shown that young
patients report a higher number of suicide attempts (Blair-West
et al., 1999; Antypa et al., 2013; Azorin et al., 2010). Although no
association was found between age and suicide attempts (Azorin
et al., 2009). Studies of adolescent suicide completers document
the substantial contribution of parental depression to offspring
suicide risk (Gould et al., 1996), even after accounting for the
child's depressive severity (Brent et al., 1993). It is possible that
familial depression contributes to offspring suicide risk via multi-
ple avenues, including decreased familial support and increased
conflict (Goldstein et al., 2012; Brent et al., 1994).
Ryu et al. (2010) investigated the descriptive characteristics of
suicide attempts and the risk factors for suicide attempts in Korean
bipolar patients by assessing sociodemographic factors, clinical
factors, and the methods of suicide attempts using retrospective
reviews of medical records . Ryu et al. (2010) reviewed medical
records of all 601 patients who were admitted to the psychiatric
wards in one mental hospital and three general hospitals (Ryu
et al., 2010). The 579 subjects who were included in the final
analysis was comprised of 262 (45.3%) men and 317 (54.7%)
women (Ryu et al., 2010).
Ryu et al. (2010) found two significant risk factors associated.
First, they found that patients with depressive first episodes
appear to be higher in suicide attempters. Bipolar patients with
 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254
a depressive episode at their initial admission or first episode tend
to have a depressed mood at the next episode (Daban et al., 2006;
Perugi et al., 2000). Moreover, 60% of suicide attempters with
depressive episodes commit suicide at the first mood episode
(Balázs et al., 2003). Prolonged exposure to depressive episodes
might increase the risk of suicide attempts in bipolar patients and
poor prognostic factor in suicide related behavior (Valtonen et al.,
2006; Ryu et al., 2010). Second it was observed that bipolar II
patients have a higher risk for suicide attempts. Bipolar II patients
are known to have greater risk of suicide than bipolar I patients
(Balázs et al., 2003; Arató et al., 1988). Bipolar II patients show a
predominantly depressive mood, mood lability, and mixed nature
(Akiskal et al., 1995; Benazzi 2007). Bipolar II patients are likely to
have depressive or mixed episodes at hospital admission rather
than bipolar I patients (Ryu et al., 2010). Also, there is a stronger
continuous relationship of suicidal risk with the proportion of total
recurrences that were depressive-or-mixed vs. depressive
(Baldessarini et al., 2012). Baldessarini et al. (2012) has shown a
strong association of predominant depression, especially with
mixed-episodes included, with suicidal behavior.
Furthermore, suicide attempts were observed in both males and
females at similar rates. Moreover, females who attempted suicide
were as likely to have attempted suicide by a more violent method as
males (Cassidy, 2011). Although, it was observed that some authors
categorized the female gender as a risk factor (Bellivier et al., 2011).
Parmentier et al. (2012) observed that reported rates of suicide
attempts among women with bipolar disorders are about twice as
high as among men with bipolar disorders, suggesting greater
lethality of suicide attempts in men (Parmentier et al., 2012;
Suicidology AAo, 2000; Tondo et al., 2006).
Ruengorn et al. (2012) proposed a risk-scoring scheme for
suicide attempts in Thai patients with BD. Ruengorn et al. (2012)
conducted a study at Suanprung Psychiatric Hospital, a total of 489
patients' medical files were reviewed and included in the final
analysis. Results revealed that suicide attempters were younger,
single, did not have children, and had little or very little social
support. They reported experiencing more stressful life events,
reported being depressed, had suffered from BD at an early age,
had a family history of suicide, had previously attempted suicide,
had previous suicidal ideation, alcohol use, and were prescribed
antipsychotics, antidepressants, anxiolytics, and mood stabilizers
(Ruengorn et al., 2012). Using multivariate logistic regression, the
author found six indicators of suicide attempts: depressive epi-
sodes, previous suicide attempt(s), stressful life event(s), inter-
mittent or poor medication adherence, and shorter duration of BD
treatment. Psychotic symptom(s) provided an inverse association
with suicide risk (Ruengorn et al., 2012).
