You are on page 1of 18

Journal of Affective Disorders 170 (2015) 237–254

Contents lists available at ScienceDirect

Journal of Affective Disorders

journal homepage:


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
Laboratório de Escrita Científica, Faculdade de Medicina, Universidade Federal do Cariri, UFCA, Barbalha, Ceará, Brazil
Programa de Pós-Graduação em Ciências da Saúde, Faculdade de Medicina do ABC, Santo André, São Paulo, Brazil
Faculdade de Medicina, Universidade Federal do Cariri, UFCA, Barbalha, Ceará, Brazil
Programa de Pós-Graduação em Saúde Pública, Faculdade de Saúde Pública, Universidade de São Paulo, USP, São Paulo, São Paulo, Brazil
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
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.


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

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: (L.d.S. Costa).
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
with the theme object of the present review. The search strategy
Bipolar disorder confers the highest risk of suicide among and the retrieved articles were reviewed on two separate occa-
major psychological disorders (Goldstein et al., 2012; Goodwin sions to ensure adequate sampling. A similar search strategy was
and Jamison, 2007). Suicide attempts and completed suicide are performed in the PubMed database, using the aforementioned
significantly more common in patients with bipolar disorder when terms and their correspondent terms.
compared with the general population (Eroglu et al., 2013; Simon The article analysis followed previously determined eligibility
et al., 2007; Weissman et al., 1999). criteria. We adopted the following inclusion criteria: Goldstein
Bipolar spectrum disorders, especially recurrent depressive epi- et al. (2012) references written in English; Goodwin and Jamison
sodes, is the major risk of repeated suicide attempt and co-morbidity (2007) studies pertaining suicide risk factors in bipolar affective
of another psychiatric disorders increase highly the risk of suicide disorder; Eroglu et al., (2013) original articles with online acces-
reattempt (Kheirabadi et al., 2012). In particular, among mental sible full text available in database SCOPUS, PubMed or CAPES
disorders, bipolar disorder is one of the leading causes of suicidal (Higher Education Co-ordination Agency) Journal Portal
behaviors and this is a major issue in the management of the disease. (, 2014), a virtual library linked to Brazil's
About 50% of patients with bipolar disorder will experience at least Ministry of Education and subjected to content subscription;
one suicide attempt (Jamison, 2000) and 11–19% will commit suicide (Simon et al., 2007) articles that included in the title at least one
(Goodwin and Jamison, 2007; Abreu et al., 2009; Angst et al., 2005; combination of terms described in the search strategy; (Weissman
Harris and Barraclough, 1997; Parmentier et al., 2012). et al., 1999) case reports, cohort studies, controlled clinical trials
This study is based on the following research question: what is and case-control studies; Kheirabadi et al. (2012) articles that
the main suicide risk factors associated with bipolar disorder? This appear in more than one database will be included only once,
issue has gained great impact in recent years with the establish- giving priority to the SCOPUS database. Exclusion criteria were:
ment of new risk factors for suicide and bipolar disorder. Thus, this Goldstein et al. (2012) studies that did not include the proposed
systematic review aims to present the main risk factors and topic; Goodwin and Jamison (2007) non-original studies, including
compares them, since the applicant was disagreement among editorials, reviews, prefaces, brief communications and letters to
authors. Therefore, it is suggested, that further studies are needed the editor.
in order to establish a stronger relationship between bipolar Then, each paper in the sample was read in entirety, and data
disorder and its risk factors that culminate in suicide. 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
2. Methods factors associated with bipolar disorder, but also to the risk factors
in other psychiatric disorders, such as schizophrenia and mood
We performed a qualitative systematic review of articles about disorder; because the focus of this study was the risk factors
suicide risk factors in bipolar affective disorder in previously associated with suicide in bipolar disorder, studies related to
chosen electronic databases. psychiatric disorders in general were not recorded or analyzed
A search of the literature was conducted via PubMed and for this study.
SCOPUS online databases in April 2014 and was limited to articles To provide a better analysis, the next phase involved comparing
published from January 1, 2010 to April 6, 2014. The reason for the studies and grouping. For heuristic reasons, the results regarding
limiting the search to 2010–2014 was that, during this period, the studied subject into six categories: Risk factors associated with
there was an expansion of research into new types of comorbid- sociodemographic components; Risk factors associated with genetic
ities that influence the risk of suicide in Bipolar disorder, such as components; Risk factors associated with Medicines and Drugs in
hopelessness, altitude and religiosity. Therefore, the Bipolar Affec- general that interfere with bipolar disorder; Risk factors associated
tive Disorder and its association with suicide had greater relevance with Biological components; Risk factors associated with Psycholo-
in the scientific community. gical causes; and Risk factors associated with components of Reli-
Initially, the search terms browsed in SCOPUS database were 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) 237–254 239

in the final sample Fig. 1). Articles from SCOPUS and PubMed (Bellivier et al., 2011; Yoon et al., 2011; Leon et al., 2012; Arias
database matched the inclusion criteria of the present study. et al., 2013; Clements et al., 2013; Finseth et al., 2012; Oquendo
Table 1 provides an overview of all studies included in the final et al., 2010; Kenneson et al., 2013); Risk factors associated with
sample and of all data elements used during the data analysis Biological components (three studies) (Kamali et al., 2012; Evans
process. Study designs included one case report (Kerner et al., et al., 2012; Gomes et al., 2010); Risk factors associated with
2013), seven transversal studies (Goldstein et al., 2012; Kheirabadi Psychological causes (seven studies) (Parmentier et al., 2012;
et al., 2012; Undurraga et al., 2012; De Abreu et al., 2012; Algorta Shabani et al., 2013; Pompili et al., 2012; Acosta et al., 2012;
et al., 2011; Evans et al., 2012; Gomes et al., 2010), nineteen cohort Song et al., 2012; Suttajit et al., 2013; Stewart et al., 2009); and Risk
studies (Parmentier et al., 2012; Huber et al., 2014; Ruengorn et al., factors associated with components of Religious and Spiritual
2012; Etain et al., 2013; Cassidy, 2011; Baldessarini et al., 2012; (three studies) components (Azorin et al., 2013; Dervic et al.,
Bellivier et al., 2011; Sears et al., 2013; Jiménez et al., 2013; Leon 2011; Pawlak et al., 2013). Among the 42 studies, 8 discussed about
et al., 2012; Finseth et al., 2012; Oquendo et al., 2010; Kenneson “suicide risk factors in Bipolar Affective disorder” — more broadly
et al., 2013; Gilbert et al., 2011; Shabani et al., 2013; Pompili et al., (Goldstein et al., 2012; Eroglu et al., 2013; Kheirabadi et al., 2012;
2012; Acosta et al., 2012; Song et al., 2012; Suttajit et al., 2013), and Undurraga et al., 2012; Etain et al., 2013; Baldessarini et al., 2012;
fifteen case-control studies (Eroglu et al., 2013; Antypa et al., 2013; Pawlak et al., 2013; Gilbert et al., 2011), being refered in more than
Ryu et al., 2010; Manchia et al., 2013; Neves et al., 2010; Magno one category. The categorization of studies aims to a better
et al., 2011; Yoon et al., 2011; Arias et al., 2013; Clements et al., organizational quality systematic review and it is not compulsory
2013; Pawlak et al., 2013; Kamali et al., 2012; de Moraes et al., that each article must be referenced only in their respective
2013; Azorin et al., 2013; Dervic et al., 2011; Pawlak et al., 2013). category.
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; 4. Discussion
Ruengorn et al., 2012; Algorta et al., 2011; Cassidy, 2011; Antypa
et al., 2013; Ryu et al., 2010); Risk factors associated with genetic Bipolar disorder (BD) is a major public health concern worldwide,
components (six studies) (Manchia et al., 2013; Sears et al., 2013; and is associated with significant morbidity and mortality (Kupfer,
Neves et al., 2010; Magno et al., 2011; Jiménez et al., 2013; Kerner 2005). In addition to an increased rate of death by suicide, community
et al., 2013); Risk factors associated with Medicines and Drugs in and clinical studies indicate that bipolar patients usually present a
general that interfere with bipolar disorder (eight studies) broadrange of comorbid general medical conditions, which contribute

Fig. 1. Flow chart showing study selections for the review. Abbreviations MeSH, Medical Subject Headings.
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 Of the 652 subjects, 42.9% had experienced at least
et al. (2012) features with the Diagnostic Interview for Genetics Studies (DIGS) one suicide attempt. Lifetime history of suicidal
and dimensional characteristics with questionnaires measuring behavior was associated with being a woman, a
impulsivity/hostility and affective lability/intensity. 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

Undurraga Journal of Clinical Accordingly, we compared selected demographic and clinical Rates of suicidal ideation (41.5%) and acts (19.7%)
et al. (2012) Psychiatry factors for long-term association with nonlethal suicidal acts or were similarly prevalent with bipolar I and II
ideation in 290 DSM-IV bipolar I (n¼ 204) and II (n¼ 86) disorder disorders and somewhat more common among
patients followed for a mean of 9.3 years at the University of women. Factors significantly and independently
Barcelona, using preliminary bivariate comparisons followed by associated with suicidal acts were determined by
multivariate logistic regression modeling. 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