Moreover, the altitude was seen as a significant risk factor
(Huber et al., 2014). Several biological theories may explain an
altitude-suicide association. Dopamine and serotonin are neuro-
transmitters associated with pleasure, reward, and mood.
Decreased levels of serotonin and increased levels of dopamine
and norepinephrine associated with hypoxia at higher altitudes
may lead to increased irritability, depression, and suicide (Huber
et al., 2014; Trouvin et al., 1986; Jou et al., 2009).
Converging lines of evidence also indicate that mitochondrial
dysfunction plays a role in the pathophysiology of BD and may
influence the severity of episodes (Scaglia, 2010; Quiroz et al.,
2008; Kato, 2006). Studies of patients with mitochondrial disease
show that both adults (Fattal et al., 2006, 2007) and children
(Morava et al., 2010; Koene et al., 2009) have elevated rates of
depressive symptoms. Metabolic stress due to hypoxia may have
important considerations for individuals with BD. Hypoxia due to
reduced oxygen partial pressure at higher altitudes may further
decrease mitochondrial function in individuals with BD (McIntyre
et al., 2008; Rezin et al., 2009). For these individuals, metabolic
247
changes associated with hypoxia may lead to depression, instabil-
ity of mood, and increased risk of suicide (Huber et al., 2014;
Vaccari et al., 1978).
4.2. Risk factors associated with genetic components
Suicide attempt was defined as an intentional self-inflicted
injury with self-destructive intent (Manchia et al., 2013). Globally,
approximately one million individuals commit suicide each year
(WHO, 2011; Sears et al., 2013). Suicidal behavior is a matter of
major concern in the management of BD patients for many
reasons. First, their suicide rates are about 60 times higher than
that observed in general population. Second, about one third to
half of these patients will make at least one suicide attempt during
their disease. Finally, their suicide acts have a higher lethality as
suggested by a much lower ratio of attempted suicide (approxi-
mately 3:1) than in the general population (approximately 30:1)
(Baldessarini et al., 2006; Neves et al., 2010).
Although many data have suggested that BD confers a higher
risk of suicide than other psychiatric illnesses (Sajatovic, 2005),
few studies have yet been conducted to investigate the contribu-
tion of the genetic component (Magno et al., 2011).
Genetic variation plays an important role in BD and suicide
susceptibility. However, little is known about the genetic influence
on the risk of suicide, particularly in BD patients (Magno et al.,
2011). The liability to suicidal behavior is influenced by genetic
factors (particularly family history of suicidal behavior and Major
Affective Disorders) (Manchia et al., 2013).
In addition, genetic determinants such as polymorphisms
within the tryptophan hydroxylase 1 (TPH1; Gene ID 7166 in
11p15.3–p14) and the tryptophan hydroxylase 2 (TPH2; Gene ID
121278 in 12q21.1) genes were found to be associated with suicide
attempts of high lethality and with completed suicides, respec-
tively (Manchia et al., 2013; Galfalvy et al., 2009; Lopez et al.,
2007). These findings are of interest considering the association
between altered serotonin system function in the brain and
suicide (Manchia et al., 2013). Neves et al. (2010) showed that
serotonin polymorphism (5-HTTLPR; Gene ID 6532 in 17q11.2) is
strongly associated with violent suicidal behavior in BD patients.
Their results could be an important step to create a genetic tool for
long-term suicide prediction (Neves et al., 2010). Biological mar-
kers, such as 5-HTTLPR (Gene ID 6532 in 17q11.2), could help for
identification of potential suicide attempters (Neves et al., 2010).