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 Twenty PBD patients had lifetime suicide attempts,
(2011) outpatient clinics with DSM-IV diagnoses of bipolar I disorder 63 had past or current suicide ideation, and 55 were
(n¼ 27), bipolar II disorder (n¼ 18), cyclothymic disorder (n¼ 48), free of suicide ideation and attempts. Attempters
and bipolar disorder not otherwise specified (n ¼45). 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 Of the 2,219 patients who provided data on their
(1995) (EMBLEM) is a two-year, prospective, observational study that lifetime history of suicide attempts, 663 (29.9%) had
enrolled 3,684 adult patients with bipolar disorder and initiated or a history of suicidal behavior (at least one attempt).
changed oral treatment for an acute manic/mixed episode. 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 We found associations (p r 0.05) between suicide
(1978) Disorders multiplex bipolar pedigrees, comprising 795 individuals, to look for attempt and 12 SNPs of CCKBR and five SNPs of
associations between suicidal behavior and 32 single nucleotide BDNF. After correction for multiple testing, seven
polymorphisms (SNPs) from across the genes brain-derived SNPs of CCKBR remained significantly associated. No
neurotrophic factor (BDNF), cholecystokinin (CCK) and the association was found between CCK and suicidal
cholecystokinin beta-receptor (CCKBR). 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) Single SNP analyses showed that suicide attempters
(2003) Neuropsychopharmacology and IMPA2 (rs66938, rs1020294, rs1250171 and rs630110), INPP1 had higher frequencies of AA genotype of the
(rs3791809, rs4853694 and 909270), GSK3α (rs3745233) and GSK3β rs669838-IMPA2 and GG genotype of the rs4853694-
(rs334558, rs1732170 and rs11921360) genes were genotyped. 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 Prevalence of comorbid SUDs was higher among
(2013) data files for 1999 to 2006. Secondary data analysis was conducted unipolar and bipolar disorder deaths than that
comparing decedents with unipolar/bipolar disorders and among all other deaths. Among unipolar and bipolar
decedents with all other causes of death, based on the death disorder deaths, comorbid SUDs were associated
records of 19,052,468 decedents in the Multiple Cause of Death with elevated risks for suicide and other unnatural
data files who died at 15 years and older 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 In the bipolar and unipolar affective disorders
(2013) Psychiatry sociodemographic and clinical factors, family history and stressful sample, we observed an association between suicidal
life events in patients with diagnosis of unipolar and bipolar attempts and the following: family history of
affective disorder (597 patients, 563 controls). 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% Ninety-three patients (45.1%) had a history of one or
(2013) women) with DSM-IV diagnosed BD-I (n¼140) and BD-II (n¼ 66) more serious suicide attempts. These constituted 60
acutely admitted to a single psychiatric hospital department from (42.9%) of the BD-I patients and 33 (50%) of the BD-II
November 2002 through June 2009 were included. 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 Compared to adolescent-onset, people with
(2001) Replication study, we identified 158 individuals with childhood- childhood-onset bipolar disorder had increased
onset ( o13 years) or adolescent-onset (13-18 years) primary likelihoods of attention deficit hyperactivity disorder
bipolar disorder (I, II or subthreshold). (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

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 Over 30% of the sample was obese and over 50% had
(2012) were consecutively recruited from the Bipolar Disorder Program at a history of suicide attempt. In the multivariate
Hospital das Clínicas de Porto Alegre and the University Hospital at model, obese patients were nearly twice (OR ¼1.97,
the Universidade Federal de Santa Maria, Brazil. 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 Patients with BD-II had higher scores on the BHS
et al. (2011) women) with a Diagnostic and Statistical Manual of Mental (9.78 7 5.37 vs. 6.87 7 4.69; t143.59 ¼  3.94; P
Disorders, Fourth Edition, Text Revision (DSM-IV-TR), BD who were o 0.001) than patients with BD-I. Hopelessness was
admitted to the Sant'Andrea Hospital's psychiatric ward in Rome associated with the individual pattern of
(Italy). 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 The data of 383 bipolar I disorder patients were included in the The demographic/clinical variables significantly
Miller (2008) and Treatment analyses. 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 Religiously affiliated patients had more children and
Organization Psychiatry (DSM-III-R criteria) in a tertiary care university research clinic was more family-oriented social networks than
(WHO) conducted. Patients who reported religious affiliation were nonaffiliated patients. As for clinical variables,
(2003) compared with 51 patients without religious affiliation in terms of religiously affiliated patients had fewer past suicide
sociodemographic and clinical characteristics and history of attempts, had fewer suicides in first-degree relatives,
suicidal behavior. 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 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.

Suttajit et al. General Hospital The aim of the study was looking for suicide risk factors among The main limitations of the study are number of
(2013) Psychiatry personality dimensions and value system in patients with diagnosis participants, lack of data about stressful life events
of unipolar and bipolar affective disorder (n¼ 189 patients, n¼ 101 and treatment with lithium. Novelty seeking and
controls). 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.

to overall mortality rates (Angst et al., 2002; Roshanaei-Moghaddam demonstrated consistent associations between childhood trauma
and Katon, 2009). and more severe clinical characteristics in bipolar disorder .
The risk of suicide for individuals with BD is approximately 60 Moreover, family history of completed suicide had the highest
times greater than that of the general population (Simon et al., odds ratio of significant findings. In previous reports in bipolar
2007). Fifteen to twenty percent of individuals with BD complete cohorts (Galfavy et al., 2006; Valtonen et al., 2006), family history
suicide and up to 40% report at least one suicide attempt during of suicide was no different between bipolar patients with and
their lifetime (Simon et al., 2007). without histories of attempts, although one study reported family
The ratio of suicide attempts to completed suicides for the history was predictive of earlier attempts (Galfavy et al., 2006;
general population is 35:1, but for individuals with BD, the same Cassidy, 2011). Also, the higher frequency of bipolar disorder
ratio is 3:1 (Simon et al., 2007). In fact, it is estimated that BD may family history in agitated depression suggests that a bipolar
account for one-quarter of all completed suicides (American vulnerability may be required to obtain such clustering of hypo-
Psychiatric Association, 2013; Huber et al., 2014). manic symptoms (Akiskal et al., 2005). Overall, findings support an
However, unlike other authors included in this review, association between family functioning and suicidality within
Undurraga et al., (2012) concluded that suicidal risk-factors found families where youths have bipolar disorder (Miklowitz and
to be independent of bipolar disorder. This fact, as well as the Chang, 2008). Results suggest that it is plausible that the youth's
different conclusions reached by the authors, which will be illness may play an active role in disrupting family processes.
demonstrated below, exposes the need for further research. Bipolar disorder may involve a potent combination of mood
dysregulation and interpersonal processes where threats of harm
4.1. Risk factors associated with sociodemographic components — against oneself or another — may occur both impulsively and/or
instrumentally (Algorta et al., 2011). In fact, bipolar disorder
Quality of life seems to be associated with suicidal behaviors imparts the greatest risk for completed suicide among youth
(i.e., suicidal ideation, suicide attempts, and complete suicide) in (Goldstein et al., 2012).
the general population and in psychiatric patients (De Abreu et al., With regard to age groups at risk for suicidal behavior, prior
2012). literature suggests that young-aged patients are at higher risk of
A recent review showed that Quality of Life (QoL) is markedly suicide compared to older patients, in line with the finding of this
impaired in patients with BD, even when they are clinically report. Studies with depressed patients have shown that young
euthymic (De Abreu et al., 2012; Michalak et al., 2005). Also, patients report a higher number of suicide attempts (Blair-West
stressful life event(s) was another preponderant factor predicting et al., 1999; Antypa et al., 2013; Azorin et al., 2010). Although no
suicide attempts, and has played an important role in predicting association was found between age and suicide attempts (Azorin
suicide attempts among BD patients in many studies, particularly et al., 2009). Studies of adolescent suicide completers document
during depressive phases (Azorin et al., 2009; Ruengorn et al., the substantial contribution of parental depression to offspring
2012). suicide risk (Gould et al., 1996), even after accounting for the
De Abreu et al. (2012) hypothesized that patients with BD and child's depressive severity (Brent et al., 1993). It is possible that
previous suicide attempts would have worse QoL than patients familial depression contributes to offspring suicide risk via multi-
with BD but no previous suicide attempts . It is possible that low ple avenues, including decreased familial support and increased
QoL may reflect the existence of poor coping skills and inadequate conflict (Goldstein et al., 2012; Brent et al., 1994).
social support, which in turn may increase the risk for suicide Ryu et al. (2010) investigated the descriptive characteristics of
attempts (De Abreu et al., 2012). Further prospective studies are suicide attempts and the risk factors for suicide attempts in Korean
needed to clarify the causal and temporal relationships between bipolar patients by assessing sociodemographic factors, clinical
low QoL and suicide attempts (De Abreu et al., 2012). factors, and the methods of suicide attempts using retrospective
Pediatric Bipolar Disorder (PBD), for example, is associated reviews of medical records . Ryu et al. (2010) reviewed medical
with substantially lower average QoL than found with many other records of all 601 patients who were admitted to the psychiatric
major medical illnesses, and worse than other mental illnesses in wards in one mental hospital and three general hospitals (Ryu
youth except for major depression (Freeman et al., 2009; Algorta et al., 2010). The 579 subjects who were included in the final
et al., 2011). Suicidality and lower youth QoL both were signifi- analysis was comprised of 262 (45.3%) men and 317 (54.7%)
cantly associated with worse family functioning (Algorta et al., women (Ryu et al., 2010).
2011). Poor family functioning, poor youth QoL, and mixed Ryu et al. (2010) found two significant risk factors associated.
features will each make unique contributions to suicidality as an First, they found that patients with depressive first episodes
outcome variable (Algorta et al., 2011). Also, Etain et al. (2013) appear to be higher in suicide attempters. Bipolar patients with
L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254 247