Several lines of evidence indicate that brain-derived neuro-
trophic factor (BDNF; Gene ID 627 in 11p13) is a good candidate
gene for involvement in suicidal behavior. Post-mortem studies
have shown that the expression of BDNF (Gene ID 627 in 11p13) is
significantly reduced in individuals that have committed suicide,
regardless of psychiatric diagnosis (Sears et al., 2013; Dwivedi
et al., 2003; Karege et al., 2005). Moreover, an association between
BDNF (Gene ID 627 in 11p13) gene and violent Suicide Attempt (SA)
has been also detected in a sample of this patients (Neves et al.,
2011; Jiménez et al., 2013). In addition, brain-derived neurotrophic
factor (BDNF; Gene ID 627 in 11p13) and lithium, well known
therapeutic drug in mood disorder (Fountoulakis et al., 2008),
reduces FoxO3a (Gene ID 2309 in 6q21) transcriptional activity
(Magno et al., 2011; Mao et al., 2007; Zhu et al., 2004). FoxO3a
(Gene ID 2309 in 6q21) influences distinct behavioral processes
linked to anxiety and depression. Recently, a study using a
knockout (KO) mice model suggested that FoxO3a (Gene ID 2309
in 6q21) may be a transcriptional target for anxiety and mood
disorder treatment (Magno et al., 2011; Polter et al., 2009). These
data suggest that FOXO3A (Gene ID 2309 in 6q21) is a novel
susceptibility locus for BD, but not for suicidal behavior in BD
patients. These results may contribute to a better understanding of
the BD genetics (Magno et al., 2011).
248 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254
Some evidence links phosphosinositol pathway to suicidal
behavior (Jiménez et al., 2013). Jiménez et al. (2013) suggest that
genetic variability at rs669838-IMPA2 (Gene ID 3613 in 18p11.2),
rs4853694-INPP1 (Gene ID 3628 in 2q32), rs1732170- GSK3b
(Gene ID 2932 in 3q13.3) and rs11921360-GSK3b (Gene ID 2932
in 3q13.3) genes is associated with a higher risk of attempting
suicide in bipolar patients (Jiménez et al., 2013). It is known that at
therapeutic concentrations, lithium immediately inhibits several
enzymes, such as both isoenzymes (1 and 2) of inositolmonopho-
sphatase (IMPA), inositolpolyphosphate-1 phosphatase (INPP1),
phosphoglucomutase and glycogen synthasekinase-3b (GSK3b)
(Jiménez et al., 2013; Quiroz et al., 2004; Serretti et al., 2009).
The phosphoinositol pathway is associated with cellular activities
such as metabolism, secretion, phototransduction, cell growth and
differentiation (Jiménez et al., 2013; Serretti et al., 2009).
The question remains how genetic risk factors contribute to the
manifestation of bipolar disorder. If we could answer this question,
early intervention and effective treatment could become a reality
(Kerner et al., 2013). Heritable factors have important effect on
susceptibility to suicidal behavior, which is supported by several
studies showing that genetic polymorphisms play a role in suicide
risk (Magno et al., 2011; Galfalvy et al., 2009; Magno et al., 2010;
Roy and Segal, 2001). Strong heritability of bipolar disorder has
been supported by many studies, but the identification of causal
variants has been challenging (Kerner et al., 2013).
4.3. Risk factors associated with medicines and drugs in general that
interfere with bipolar disorder
Prevalence of comorbid substance use disorders was higher
among unipolar and bipolar disorder deaths than that among all
other deaths. Among unipolar and bipolar disorder deaths, comor-
bid substance use disorders were associated with elevated risks for
suicide and other unnatural death in both males and females
(Yoon et al., 2011). Antiepileptic drugs are approved for the
treatment of epilepsy, bipolar disorder, and neuropathic pain. Each
of these conditions is associated with an elevated risk of suicide
(Simon et al., 2007; Christensen et al., 2007; Nilsson et al., 2002;
Ratcliffe et al., 2008; Tsai et al., 2002; Leon et al., 2012). Alcohol
addicts were associated with diagnoses of several types of person-
ality disorder and bipolar disorder and presented a greater suicide
risk than the subgroup of other substance use disorders (SUDs)
(Arias et al., 2013). Personality disorder and alcohol dependence
were the most common secondary diagnoses in the BD group
(Clements et al., 2013). Twenty-five percent of persons consume
alcohol prior to suicidal attempt (Raja and Azzoni, 2004). Leverich
et al. (2003) also point to family history of abuse of medicinal
drugs as a suicide risk factor (Leverich et al., 2003; Pawlak et al.,
2013).