a depressive episode at their initial admission or first episode tend changes associated with hypoxia may lead to depression, instabil-
to have a depressed mood at the next episode (Daban et al., 2006; ity of mood, and increased risk of suicide (Huber et al., 2014;
Perugi et al., 2000). Moreover, 60% of suicide attempters with Vaccari et al., 1978).
depressive episodes commit suicide at the first mood episode
(Balázs et al., 2003). Prolonged exposure to depressive episodes 4.2. Risk factors associated with genetic components
might increase the risk of suicide attempts in bipolar patients and
poor prognostic factor in suicide related behavior (Valtonen et al., Suicide attempt was defined as an intentional self-inflicted
2006; Ryu et al., 2010). Second it was observed that bipolar II injury with self-destructive intent (Manchia et al., 2013). Globally,
patients have a higher risk for suicide attempts. Bipolar II patients approximately one million individuals commit suicide each year
are known to have greater risk of suicide than bipolar I patients (WHO, 2011; Sears et al., 2013). Suicidal behavior is a matter of
(Balázs et al., 2003; Arató et al., 1988). Bipolar II patients show a major concern in the management of BD patients for many
predominantly depressive mood, mood lability, and mixed nature reasons. First, their suicide rates are about 60 times higher than
(Akiskal et al., 1995; Benazzi 2007). Bipolar II patients are likely to that observed in general population. Second, about one third to
have depressive or mixed episodes at hospital admission rather half of these patients will make at least one suicide attempt during
than bipolar I patients (Ryu et al., 2010). Also, there is a stronger their disease. Finally, their suicide acts have a higher lethality as
continuous relationship of suicidal risk with the proportion of total suggested by a much lower ratio of attempted suicide (approxi-
recurrences that were depressive-or-mixed vs. depressive mately 3:1) than in the general population (approximately 30:1)
(Baldessarini et al., 2012). Baldessarini et al. (2012) has shown a (Baldessarini et al., 2006; Neves et al., 2010).
strong association of predominant depression, especially with Although many data have suggested that BD confers a higher
mixed-episodes included, with suicidal behavior. risk of suicide than other psychiatric illnesses (Sajatovic, 2005),
Furthermore, suicide attempts were observed in both males and few studies have yet been conducted to investigate the contribu-
females at similar rates. Moreover, females who attempted suicide tion of the genetic component (Magno et al., 2011).
were as likely to have attempted suicide by a more violent method as Genetic variation plays an important role in BD and suicide
males (Cassidy, 2011). Although, it was observed that some authors susceptibility. However, little is known about the genetic influence
categorized the female gender as a risk factor (Bellivier et al., 2011). on the risk of suicide, particularly in BD patients (Magno et al.,
Parmentier et al. (2012) observed that reported rates of suicide 2011). The liability to suicidal behavior is influenced by genetic
attempts among women with bipolar disorders are about twice as factors (particularly family history of suicidal behavior and Major
high as among men with bipolar disorders, suggesting greater Affective Disorders) (Manchia et al., 2013).
lethality of suicide attempts in men (Parmentier et al., 2012; In addition, genetic determinants such as polymorphisms
Suicidology AAo, 2000; Tondo et al., 2006). within the tryptophan hydroxylase 1 (TPH1; Gene ID 7166 in
Ruengorn et al. (2012) proposed a risk-scoring scheme for 11p15.3–p14) and the tryptophan hydroxylase 2 (TPH2; Gene ID
suicide attempts in Thai patients with BD. Ruengorn et al. (2012) 121278 in 12q21.1) genes were found to be associated with suicide
conducted a study at Suanprung Psychiatric Hospital, a total of 489 attempts of high lethality and with completed suicides, respec-
patients' medical files were reviewed and included in the final tively (Manchia et al., 2013; Galfalvy et al., 2009; Lopez et al.,
analysis. Results revealed that suicide attempters were younger, 2007). These findings are of interest considering the association
single, did not have children, and had little or very little social between altered serotonin system function in the brain and
support. They reported experiencing more stressful life events, suicide (Manchia et al., 2013). Neves et al. (2010) showed that
reported being depressed, had suffered from BD at an early age, serotonin polymorphism (5-HTTLPR; Gene ID 6532 in 17q11.2) is
had a family history of suicide, had previously attempted suicide, strongly associated with violent suicidal behavior in BD patients.
had previous suicidal ideation, alcohol use, and were prescribed Their results could be an important step to create a genetic tool for
antipsychotics, antidepressants, anxiolytics, and mood stabilizers long-term suicide prediction (Neves et al., 2010). Biological mar-
(Ruengorn et al., 2012). Using multivariate logistic regression, the kers, such as 5-HTTLPR (Gene ID 6532 in 17q11.2), could help for
author found six indicators of suicide attempts: depressive epi- identification of potential suicide attempters (Neves et al., 2010).
sodes, previous suicide attempt(s), stressful life event(s), inter- Several lines of evidence indicate that brain-derived neuro-
mittent or poor medication adherence, and shorter duration of BD trophic factor (BDNF; Gene ID 627 in 11p13) is a good candidate
treatment. Psychotic symptom(s) provided an inverse association gene for involvement in suicidal behavior. Post-mortem studies
with suicide risk (Ruengorn et al., 2012). have shown that the expression of BDNF (Gene ID 627 in 11p13) is
Moreover, the altitude was seen as a significant risk factor significantly reduced in individuals that have committed suicide,
(Huber et al., 2014). Several biological theories may explain an regardless of psychiatric diagnosis (Sears et al., 2013; Dwivedi
altitude-suicide association. Dopamine and serotonin are neuro- et al., 2003; Karege et al., 2005). Moreover, an association between
transmitters associated with pleasure, reward, and mood. BDNF (Gene ID 627 in 11p13) gene and violent Suicide Attempt (SA)
Decreased levels of serotonin and increased levels of dopamine has been also detected in a sample of this patients (Neves et al.,
and norepinephrine associated with hypoxia at higher altitudes 2011; Jiménez et al., 2013). In addition, brain-derived neurotrophic
may lead to increased irritability, depression, and suicide (Huber factor (BDNF; Gene ID 627 in 11p13) and lithium, well known
et al., 2014; Trouvin et al., 1986; Jou et al., 2009). therapeutic drug in mood disorder (Fountoulakis et al., 2008),
Converging lines of evidence also indicate that mitochondrial reduces FoxO3a (Gene ID 2309 in 6q21) transcriptional activity
dysfunction plays a role in the pathophysiology of BD and may (Magno et al., 2011; Mao et al., 2007; Zhu et al., 2004). FoxO3a
influence the severity of episodes (Scaglia, 2010; Quiroz et al., (Gene ID 2309 in 6q21) influences distinct behavioral processes
2008; Kato, 2006). Studies of patients with mitochondrial disease linked to anxiety and depression. Recently, a study using a
show that both adults (Fattal et al., 2006, 2007) and children knockout (KO) mice model suggested that FoxO3a (Gene ID 2309
(Morava et al., 2010; Koene et al., 2009) have elevated rates of in 6q21) may be a transcriptional target for anxiety and mood
depressive symptoms. Metabolic stress due to hypoxia may have disorder treatment (Magno et al., 2011; Polter et al., 2009). These
important considerations for individuals with BD. Hypoxia due to data suggest that FOXO3A (Gene ID 2309 in 6q21) is a novel
reduced oxygen partial pressure at higher altitudes may further susceptibility locus for BD, but not for suicidal behavior in BD
decrease mitochondrial function in individuals with BD (McIntyre patients. These results may contribute to a better understanding of