The risk of suicidal behavior or ideation was significantly
elevated in patients who received an antiepileptic compared with
those who received placebo when no adjustments were made for
trial differences (Leon et al., 2012). This warning was based on an
U.S. Food and Drug Administration (FDA) examination of data from
199 randomized clinical trials of 11 antiepileptic medications
(carbamazepine, divalproex, felbamate, gabapentin, lamotrigine,
levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate,
and zonisamide) (Leon et al., 2012). The role of antidepressants
(AD) in suicide risk is important, and this has received much
attention in recent years (McElroy et al., 2006). There is an
association between the use of AD and a risk of acute manic
switch in BD (Ghaemi et al., 2003), and McElroy et al. (2006)
concluded that AD may induce suicidal intention by manic con-
version in a subset of depressive presentations (Finseth et al.,
2012). In general, these effects were much stronger for Drug Use
Disorders (DUD) than for Alcohol Use Disorders (AUD). Both
substance use disorders had stronger effects on suicide among
females, whereas their effects on other unnatural deaths were
stronger among males (Yoon et al., 2011).
According to the National Epidemiologic Survey on Alcohol and
Related Conditions (NESARC) estimates, among individuals with
12-month unipolar depressive disorder, 14.1% had alcohol use
disorders (AUD) and 4.6% had drug use disorders (DUD). These
represented significantly elevated risks for the comorbid sub-
stance use disorders (Yoon et al., 2011; Hasin et al., 2005). In a
sample consisted of 837 outpatients from Madrid, Spain. Arias
et al., (2013) compared 528 subjects with a lifetime diagnosis of
alcohol abuse or dependence and 182 with other substance use
disorders (SUDs) not involving alcohol. The Mini International
Neuropsychiatric Interview (MINI) was used to evaluate Axis I
disorders and the Personality Disorder Questionnaire to evaluate
personality disorders. It was considered that 76.1% of the alcohol
addicts had a current dual diagnosis, the most prevalent being
mood and anxiety disorders. Fifty-two percent had a personality
disorder and most of them (81.6%) had other SUDs Compared to
people with bipolar disorder alone, those who have bipolar
disorder with comorbid SUD have an increased prevalence of
suicide attempts (Sublette et al., 2009; Dalton et al., 2003; Lopez
et al., 2001; Oquendo et al., 2010; Potash et al., 2000; Kenneson
et al., 2013).
Gilbert et al. (2011) identified the extremely difficult to predict
suicidal behavior, even when comprehensive clinical information
is available. However, empirical evidence has shown that people
with mood disorders and/or substance use disorders experience
excess mortality (Yoon et al., 2011; Amaddeo et al., 1995; Black
et al., 1985; Bruce et al., 1994; Cuijpers and Smit, 2002; Harris and
Barraclough, 1998; Hiroeh et al., 2001; Mykletun et al., 2007;
Wulsin et al., 1999). Actually, only a few studies have examined the
association between mood disorders and other causes of unnatural
death (Black et al., 1985; Hiroeh et al., 2001; Mykletun et al., 2007;
Gau and Cheng, 2004; Joukamaa et al., 2001; Ösby et al., 2001),
despite the fact that individuals with mood disorders, especially
those with bipolar disorder, are more likely to engage in fatal
accidents due to impaired attention and concentration (Stahl,
2000) or to be victims of homicide due to affective psychoses
(Yoon et al., 2011; Hiroeh et al., 2001). These findings suggest that
abuse of alcohol or drugs could be considered as an important
characteristic to identify subgroups at risk for suicidal behavior
(Akiskal et al., 1995; Maremmani et al., 2007). Leverich et al.
(2003) have found a correlation between suicidal behaviors and
the family history of suicide attempts or committed suicides, as
well as the family history of abuse of medicinal drugs (Leverich
et al., 2003; Pawlak et al., 2013). Interventions to reduce suicide
risk in bipolar disorder need to address the common and high risk
comorbidity with alcohol use disorders (Oquendo et al., 2010).