et al., 2008; Rezin et al., 2009). For these individuals, metabolic 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 substance use disorders had stronger effects on suicide among
behavior (Jiménez et al., 2013). Jiménez et al. (2013) suggest that females, whereas their effects on other unnatural deaths were
genetic variability at rs669838-IMPA2 (Gene ID 3613 in 18p11.2), stronger among males (Yoon et al., 2011).
rs4853694-INPP1 (Gene ID 3628 in 2q32), rs1732170- GSK3b According to the National Epidemiologic Survey on Alcohol and
(Gene ID 2932 in 3q13.3) and rs11921360-GSK3b (Gene ID 2932 Related Conditions (NESARC) estimates, among individuals with
in 3q13.3) genes is associated with a higher risk of attempting 12-month unipolar depressive disorder, 14.1% had alcohol use
suicide in bipolar patients (Jiménez et al., 2013). It is known that at disorders (AUD) and 4.6% had drug use disorders (DUD). These
therapeutic concentrations, lithium immediately inhibits several represented significantly elevated risks for the comorbid sub-
enzymes, such as both isoenzymes (1 and 2) of inositolmonopho- stance use disorders (Yoon et al., 2011; Hasin et al., 2005). In a
sphatase (IMPA), inositolpolyphosphate-1 phosphatase (INPP1), sample consisted of 837 outpatients from Madrid, Spain. Arias
phosphoglucomutase and glycogen synthasekinase-3b (GSK3b) et al., (2013) compared 528 subjects with a lifetime diagnosis of
(Jiménez et al., 2013; Quiroz et al., 2004; Serretti et al., 2009). alcohol abuse or dependence and 182 with other substance use
The phosphoinositol pathway is associated with cellular activities disorders (SUDs) not involving alcohol. The Mini International
such as metabolism, secretion, phototransduction, cell growth and Neuropsychiatric Interview (MINI) was used to evaluate Axis I
differentiation (Jiménez et al., 2013; Serretti et al., 2009). disorders and the Personality Disorder Questionnaire to evaluate
The question remains how genetic risk factors contribute to the personality disorders. It was considered that 76.1% of the alcohol
manifestation of bipolar disorder. If we could answer this question, addicts had a current dual diagnosis, the most prevalent being
early intervention and effective treatment could become a reality mood and anxiety disorders. Fifty-two percent had a personality
(Kerner et al., 2013). Heritable factors have important effect on disorder and most of them (81.6%) had other SUDs Compared to
susceptibility to suicidal behavior, which is supported by several people with bipolar disorder alone, those who have bipolar
studies showing that genetic polymorphisms play a role in suicide disorder with comorbid SUD have an increased prevalence of
risk (Magno et al., 2011; Galfalvy et al., 2009; Magno et al., 2010; suicide attempts (Sublette et al., 2009; Dalton et al., 2003; Lopez
Roy and Segal, 2001). Strong heritability of bipolar disorder has et al., 2001; Oquendo et al., 2010; Potash et al., 2000; Kenneson
been supported by many studies, but the identification of causal et al., 2013).
variants has been challenging (Kerner et al., 2013). Gilbert et al. (2011) identified the extremely difficult to predict
suicidal behavior, even when comprehensive clinical information
4.3. Risk factors associated with medicines and drugs in general that is available. However, empirical evidence has shown that people
interfere with bipolar disorder with mood disorders and/or substance use disorders experience
excess mortality (Yoon et al., 2011; Amaddeo et al., 1995; Black
Prevalence of comorbid substance use disorders was higher et al., 1985; Bruce et al., 1994; Cuijpers and Smit, 2002; Harris and
among unipolar and bipolar disorder deaths than that among all Barraclough, 1998; Hiroeh et al., 2001; Mykletun et al., 2007;
other deaths. Among unipolar and bipolar disorder deaths, comor- Wulsin et al., 1999). Actually, only a few studies have examined the
bid substance use disorders were associated with elevated risks for association between mood disorders and other causes of unnatural
suicide and other unnatural death in both males and females death (Black et al., 1985; Hiroeh et al., 2001; Mykletun et al., 2007;
(Yoon et al., 2011). Antiepileptic drugs are approved for the Gau and Cheng, 2004; Joukamaa et al., 2001; Ösby et al., 2001),
treatment of epilepsy, bipolar disorder, and neuropathic pain. Each despite the fact that individuals with mood disorders, especially
of these conditions is associated with an elevated risk of suicide those with bipolar disorder, are more likely to engage in fatal
(Simon et al., 2007; Christensen et al., 2007; Nilsson et al., 2002; accidents due to impaired attention and concentration (Stahl,
Ratcliffe et al., 2008; Tsai et al., 2002; Leon et al., 2012). Alcohol 2000) or to be victims of homicide due to affective psychoses
addicts were associated with diagnoses of several types of person- (Yoon et al., 2011; Hiroeh et al., 2001). These findings suggest that
ality disorder and bipolar disorder and presented a greater suicide abuse of alcohol or drugs could be considered as an important
risk than the subgroup of other substance use disorders (SUDs) characteristic to identify subgroups at risk for suicidal behavior
(Arias et al., 2013). Personality disorder and alcohol dependence (Akiskal et al., 1995; Maremmani et al., 2007). Leverich et al.
were the most common secondary diagnoses in the BD group (2003) have found a correlation between suicidal behaviors and
(Clements et al., 2013). Twenty-five percent of persons consume the family history of suicide attempts or committed suicides, as
alcohol prior to suicidal attempt (Raja and Azzoni, 2004). Leverich well as the family history of abuse of medicinal drugs (Leverich
et al. (2003) also point to family history of abuse of medicinal et al., 2003; Pawlak et al., 2013). Interventions to reduce suicide
drugs as a suicide risk factor (Leverich et al., 2003; Pawlak et al., risk in bipolar disorder need to address the common and high risk
2013). comorbidity with alcohol use disorders (Oquendo et al., 2010).
The risk of suicidal behavior or ideation was significantly
elevated in patients who received an antiepileptic compared with 4.4. Risk factors associated with biological components
those who received placebo when no adjustments were made for
trial differences (Leon et al., 2012). This warning was based on an Altered functioning of the Hypothalamic-pituitary-adrenal
U.S. Food and Drug Administration (FDA) examination of data from (HPA) axis has been reported in suicidal behavior and in Bipolar
199 randomized clinical trials of 11 antiepileptic medications Disorder (BD) (Daban et al., 2005; Mann, 2003). However, many
(carbamazepine, divalproex, felbamate, gabapentin, lamotrigine, studies of HPA axis function in bipolar disorder have not examined
levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, the potential effects of Suicidal Behavior (SB) (Cassidy et al., 1998;
and zonisamide) (Leon et al., 2012). The role of antidepressants Cervantes et al., 2001; Cookson et al., 1985; Godwin, 1984;
(AD) in suicide risk is important, and this has received much Linkowski et al., 1994; Rybakowski and Twardowska, 1999;
attention in recent years (McElroy et al., 2006). There is an Schmider et al., 1995) and studies of the association between
association between the use of AD and a risk of acute manic HPA axis activity and suicidal behavior in varied diagnostic groups
switch in BD (Ghaemi et al., 2003), and McElroy et al. (2006) have had mixed results (Black et al., 2002; Coryell and Schlesser,
concluded that AD may induce suicidal intention by manic con- 2001; Dahl et al., 1991; Duval et al., 2001; Jokinen and Nordström,
version in a subset of depressive presentations (Finseth et al., 2008; Jokinen and Nordström, 2009; Jokinen et al., 2009; Lindqvist
2012). In general, these effects were much stronger for Drug Use et al., 2008; Pfennig et al., 2005; Pitchot et al., 2008; Tripodianakis
Disorders (DUD) than for Alcohol Use Disorders (AUD). Both et al., 2000; Yerevanian et al., 2004; Kamali et al., 2012).
L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254 249

The HPA axis has been examined using a number of methods. Several potential risk factors have been linked to suicidal
Basal cortisol secretion has been measured with 24 h urinary behavior. Two of these include personality factors and Polyunsa-
cortisol secretion and serum or salivary cortisol levels. The feed- turated fatty acids (PUFA) serum levels. It is unknown whether
back and suppression mechanisms of the HPA axis have been PUFA serum levels are associated with personality factors and if
investigated with the dexamethasone suppression test (DST) these may interact to affect suicidal behavior (Evans et al., 2012).
(Kamali et al., 2012) or the dexamethasone/corticotropin-releasing Supplementation with the long-chain n-3 (n-3) fatty acids, doc-
hormone (DEX/CRH) challenge test (Carroll et al., 1981; Heuser osahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), either
et al., 1994). as stand alone or adjunctive therapies have shown efficacy in the
Kamali et al. (2012) examined HPA axis activity as a trait treatment of bipolar disorder (Evans et al., 2012). Epidemiological
marker for bipolar disorder and suicide by measuring salivar studies have pointed to an association between n-3 and n-6
cortisol in a bipolar cohort with a history of suicide and compares dietary intake and lifetime prevalence of bipolar disorder. Popula-
it with non-suicidal bipolar individuals and unaffected controls. tions that consume greater long-chain n-3 s and less long chain
Kamali et al., (2012) hypothesis was that those with bipolar n-6 s have a lower incidence of bipolar disease (Evans et al., 2012;
disorder would have elevated basal salivary cortisol compared to Hibbeln et al., 2006).
unaffected controls, and that the suicidal bipolar individuals N-3 intake inversely associates with violent behavior and
(defined by a lifetime history of attempted suicide) would have suicidality, Evan et al. hypothesize that serum levels of the long
higher levels of salivary cortisol compared to those with no history chain n-3 s, DHA and EPA, may positively associate with person-
of suicidal behavior and unaffected controls. ality factors that may be protective against suicide behavior and/or
A total of 185 individuals participated in the study and negatively associate with personality factors that, themselves,
provided at least one salivary cortisol sample. The majority (152 associate with increased risk of suicide behavior (Evans et al.,
individuals) were enrolled in the Prechter Longitudinal Study. One 2012). Several studies suggest that BD patients' previous suicide
subject subsequently retracted their consent, the salivary samples attempt(s) may indicate that they are more than 50% more likely
from one subject were missing at time of analysis, the saliva to go on to complete suicide (Ruengorn et al., 2012; Tsai et al.,
volume from two individuals was insufficient for analysis and 2002; Isometsa et al., 1994).
three individuals did not complete enough of the diagnostic Identifying metabolic or dietary factors that influence factors
interview to reach a diagnosis. Of the remaining 178, 118 (66.3%) associated with psychiatric illness may provide a path to improv-
had a diagnosis of bipolar I, 14 (7.9%) had bipolar II with recurrent ing therapeutic tools. Evans et al. found associations between lipid
depression, 7 (3.9%) had schizoaffective disorder—bipolar type, 8 profiles and suicidal history in bipolar subjects (Evans et al., 2012).
(4.5%) had other affective diagnosis (depressive disorder NOS, These data further support a link between essential fatty acid
MDD, Bipolar II with single depressive episode), 2 (1.1%) had only metabolism and mood disorders. While the current pilot study is
non-affective diagnoses (alcohol abuse and dependence) and 29 an observational, cross-sectional study, it raises important ques-
(16.3%) were unaffected controls. For the purpose of this study, tions regarding potential causative roles for lipid profiles in
those with bipolar I, bipolar II with recurrent depression and regulating personality phenotypes that may impact the treatment
schizoaffective disorder bipolar type were grouped together as the of bipolar disorder. Nevertheless, the fact that personality factors,
bipolar group (N ¼139) and were categorized based on reported promoted as trait markers in bipolar disorder are not entirely
suicide history obtained during the Diagnostic Interview for stable (Barnett and Huang, 2010) and longer-term longitudinal
Genetic Studies (DIGS) (Kamali et al., 2012). studies are necessary to examine the relationship between per-
Kamali et al., (2012) found elevated bedtime salivary cortisol in sonality traits and fatty acid profiles. Evans et al., (2012)
bipolar individuals with a history of suicide attempts compared to Of significant interest is the co-occurrence of metabolic dis-
nonsuicidal bipolar individuals. Secondary analysis of the intensity turbances in bipolar disorder, particularly obesity (Gomes et al.,
of suicidal behavior and level of bedtime cortisol indicated a 2010). Gomes, et al. find adds to the notion that obesity is a
positive correlation, with the highest cortisol levels reported in correlate of severity in patients with bipolar disorder. Obese
individuals that had made a past serious suicide attempt. The patients usually have more markers of illness severity, such as
difference in bedtime salivary cortisol between suicidal and non- more previous affective episodes (Fagiolini et al., 2002) and suicide
suicidal bipolar individuals remained significant even after con- attempts (Fagiolini et al., 2004; Fagiolini et al., 2005; Wang et al.,
trolling for age and sex, body mass index (BMI), smoking status, 2006). Recent data have stressed common features in the under-
childhood sexual abuse, medications, mood state at time of lying pathophysiology of obesity and bipolar disorder. Leptin, a key
sampling and several clinical factors related to course and severity hormone in regulation of adiposity has been shown to be posi-
of illness (substance use disorders, chronicity of illness, rapid tively associated with risk for depression in a prospective study
cycling, mixed states, years of illness, age of onset, anxiety and (Pasco et al., 2007). Disturbances in metabolic pathways such as
psychosis). This is a strong indicator that their finding is related to insulin-mediated glucose homeostasis, overactivation of the
the presence of a past history of suicidality and not related to hypothalamic–pituitary–adrenal axis, dysregulated immune and
severity of illness, mood state, or demographic confounders. The inflammatory processes and adipocytokines profiles are present in
presence of this finding during different mood states and also in both conditions (Gomes et al., 2010; McIntyre et al., 2007).
the euthymic state indicates that hyperactivity of the HPA axis is a
biological marker related to suicidality in bipolar disorder and 4.5. Risk factors associated with psychological causes
warrants more detailed investigation (Kamali et al., 2012).
The difference between bipolar participants with and without BD is a frequent and chronic psychiatric disorder associated with
suicidal behavior was only 0.05 μg/dl. Currently, the test has low an increase in all-cause mortality (Ösby et al., 2001; McIntyre and
sensitivity and specificity in detecting individuals with suicidal Konarski, 2004; McIntyre et al., 2008). In particular, among mental
history in practical clinical applications. However, the observation disorders, BD is one of the leading causes of suicidal behaviors and
of a sustained correlation between increasing suicidality and this is a major issue in the management of the disease (Parmentier
cortisol levels while controlling for confounding clinical and et al., 2012). Mixed-states and well as depressions are strongly
biological factors clearly indicates the relevance of HPA axis associated with suicidal behavior in patients with BD (Algorta
abnormalities in this potentially lethal clinical condition (Kamali et al., 2011; Baldessarini et al., 2012; Azorin et al., 2009; Pompili
et al., 2012). 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, associated with suicidal behavior in patients with BD may stimu-
attempts and commissions (Shabani et al., 2013). Cyclothymic late the development of specific therapeutic strategies; these may
temperament may influence suicide risk on multiple levels, from include emotional and hostility regulation and problem-solving
determining emotional reactivity in stressful situations at the level therapies or specific treatment of comorbid social phobia or
of the personality, through determining illness and illness course addiction (Parmentier et al., 2012; Gray and Otto, 2001; Stewart
characteristics, to influencing within-episode dynamics (Rihmer et al., 2009). Suicide prevention strategies are currently based on
et al., 2013). screening for the numerous risk factors (de Moraes et al., 2013).
There are also no previous studies investigating the role of
possible mediating factors, such as hopelessness, in the association 4.6. Risk factors associated with components of religious and
between affective temperaments and suicidal behavior. Because it spiritual components
is well known that patients with BD-II are at a higher risk for
attempting and completing suicide (Pompili et al., 2009; Rihmer Religiosity and Spirituality are important aspects to identify
and Pestality, 1999) and that hopelessness has been found to be a groups at risk of suicide in BD. However, there is a lack of studies
good predictor of suicidal behavior (Beck et al., 1990; Akiskal, on their impact on bipolar disorder and little is known about them
2007), understanding the relationship between these factors, and (Azorin et al., 2013).
the possibly differential association of these factors, in patients Dervic et al. (2011) related higher score on the moral or
with BD-I and BD-II disorders would give us better insight in to the religious objections to suicide subscale of the Reason for Living
nature of the emergence of suicidal behavior (Pompili et al., 2012). Inventory (RFLI) with fewer suicidal acts in depressed bipolar
The finding of hopelessness as the most important variable patients. The strength of this association was comparable to that of
when compared with depression is consistent with the nature of aggression scores and suicidal behavior, and had an independent
these psychopathological features (Acosta et al., 2012). A recent effect. A possible protective role of moral or religious objections to
meta-analysis revealed that previous suicide attempts and hope- suicide deserves consideration in the assessment and treatment of
lessness were the main risk factors for suicide, and that early suicidality in bipolar disorder. In this study (Dervic et al., 2011),
onset, depressive symptoms, and family history of suicide were patients who reported religious affiliation were compared with 51
the main risk factors for nonfatal suicide related behavior (Ryu patients without religious affiliation in terms of sociodemographic
et al., 2010; Hawton et al., 2005). We cannot dismiss the possibility and clinical characteristics and history of suicidal behavior. The
that hopelessness may also, at least in part, represent a conse- results were patients with religious affiliation had comparatively
quence of a more severe course of illness, especially those with higher scores on the moral or religious objections to suicide
lifetime depressive burden, and predispose to suicidality from that subscale of the RFLI, lower lifetime aggression, and less comorbid
perspective as well (Acosta et al., 2012). Hopelessness about the alcohol and substance abuse and childhood abuse experience
future in suicidal individuals is a multi-faceted construct but lack (Dervic et al., 2011).
of positive future thinking is more important than presence of In another hand, Azorin et al. (2013) identified another point of
negative future thinking (Fountoulakis et al., 2012). view. In their sample, Compared to Low Religious Involvement
Patients with bipolar disorder have recurrent fluctuating mood (LRI), High Religious Involvement (HRI) patients did not differ with
episodes with functional impairment, (Weinstock and Miller, 2008) respect to their religious affiliation but had a later age at onset of
which might induce chronic distress and increase suicide related their affective illness with more hospitalizations, suicide attempts,
behaviors (Ryu et al., 2010; MacKinnon et al., 2003). Because suicide associated hypomanic features, switches under antidepressant
and suicidal behaviors are the result of a combination of individual risk treatment, prescription of tricyclics, comorbid obsessive compul-
factors, precipitating stressors, and current disease features, the sive disorder, and family history of affective disorder in first-
prediction of a suicide attempt for a given patient on the basis of risk degree relatives. The following independent variables were asso-
factors statistically associated with suicide or suicide attempts in ciated with religious involvement: age, depressive temperament,
populations of patients with bipolar disorder is difficult (Song et al., mixed polarity of first episode, and chronic depression. The study
2012). For Pompili et al. not only the absolute elevations of each concluded that in depressive patients belonging to the bipolar
temperament may be associated with psychopathological symptoms spectrum, high religious involvement associated with mixed
but also that the individual pattern of temperaments may be features may increase the risk of suicidal behavior, despite the
associated with a higher suicidal risk (Pompili et al., 2012). However, existence of religious affiliation.
what we so far know about the risk factors associated with suicidal The current study (Azorin et al., 2013) may help understand
thinking and behavior in bipolar disorder has overwhelmingly been some potential negative effects of religious involvement in depres-
derived by studying individuals who are in the “acute” phase of their sive patients belonging to the bipolar spectrum. First of all, their
disorder (Acosta et al., 2012). findings may be in line with the hypothesis of Cruz et al. (2010)
Many studies have investigated clinical characteristics asso- that higher levels of distress as such caused by mixed episodes
ciated with suicidal behavior. Gender has been associated with and/or chronic depression, would prompt patients to seek relief
suicidal behavior in BD: men have a 4-fold greater risk for suicide from religion, and therefore increase the frequency of their
than women (Suicidology AAo, 2000; American Psychiatric religious behaviors. However, it could be that, once depressed,
Association, 2003; World Health Organization WHO, 2003). Rela- HRI patients become the victims of their religious commitment
tive to the risk in the general population, BD is associated with an and that, in this case, religion exerts harmful effects on health.
increased risk of suicidal behavior in women and a higher lethality Actually, for an individual with depressive temperament char-
in men (Parmentier et al., 2012). acterized by a rigid duty - orientation of his behavior, which
In particular, careful evaluation and effective management of distinguishes itself by an overidentification with what is norma-
bipolar depression among patients with mood disorder during tively expected or by a meticulous fulfillment of social norms
major depressive episodes is necessary to prevent suicide attempts (Tellenbach, 1974), experiencing hypomanic social desinhibition
in bipolar disorder (Ryu et al., 2010). While suicidal ideation and a may hardly be assimilated in his usual way of life. This “egodys-
history of attempted suicide are among the most important risks tonic” experience could therefore appear to consciousness under
for suicide (Osman et al., 2001; Kuo et al., 2001), only a few studies the form of obsessive thoughts such as the “fear of committing a
have taken into account both suicidal ideas and attempts in sin” or an “excessive guilt” and give rise to compulsive religious
assessing the risk factors (Suttajit et al., 2013). The characteristics behaviors, such as those found in our HRI patients. In those cases,
L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254 251