4.4. Risk factors associated with biological components
Altered functioning of the Hypothalamic-pituitary-adrenal
(HPA) axis has been reported in suicidal behavior and in Bipolar
Disorder (BD) (Daban et al., 2005; Mann, 2003). However, many
studies of HPA axis function in bipolar disorder have not examined
the potential effects of Suicidal Behavior (SB) (Cassidy et al., 1998;
Cervantes et al., 2001; Cookson et al., 1985; Godwin, 1984;
Linkowski et al., 1994; Rybakowski and Twardowska, 1999;
Schmider et al., 1995) and studies of the association between
HPA axis activity and suicidal behavior in varied diagnostic groups
have had mixed results (Black et al., 2002; Coryell and Schlesser,
2001; Dahl et al., 1991; Duval et al., 2001; Jokinen and Nordström,
2008; Jokinen and Nordström, 2009; Jokinen et al., 2009; Lindqvist
et al., 2008; Pfennig et al., 2005; Pitchot et al., 2008; Tripodianakis
et al., 2000; Yerevanian et al., 2004; Kamali et al., 2012).
 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254
The HPA axis has been examined using a number of methods.
Basal cortisol secretion has been measured with 24 h urinary
cortisol secretion and serum or salivary cortisol levels. The feed-
back and suppression mechanisms of the HPA axis have been
investigated with the dexamethasone suppression test (DST)
(Kamali et al., 2012) or the dexamethasone/corticotropin-releasing
hormone (DEX/CRH) challenge test (Carroll et al., 1981; Heuser
et al., 1994).
Kamali et al. (2012) examined HPA axis activity as a trait
marker for bipolar disorder and suicide by measuring salivar
cortisol in a bipolar cohort with a history of suicide and compares
it with non-suicidal bipolar individuals and unaffected controls.
Kamali et al., (2012) hypothesis was that those with bipolar
disorder would have elevated basal salivary cortisol compared to
unaffected controls, and that the suicidal bipolar individuals
(defined by a lifetime history of attempted suicide) would have
higher levels of salivary cortisol compared to those with no history
of suicidal behavior and unaffected controls.
A total of 185 individuals participated in the study and
provided at least one salivary cortisol sample. The majority (152
individuals) were enrolled in the Prechter Longitudinal Study. One
subject subsequently retracted their consent, the salivary samples
from one subject were missing at time of analysis, the saliva
volume from two individuals was insufficient for analysis and
three individuals did not complete enough of the diagnostic
interview to reach a diagnosis. Of the remaining 178, 118 (66.3%)
had a diagnosis of bipolar I, 14 (7.9%) had bipolar II with recurrent
depression, 7 (3.9%) had schizoaffective disorder—bipolar type, 8
(4.5%) had other affective diagnosis (depressive disorder NOS,
MDD, Bipolar II with single depressive episode), 2 (1.1%) had only
non-affective diagnoses (alcohol abuse and dependence) and 29
(16.3%) were unaffected controls. For the purpose of this study,
those with bipolar I, bipolar II with recurrent depression and
schizoaffective disorder bipolar type were grouped together as the
bipolar group (N ¼139) and were categorized based on reported
suicide history obtained during the Diagnostic Interview for
Genetic Studies (DIGS) (Kamali et al., 2012).
Kamali et al., (2012) found elevated bedtime salivary cortisol in
bipolar individuals with a history of suicide attempts compared to
nonsuicidal bipolar individuals. Secondary analysis of the intensity
of suicidal behavior and level of bedtime cortisol indicated a
positive correlation, with the highest cortisol levels reported in
individuals that had made a past serious suicide attempt. The
difference in bedtime salivary cortisol between suicidal and non-
suicidal bipolar individuals remained significant even after con-
trolling for age and sex, body mass index (BMI), smoking status,
childhood sexual abuse, medications, mood state at time of
sampling and several clinical factors related to course and severity
of illness (substance use disorders, chronicity of illness, rapid
cycling, mixed states, years of illness, age of onset, anxiety and
psychosis). This is a strong indicator that their finding is related to
the presence of a past history of suicidality and not related to
severity of illness, mood state, or demographic confounders. The
presence of this finding during different mood states and also in
the euthymic state indicates that hyperactivity of the HPA axis is a
biological marker related to suicidality in bipolar disorder and
warrants more detailed investigation (Kamali et al., 2012).
The difference between bipolar participants with and without
suicidal behavior was only 0.05 μg/dl. Currently, the test has low
sensitivity and specificity in detecting individuals with suicidal
history in practical clinical applications. However, the observation
of a sustained correlation between increasing suicidality and
cortisol levels while controlling for confounding clinical and
biological factors clearly indicates the relevance of HPA axis
abnormalities in this potentially lethal clinical condition (Kamali
et al., 2012).