it is likely that religious involvement may aggravate their guilt Antypa, N., Antonioli, M., Serretti, A., 2013. Clinical, psychological and environ-
feelings or the sinful character of their hypomanic experiences, mental predictors of prospective suicide events in patients with Bipolar
Disorder. J. Psychiatr. Res. 47 (11), 1800–1808.
enhancing thereby the suicidal tendencies. This may contribute to Arató, M., Demeter, E., Rihmer, Z., et al., 1988. Retrospective psychiatric assessment
explain why in the case of some mixed depressive patients, of 200 suicides in Budapest. Acta Psychiatr. Scand. 77, 454–456.
religiosity is unlikely to be associated with less suicidal behavior Arias, F., Szerman, N., Vega, P., et al., 2013. Alcohol abuse or dependence and other
psychiatric disorders. Madrid study on the prevalence of dual pathology. Ment.
(Azorin et al., 2013).
Health Subst. Use: Dual Diagn. 6 (4), 339–350.
The last study (Pawlak et al., 2013) confirms what Dervic et al. Azorin, J.-M., Kaladijan, A., Fakra, E., et al., 2013. Religious involvement in major
analyzed, affirming that subjective sense of religious involvement depression: protective or risky behavior? The relevance of bipolar spectrum. J.
may play a protective role in some communities (Sisask et al., Affect Disord. 150 (3), 753–759.
Azorin, J.M., Kaladjian, A., Adida, M., et al., 2009. Risk factors associated with
2010). Patients, who have not declared their commitment to any lifetime suicide attempts in bipolar I patients: findings from a French national
religion, undertook suicidal attempts significantly more often and Cohort. Compr. Psychiatry 50 (2), 115–120.
had more relatives, who had died of suicide, in comparison with Azorin, J.M., Aubrun, E., Bertsch, J., et al., 2009. Mixed states vs. pure mania in the
French sample of the EMBLEM study: results at baseline and 24 months–
those involved in religion (Dervic et al., 2004).
European mania in bipolar longitudinal evaluation of medication. BMC Psy-
chiatry 9, 33–40.
Azorin, J.M., Kaladjian, A., Adida, M., et al., 2009. Risk factors associated with
5. Conclusion lifetime suicide attempts in bipolar I patients: findings from a French National
Cohort. Compr. Psychiatry 50 (2), 115–120.
Azorin, J.M., Kaladjian, A., Besnier, N., et al., 2010. Suicidal behavior in a French
The results of the studies in the literature show that the risk Cohort of major depressive patients: characteristics of attempters and non-
factors associated with bipolar disorder and suicide exist and are attempters. J. Affect Disord. 123 (1–3), 87–94.
relevant to clinicians and researchers, whereas knowledge of such Balázs, J., Lecrubier, Y., Csiszér, N., et al., 2003. Prevalence and comorbidity of affective
disorders in persons making suicide attempts in Hungary: importance of the first
influence better diagnosis and prognosis of BD cases involving
depressive episodes and of bipolar II diagnoses. J. Affect Disord. 76, 113–119.
suicide risk. Notwithstanding the differences in some points of the Baldessarini, R.J., Pompili, M., Tondo, L., 2006. Suicide in bipolar disorder: risks and
studies, research becomes important to maintain the high quality management. CNS Spectr. 11, 465–471.
of knowledge of the disorder and its peculiarities, seeking Baldessarini, R.J., Salvatore, P., Khalsa, H.-M.K., 2010. Dissimilar morbidity following
initial mania versus mixed-states in type-I bipolar disorder. J. Affect Disord.
improved quality of life for people suffering from bipolar disorder. 126, 299–302.
Baldessarini, R.J., Undurraga, J., Vázquez, G.H., et al., 2012. Predominant recurrence
polarity among 928 adult international bipolar I disorder patients. Acta
Role of funding source Psychiatr. Scand. 125 (4), 293–302.
We have no foundation source. Barnett, J.H., Huang, J., Perlis, R.H., 2010. Personality and bipolar disorder: dissecting
state and trait associations between mood and personality. Psychol. Med., 1–12.
Beck, A.T., Brown, G., Berchick, R.J., et al., 1990. Relationship between hopelessness
Conflict of interest and ultimate suicide: a replication with psychiatric outpatients. Am. J. Psychia-
Mr. Costa, Mr. Alencar, Mr. Nascimento and Drs. Maria do Socorro, Cláudio, try 147, 190–195.
Sally, Regiane, Bianca, Roberto, Marcos Antonio, Alberto and Modesto have no Bellivier, F., Yon, L., Luquiens, A., et al., 2011. Suicidal attempts in bipolar disorder:
results from an observational study (EMBLEM). Bipolar Disord. 13 (4), 377–386.
conflicts of interest or financial ties to report.
Benazzi, F., 2007. Bipolar disorder–focus on bipolar II disorder and mixed depres-
sion. Lancet 369, 935–945.
Black, D., Monahan, P., Winokur, G., 2002. The relationship between DST results and
Acknowledgments suicidal behavior. Ann. Clin. Psychiatry 14, 83–88.
The authors of this review would like to thank the support of the Suicidology Black, D.W., Warrack, G., Winokur, G., 1985. Excess mortality among psychiatric
Research Group, Federal University of Ceará (UFC/Brazil)/Conselho Nacional de patients. The Iowa record-linkage study. J. Am. Med. Assoc. 253, 58–61.
Desenvolvimento Científico e Tecnológico (CNPq/Brazil) and the Laboratório de Blair-West, G.W., Cantor, C.H., Mellsop, G.W., et al., 1999. Lifetime suicide risk in
Escrita Científica (LABESCI/Brazil)—Medical School of Federal University of Cariri major depression: sex and age determinants. J. Affect. Disord. 55, 171e8.
(UFCA/Brazil). Brent, D.A., Perper, J.A., Moritz, G., et al., 1993. Stressful life events, psychopathol-
ogy, and adolescent suicide: a case control study. Suicide Life Threat. Behav. 23
(3), 179–187.
References Brent, D.A., Perper, J.A., Moritz, G., et al., 1994. Familial risk factors for adolescent
suicide: a case-control study. Acta Psychiatr. Scand. 89 (1), 52–58.
Bruce, M.L., Leaf, P.J., Rozal, G.P., et al., 1994. Psychiatric status and 9-year mortality
Abreu, L.N., Lafer, B., Baca-Garcia, E., et al., 2009. Suicidal ideation and suicide
data in the New haven epidemiologic catchment area study. Am. J. Psychiatry
attempts in bipolar disorder type I: an update for the clinician. Rev. Bras.
151, 716–721.
Psiquiatr. 31 (3), 271–280.
Carroll, B.J., Feinberg, M., Greden, J.F., et al., 1981. A specific laboratory test for the
Acosta, F.J., Vega, D., Navarro, S., et al., 2012. Hopelessness and suicidal risk in
bipolar disorder. A study in clinically nonsyndromal patients. Compr. Psychiatry diagnosis of melancholia. Standardization, validation, and clinical utility. Arch.
53 (8), 1103–1109. Gen. Psychiatry 38, 15–22.
Akiskal, H., 2007. Targeting suicide preventing to modifiable risk factors: has Cassidy, F., 2011. Risk factors of attempted suicide in bipolar disorder. Suicide Life
bipolar II been overlooked? Acta Psychiatr. Scand. 116 (6), 395–402. Threat. Behav. 41 (1), 6–11.
Akiskal, H.S., Maser, J.D., Zeller, P.J., et al., 1995. Switching from unipolar‘ to bipolar Cassidy, F., Ritchie, J.C., Carroll, B.J., 1998. Plasma dexamethasone concentration and
II. An 11-year prospective study of clinical and temperamental predictors in 559 cortisol response during manic episodes. Biol. Psychiatry 43, 747–754.
patients. Arch. Gen. Psychiatry 52, 114–123. Cervantes, P., Gelber, S., Kin, F.N., et al., 2001. Circadian secretion of cortisol in
Akiskal, H.S., Benazzi, F., Perugi, G., et al., 2005. Agitated “unipolar” depression re- bipolar disorder. J. Psychiatry Neurosc. 26, 411–416.
conceptualized as a depressive mixed state: Implications for the Christensen, J., Vestergaard, M., Mortensen, P.B., et al., 2007. Epilepsy and risk of
antidepressant-suicide controversy. J. Affect. Disord. 85 (3), 245–258. suicide: a population-based case-control study. Lancet Neurol. 6, 693–698.
Algorta, G.P., Youngstrom, E.A., Frazier, T.W., et al., 2011. Suicidality in pediatric Clements, C., Morriss, R., Jones, S., et al., 2013. Suicide in bipolar disorder in a
bipolar disorder: predictor or outcome of family processes and mixed mood national English sample, 1996–2009: frequency, trends and characteristics.
presentation? Bipolar Disord. 13 (1), 76–86. Psychol. Med. 43 (12), 2593–2602.
Amaddeo, F., Bisoffi, G., Bonizzato, P., et al., 1995. Mortality among patients with Cookson, J.C., Silverstone, T., Williams, S., et al., 1985. Plasma cortisol levels in
psychiatric illness. A ten-year case register study in an area with a community- mania: associated clinical ratings and changes during treatment with haloper-
based system of care. Br. J. Psychiatry 166, 783–788. idol. Br. J. Psychiatry 146, 498–502.
American Psychiatric Association, 2003. Practice guideline for the assessment and Coryell, W., Schlesser, M., 2001. The dexamethasone suppression test and suicide
treatment of patients with suicidal behaviors. Am. J. Psychiatry 160 (Suppl. 11), prediction. Am. J. Psychiatry 2001 (158), 748.
S1–S60. Cruz, M., Pincus, H.A., Welsh, D.E., et al., 2010. The relationship between religious
American Psychiatric Association, 2013. Diagnostic and statistical manual of mental involvement and clinical status of patients with bipolar disorder. Bipolar
Disorders, 5th ed. American Psychiatric Association, Arlington, VA (DSM-5). Disord. 12, 68–76.
Angst, F., Stassen, H.H., Clayton, P.J., et al., 2002. Mortality of patients with mood Cuijpers, P., Smit, F., 2002. Excess mortality in depression: a meta-analysis of
disorders: follow-up over 34–38 years. J. Affect. Disord. 68, 167–181. community studies. J. Affect. Disord. 72, 227–236.
Angst, J., Angst, F., Gerber-Werder, R., et al., 2005. Suicide in 406 mood-disorder de Moraes, P.H.P., Neves, F.S., Vasconcelos, A.G., et al., 2013. Relationship between
patients with and without long-term medication: a 40 to 44 years' follow- up. neuropsychological and clinical aspects and suicide attempts in euthymic
Arch. Suicide Res. 9 (3), 279–300. bipolar patients. Psicologia: Reflexao e Critica 26 (1), 160–167.
252 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

Daban, C., Vieta, E., Mackin, P., et al., 2005. Hypothalamic-pituitaryadrenal axis and Hasin, D.S., Goodwin, R.D., Stinson, F.S., et al., 2005. Epidemiology of major
bipolar disorder. Psychiatric Clin N. Am. 28, 469–480. depressive disorder: results from the National Epidemiologic Survey on
Daban, C., Colom, F., Sanchez-Moreno, J., et al., 2006. Clinical correlates of first- Alcoholism and Related Conditions. Arch. Gen. Psychiatry 62, 1097–1106.
episode polarity in bipolar disorder. Compr. Psychiatry 47, 433–437. Hawton, K., Sutton, L., Haw, C., et al., 2005. Suicide and attempted suicide in bipolar
Dahl, R.E., Ryan, N.D., Puig-Antich, J., et al., 1991. 24-hour cortisol measures in disorder: a systematic review of risk factors. J. Clin. Psychiatry 66, 693–704.
adolescents with major depression: a controlled study. Biol. Psychiatry 1991 Heuser, I., Yassouridis, A., Holsboer, F., 1994. The combined dexamethasone/CRH
(30), 25–36. test: a refined laboratory test for psychiatric disorders. J. Psychiatr. Res. 28
Dalton, J.E., Cate-Carter, T.D., Mundo, E., et al., 2003. Suicide risk in bipolar patients: (341–356), 138.
the role of co-morbid substance use disorders. Bipolar Disord. 5, 58–61. Hibbeln, J.R., Nieminen, L.R., Blasbalg, T.L., et al., 2006. Healthy intakes of n-3 and n-
De Abreu, L.N., Nery, F.G., Harkavy-Friedman, J.M., et al., 2012. Suicide attempts are 6 fatty acids: estimations considering worldwide diversity. Am. J. Clin. Nutr. 83,
associated with worse quality of life in patients with bipolar disorder type I. 1483S–1493S.
Compr. Psychiatry 53 (2), 125–129. Hiroeh, U., Appleby, L., Mortensen, P.B., et al., 2001. Death by homicide, suicide, and
Dervic, K., et al., 2004. Religious affiliation an suicide attempt. Am. J. Psychiatry 161 other unnatural causes in people with mental illness: a population- based
(12), 2303–2308. study. Lancet 358, 2110–2112.
Dervic, K., Carballo, J.J., Baca-Garcia, E., et al., 2011. Moral or religious objections to Huber, R.S., Coon, H., Kim, N., et al., 2014. Altitude is a risk factor for completed
suicide may protect against suicidal behavior in bipolar disorder. J. Clin. suicide in bipolar disorder. Med. Hypotheses 82 (3), 377–381.
Psychiatry 72 (10), 1390–1396. Isometsa, E.T., Henriksson, M.M., Aro, H.M., et al., 1994. Suicide in bipolar disorder
Duval, F., Mokrani, M.C., Correa, H., et al., 2001. Lack of effect of HPA axis in Finland. Am J Psychiatry. 151 (7), 1020–1024.
hyperactivity on hormonal responses to d-fenfluramine in major depressed Jamison, K.R., 2000. Suicide and bipolar disorder. J. Clin. Psychiatry 61 (Supp l9),
patients: implications for pathogenesis of suicidal behavior. Psychoneuroendo- S47–S51.
crinology 26, 521–537. Jiménez, E., Arias, B., Mitjans, M., et al., 2013. Genetic variability at IMPA2, INPP1
Dwivedi, Y., Rizavi, H.S., Conley, R.R., et al., 2003. Altered gene expression of brain- and GSK3b increases the risk of suicidal behavior in bipolar patients. Eur.
derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain Neuropsychopharmacol. 23 (11), 1452–1462.
of suicide subjects. Arch. Gen. Psychiatry 60 (8), 804–815. Jokinen, J., Nordström, P., 2008. HPA axis hyperactivity as suicide predictor in
Eroglu, M.Z., Karakus, G., Tamam, L., 2013. Bipolar disorder and suicide. Dusunen elderly mood disorder inpatients. Psychoneuroendocrinology 33, 1387.
Adam. 26 (2), 139–147. Jokinen, J., Nordström, P., 2009. HPA axis hyperactivity and attempted suicide in
Etain, B., Aas, M., Andreassen, O.A., et al., 2013. Childhood trauma is associated with young adult mood disorder inpatients. J. Affective Disord. 2009 (116), 117.
severe clinical characteristics of bipolar disorders. J. Clin. Psychiatry 74 (10), Jokinen, J., Nordström, A., Nordström, P., 2009. CSF 5-HIAA and DST nonsuppres-
991–998. sion–orthogonal biologic risk factors for suicide in male mood disorder
Evans, S.J., Prossin, A.R., Harrington, G.J., et al., 2012. Fats and factors: lipid profiles inpatients. Psychiat. Res. 165, 96.
associate with personality factors and suicidal history in bipolar subjects. PLoS Jou, S.H., Chiu, N.Y., Liu, C.S., 2009. Mitochondrial dysfunction and psychiatric
One 7 (1), e29297. disorders. Chang Gung. Med. J. 32, 370–379.
Fagiolini, A., Frank, E., Houck, P.R., et al., 2002. Prevalence of obesity and weight Joukamaa, M., Heliövaara, M., Knekt, P., et al., 2001. Mental disorders and cause-
change during treatment in patients with bipolar I disorder. J. Clin. Psychiatry specific mortality. Br. J. Psychiatry 179, 498–502.
63, 528–533. Kamali, M., Saunders, E.F.H., Prossin, A.R., et al., 2012. Associations between suicide
Fagiolini, A., Kupfer, D.J., Rucci, P., et al., 2004. Suicide attempts and ideation in attempts and elevated bedtime salivary cortisol levels in bipolar disorder. J.
patients with bipolar I disorder. J. Clin. Psychiatry 65, 509–514. Affect. Disord. 136 (3), 350–358.
Fagiolini, A., Frank, E., Scott, J.A., et al., 2005. Metabolic syndrome in bipolar Karege, F., Vaudan, G., Schwald, M., et al., 2005. Neurotrophin levels in postmortem
disorder: findings from the Bipolar Disorder Center for Pennsylvanians. Bipolar brains of suicide victims and the effects of antemortem diagnosis and
Disord. 7, 424–430. psychotropic drugs. Mol. Brain Res. 136 (1–2), 29–37.
Fattal, O., Budur, K., Vaughan, A.J., et al., 2006. Review of the literature on major Kato, T., 2006. The role of mitochondrial dysfunction in bipolar disorder. Drug News
mental disorders in adult patients with mitochondrial diseases. Psychosomatics Perspect. 19, 597–602.
47, 1–7. Kenneson, A., Funderburk, J.S., Maisto, S.A., 2013. Risk factors for secondary
Fattal, O., Link, J., Quinn, K., et al., 2007. Psychiatric comorbidity in 36 adults with substance use disorders in people with childhood and adolescent-onset bipolar
mitochondrial cytopathies. CNS Spectr. 12, 429–438. disorder: opportunities for prevention. Compr. Psychiatry 54 (5), 439–446.
Finseth, P.I., Morken, G., Andreassen, O.A., et al., 2012. Risk factors related to lifetime Kerner, B., Rao, A.R., Christensen, B., et al., 2013. Rare genomic variants link bipolar
suicide attempts in acutely admitted bipolar disorder inpatients. Bipolar Disord. disorder with anxiety disorders to CREB-regulated intracellular signaling
14 (7), 727–734. pathways. Front Psychiat. 4, 154.
Fountoulakis, K.N., Grunze, H., Panagiotidis, P., et al., 2008. Treatment of bipolar Kheirabadi, G.R., Hashemi, S.J., Akbaripour, S., et al., 2012. Risk factors of suicide
depression: an update. J. Affect. Disord. 109, 21–34. reattempt in patients admitted to khorshid hospital, Isfahan, Iran, 2009. Iran. J.
Fountoulakis, K.N., Pantoula, E., Siamouli, M., et al., 2012. Development of the Risk Epidemiology. 8 (3), 39–46.
Assessment Suicidality Scale (RASS): a population-based study. J. Affect. Disord. Koene, S., Kozicz, T.L., Rodenburg, R.J., et al., 2009. Major depression in adolescent
138 (3), 449–457. children consecutively diagnosed with mitochondrial disorder. J. Affect. Disord.
Freeman, A.J., Youngstrom, E.A., Michalak, E., et al., 2009. Quality of life in pediatric 114, 327–332.
bipolar disorder. Pediatrics 123, e446–e452. Kuo, W.H., Gallo, J.J., Tien, A.Y., 2001. Incidence of suicide ideation and attempts in
Galfalvy, H., Huang, Y.Y., Oquendo, M.A., et al., 2009. Increased risk of suicide adults: the 13-year follow-up of a community sample in Baltimore, Maryland.
attempt in mood disorders and TPH1 genotype. J. Affect. Disord. 115, 331–338. Psychol. Med. 31 (7), 1181–1191.
Galfavy, H., Oquendo, M.A., Carballo, J.J., et al., 2006. Clinical predictors of suicidal Kupfer, D.J., 2005. The increasing medical burden in bipolar disorder. J. Am. Med.
acts after major depression in bipolar disorder: a prospective study. Bipolar Assoc. 293, 2528–2530.
Disord. 8 (5 Pt 2), 586–595. Leon, A.C., Solomon, D.A., Li, C., et al., 2012. Antiepileptic drugs for bipolar disorder
Gau, S.S., Cheng, A.T., 2004. Mental illness and accidental death. Case-control and the risk of suicidal behavior: a 30-year observational study. Am. J.
psychological autopsy study. Br. J. Psychiatry 185, 422–428. Psychiatry 169 (3), 285–291.
Ghaemi, S.N., Hsu, D.J., Soldani, F., et al., 2003. Antidepressants in bipolar disorder: Leverich, G.S., et al., 2003. Factors associated with suicide attempts in 648 patients
the case for caution. Bipolar Disord. 5, 421–433. with bipolar disorder in the Stanley Foundation Bipolar Network. J. Clin.
Gilbert, A.M., Garno, J.L., Braga, R.J., et al., 2011. Clinical and cognitive correlates of Psychiatry 64 (5), 506–515.
suicide attempts in bipolar disorder: Is suicide predictable? J. Clin. Psychiatry Lindqvist, D., Isaksson, A., Trskman-Bendz, L., et al., 2008. Salivary cortisol and
72 (8), 1027–1033. suicidal behavior—a follow-up study. Psychoneuroendocrinology 33, 1061.
Godwin, C.D., 1984. The dexamethasone suppression test in acute mania. J. Affect. Linkowski, P., Kerkhofs, M., Van Onderbergen, A., et al., 1994. The 24-hour profiles
Disord. 7, 281–286. of cortisol, prolactin, and growth hormone secretion in mania. Arch. Gen.
Goldstein, T.R., Ha, W., Axelson, D.A., et al., 2012. Predictors of prospectively Psychiatry 51, 616–624.
examined suicide attempts among youth with bipolar disorder. Arch. Gen. Lopez, D.L., Brezo, J., Rouleau, G., et al., 2007. Effect of tryptophan hydroxylase-2
Psychiatry 69 (11), 1113–1122. gene variants on suicide risk in major depression. Biol. Psychiatry 62, 72–80.
Gomes, F.A., Kauer-Sant‘Anna, M., Magalhães, P.V., et al., 2010. Obesity is associated Lopez, P., Mosquera, F., deLeon, J., et al., 2001. Suicide attempts in bipolar patients. J.
with previous suicide attempts in bipolar disorder. Acta Neuropsychiatr. 22 (2), Clin. Psychiatry 62, 963–966.
63–67. MacKinnon, D.F., Zandi, P.P., Gershon, E., et al., 2003. Rapid switching of mood in
Goodwin, F.K., Jamison, K.R., 2007. Manic-Depressive Illness: Bipolar Disorders and families with multiple cases of bipolar disorder. Arch. Gen. Psychiatry 60,
Recurrent Depression. Oxford University Press, New York, NY. 921–928.
Gould, M.S., Fisher, P., Parides, M., et al., 1996. Psychosocial risk factors of child and Magno, L.A., Miranda, D.M., Neves, F.S., et al., 2010. Association between AKT1 but
adolescent completed suicide. Arch. Gen. Psychiatry 53 (12), 1155–1162. not AKTIP genetic variants and increased risk for suicidal behavior in bipolar
Gray, S.M., Otto, M.W., 2001. Psychosocial approaches to suicide prevention: patients. Genes Brain Behav. 9, 411–418.
applications to patients with bipolar disorder. J. Clin. Psychiatry 62 (Suppl. Magno, L.A.V., Santana, C.V.N., Rezende, V.B., et al., 2011. Genetic variations in
25), S56–S64. FOXO3A are associated with Bipolar Disorder without confering vulnerability
Harris, E.C., Barraclough, B., 1997. Suicide as an outcome for mental disorders. A for suicidal behavior. J. Affect. Disord. 133 (3), 633–637.
metaanalysis. Br. J. Psychiatry 170, 205–228. Manchia, M., Hajek, T., O‘Donovan, C., et al., 2013. Genetic risk of suicidal behavior
Harris, E.C., Barraclough, B., 1998. Excess mortality of mental disorder. Br. J. in bipolar spectrum disorder: analysis of 737 pedigrees. Bipolar Disord. 15 (5),
Psychiatry 173, 11–53. 496–506.
L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254 253