249
Several potential risk factors have been linked to suicidal
behavior. Two of these include personality factors and Polyunsa-
turated fatty acids (PUFA) serum levels. It is unknown whether
PUFA serum levels are associated with personality factors and if
these may interact to affect suicidal behavior (Evans et al., 2012).
Supplementation with the long-chain n-3 (n-3) fatty acids, doc-
osahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), either
as stand alone or adjunctive therapies have shown efficacy in the
treatment of bipolar disorder (Evans et al., 2012). Epidemiological
studies have pointed to an association between n-3 and n-6
dietary intake and lifetime prevalence of bipolar disorder. Popula-
tions that consume greater long-chain n-3 s and less long chain
n-6 s have a lower incidence of bipolar disease (Evans et al., 2012;
Hibbeln et al., 2006).
N-3 intake inversely associates with violent behavior and
suicidality, Evan et al. hypothesize that serum levels of the long
chain n-3 s, DHA and EPA, may positively associate with person-
ality factors that may be protective against suicide behavior and/or
negatively associate with personality factors that, themselves,
associate with increased risk of suicide behavior (Evans et al.,
2012). Several studies suggest that BD patients' previous suicide
attempt(s) may indicate that they are more than 50% more likely
to go on to complete suicide (Ruengorn et al., 2012; Tsai et al.,
2002; Isometsa et al., 1994).
Identifying metabolic or dietary factors that influence factors
associated with psychiatric illness may provide a path to improv-
ing therapeutic tools. Evans et al. found associations between lipid
profiles and suicidal history in bipolar subjects (Evans et al., 2012).
These data further support a link between essential fatty acid
metabolism and mood disorders. While the current pilot study is
an observational, cross-sectional study, it raises important ques-
tions regarding potential causative roles for lipid profiles in
regulating personality phenotypes that may impact the treatment
of bipolar disorder. Nevertheless, the fact that personality factors,
promoted as trait markers in bipolar disorder are not entirely
stable (Barnett and Huang, 2010) and longer-term longitudinal
studies are necessary to examine the relationship between per-
sonality traits and fatty acid profiles. Evans et al., (2012)
Of significant interest is the co-occurrence of metabolic dis-
turbances in bipolar disorder, particularly obesity (Gomes et al.,
2010). Gomes, et al. find adds to the notion that obesity is a
correlate of severity in patients with bipolar disorder. Obese
patients usually have more markers of illness severity, such as
more previous affective episodes (Fagiolini et al., 2002) and suicide
attempts (Fagiolini et al., 2004; Fagiolini et al., 2005; Wang et al.,
2006). Recent data have stressed common features in the under-
lying pathophysiology of obesity and bipolar disorder. Leptin, a key
hormone in regulation of adiposity has been shown to be posi-
tively associated with risk for depression in a prospective study
(Pasco et al., 2007). Disturbances in metabolic pathways such as
insulin-mediated glucose homeostasis, overactivation of the
hypothalamic–pituitary–adrenal axis, dysregulated immune and
inflammatory processes and adipocytokines profiles are present in
both conditions (Gomes et al., 2010; McIntyre et al., 2007).
4.5. Risk factors associated with psychological causes
BD is a frequent and chronic psychiatric disorder associated with
an increase in all-cause mortality (Ösby et al., 2001; McIntyre and
Konarski, 2004; McIntyre et al., 2008). In particular, among mental
disorders, BD is one of the leading causes of suicidal behaviors and
this is a major issue in the management of the disease (Parmentier
et al., 2012). Mixed-states and well as depressions are strongly
associated with suicidal behavior in patients with BD (Algorta
et al., 2011; Baldessarini et al., 2012; Azorin et al., 2009; Pompili
et al., 2009; Baldessarini et al., 2010; Undurraga et al., 2011).
250 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254
Bipolar disorder is strongly associated with suicidal ideations,
attempts and commissions (Shabani et al., 2013). Cyclothymic
temperament may influence suicide risk on multiple levels, from
determining emotional reactivity in stressful situations at the level
of the personality, through determining illness and illness course
characteristics, to influencing within-episode dynamics (Rihmer
et al., 2013).
There are also no previous studies investigating the role of
possible mediating factors, such as hopelessness, in the association
between affective temperaments and suicidal behavior. Because it
is well known that patients with BD-II are at a higher risk for
attempting and completing suicide (Pompili et al., 2009; Rihmer
and Pestality, 1999) and that hopelessness has been found to be a
good predictor of suicidal behavior (Beck et al., 1990; Akiskal,
2007), understanding the relationship between these factors, and
the possibly differential association of these factors, in patients
with BD-I and BD-II disorders would give us better insight in to the
nature of the emergence of suicidal behavior (Pompili et al., 2012).
The finding of hopelessness as the most important variable
when compared with depression is consistent with the nature of
these psychopathological features (Acosta et al., 2012). A recent
meta-analysis revealed that previous suicide attempts and hope-
lessness were the main risk factors for suicide, and that early
onset, depressive symptoms, and family history of suicide were
the main risk factors for nonfatal suicide related behavior (Ryu
et al., 2010; Hawton et al., 2005). We cannot dismiss the possibility
that hopelessness may also, at least in part, represent a conse-
quence of a more severe course of illness, especially those with
lifetime depressive burden, and predispose to suicidality from that
perspective as well (Acosta et al., 2012). Hopelessness about the
future in suicidal individuals is a multi-faceted construct but lack
of positive future thinking is more important than presence of
negative future thinking (Fountoulakis et al., 2012).
Patients with bipolar disorder have recurrent fluctuating mood
episodes with functional impairment, (Weinstock and Miller, 2008)
which might induce chronic distress and increase suicide related
behaviors (Ryu et al., 2010; MacKinnon et al., 2003). Because suicide
and suicidal behaviors are the result of a combination of individual risk
factors, precipitating stressors, and current disease features, the
prediction of a suicide attempt for a given patient on the basis of risk
factors statistically associated with suicide or suicide attempts in
populations of patients with bipolar disorder is difficult (Song et al.,
2012). For Pompili et al. not only the absolute elevations of each
temperament may be associated with psychopathological symptoms
but also that the individual pattern of temperaments may be
associated with a higher suicidal risk (Pompili et al., 2012). However,
what we so far know about the risk factors associated with suicidal
thinking and behavior in bipolar disorder has overwhelmingly been
derived by studying individuals who are in the “acute” phase of their
disorder (Acosta et al., 2012).
Many studies have investigated clinical characteristics asso-
ciated with suicidal behavior. Gender has been associated with
suicidal behavior in BD: men have a 4-fold greater risk for suicide
than women (Suicidology AAo, 2000; American Psychiatric
Association, 2003; World Health Organization WHO, 2003). Rela-
tive to the risk in the general population, BD is associated with an
increased risk of suicidal behavior in women and a higher lethality
in men (Parmentier et al., 2012).
In particular, careful evaluation and effective management of
bipolar depression among patients with mood disorder during
major depressive episodes is necessary to prevent suicide attempts
in bipolar disorder (Ryu et al., 2010). While suicidal ideation and a
history of attempted suicide are among the most important risks
for suicide (Osman et al., 2001; Kuo et al., 2001), only a few studies
have taken into account both suicidal ideas and attempts in
assessing the risk factors (Suttajit et al., 2013). The characteristics
associated with suicidal behavior in patients with BD may stimu-
late the development of specific therapeutic strategies; these may
include emotional and hostility regulation and problem-solving
therapies or specific treatment of comorbid social phobia or
addiction (Parmentier et al., 2012; Gray and Otto, 2001; Stewart
et al., 2009). Suicide prevention strategies are currently based on
screening for the numerous risk factors (de Moraes et al., 2013).
4.6. Risk factors associated with components of religious and
spiritual components
Religiosity and Spirituality are important aspects to identify
groups at risk of suicide in BD. However, there is a lack of studies
on their impact on bipolar disorder and little is known about them
(Azorin et al., 2013).
Dervic et al. (2011) related higher score on the moral or
religious objections to suicide subscale of the Reason for Living
Inventory (RFLI) with fewer suicidal acts in depressed bipolar
patients. The strength of this association was comparable to that of
aggression scores and suicidal behavior, and had an independent
effect. A possible protective role of moral or religious objections to
suicide deserves consideration in the assessment and treatment of
suicidality in bipolar disorder. In this study (Dervic et al., 2011),
patients who reported religious affiliation were compared with 51
patients without religious affiliation in terms of sociodemographic
and clinical characteristics and history of suicidal behavior. The
results were patients with religious affiliation had comparatively
higher scores on the moral or religious objections to suicide
subscale of the RFLI, lower lifetime aggression, and less comorbid
alcohol and substance abuse and childhood abuse experience
(Dervic et al., 2011).
In another hand, Azorin et al. (2013) identified another point of
view. In their sample, Compared to Low Religious Involvement
(LRI), High Religious Involvement (HRI) patients did not differ with
respect to their religious affiliation but had a later age at onset of
their affective illness with more hospitalizations, suicide attempts,
associated hypomanic features, switches under antidepressant
treatment, prescription of tricyclics, comorbid obsessive compul-
sive disorder, and family history of affective disorder in first-
degree relatives. The following independent variables were asso-
ciated with religious involvement: age, depressive temperament,
mixed polarity of first episode, and chronic depression. The study
concluded that in depressive patients belonging to the bipolar
spectrum, high religious involvement associated with mixed
features may increase the risk of suicidal behavior, despite the
existence of religious affiliation.
The current study (Azorin et al., 2013) may help understand
some potential negative effects of religious involvement in depres-
sive patients belonging to the bipolar spectrum. First of all, their
findings may be in line with the hypothesis of Cruz et al. (2010)
that higher levels of distress as such caused by mixed episodes
and/or chronic depression, would prompt patients to seek relief
from religion, and therefore increase the frequency of their
religious behaviors. However, it could be that, once depressed,
HRI patients become the victims of their religious commitment
and that, in this case, religion exerts harmful effects on health.
Actually, for an individual with depressive temperament char-
acterized by a rigid duty - orientation of his behavior, which
distinguishes itself by an overidentification with what is norma-
tively expected or by a meticulous fulfillment of social norms
(Tellenbach, 1974), experiencing hypomanic social desinhibition
may hardly be assimilated in his usual way of life. This “egodys-
tonic” experience could therefore appear to consciousness under
the form of obsessive thoughts such as the “fear of committing a
sin” or an “excessive guilt” and give rise to compulsive religious
behaviors, such as those found in our HRI patients. In those cases,
 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254
it is likely that religious involvement may aggravate their guilt
feelings or the sinful character of their hypomanic experiences,
enhancing thereby the suicidal tendencies. This may contribute to
explain why in the case of some mixed depressive patients,
religiosity is unlikely to be associated with less suicidal behavior
(Azorin et al., 2013).
The last study (Pawlak et al., 2013) confirms what Dervic et al.
analyzed, affirming that subjective sense of religious involvement
may play a protective role in some communities (Sisask et al.,
2010). Patients, who have not declared their commitment to any
religion, undertook suicidal attempts significantly more often and
had more relatives, who had died of suicide, in comparison with
those involved in religion (Dervic et al., 2004).
5. Conclusion
The results of the studies in the literature show that the risk
factors associated with bipolar disorder and suicide exist and are
relevant to clinicians and researchers, whereas knowledge of such
influence better diagnosis and prognosis of BD cases involving
suicide risk. Notwithstanding the differences in some points of the
studies, research becomes important to maintain the high quality
of knowledge of the disorder and its peculiarities, seeking
improved quality of life for people suffering from bipolar disorder.
Role of funding source
We have no foundation source.
Conflict of interest
Mr. Costa, Mr. Alencar, Mr. Nascimento and Drs. Maria do Socorro, Cláudio,
Sally, Regiane, Bianca, Roberto, Marcos Antonio, Alberto and Modesto have no
conflicts of interest or financial ties to report.
Acknowledgments
The authors of this review would like to thank the support of the Suicidology
Research Group, Federal University of Ceará (UFC/Brazil)/Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq/Brazil) and the Laboratório de
Escrita Científica (LABESCI/Brazil)—Medical School of Federal University of Cariri
(UFCA/Brazil).
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