Mann, J.J., 2003. Neurobiology of suicidal behavior. Nat. Rev. Neurosci. 4, 819. Raja, M., Azzoni, A., 2004. Suicide attempts: differences between unipolar and
Mao, Z., Liu, L., Zhang, R., et al., 2007. Lithium reduces FoxO3a transcriptional bipolar patients and among groups with different lethality risk. J. Affect. Disord.
activity by decreasing its intracellular content. Biol. Psychiatry 62, 1423–1430. 82 (3), 437–442.
Maremmani, I., Pani, P.P., Canoniero, S., et al., 2007. Is the bipolar spectrum the Ratcliffe, G.E., Enns, M.W., Belik, S.L., et al., 2008. Chronic pain conditions and
psychopathological substrate of suicidality in heroin addicts? Psychopathology suicidal ideation and suicide attempts: an epidemiologic perspective. Clin. J.
40 (5), 269–277. Pain 24, 204–210.
McElroy, S.L., Kotwal, R., Kaneria, R., et al., 2006. Antidepressants and suicidal Rezin, G.T., Amboni, G., Zugno, A.I., et al., 2009. Mitochondrial dysfunction and
behavior in bipolar disorder. Bipolar Disord. 8, 596–617. psychiatric disorders. Neurochem. Res. 34, 1021–1029.
McIntyre, R.S., Konarski, J.Z., 2004. Bipolar disorder: a national health concern. CNS Rihmer, Z., Pestality, P., 1999. Bipolar II disorder and suicidal behavior. Psychiatr.
Spectr. 9 (11 Suppl 12), S6–S15. Clin. N. Am. 22 (667–73), ix–x.
McIntyre, R.S., Soczynska, J.K., Konarski, J.Z., et al., 2007. Should depressive Rihmer, Z., Gonda, X., Torzsa, P., et al., 2013. Affective temperament, history of
syndromes be reclassified as "metabolic syndrome type II"? Ann. Clin. Psy- suicide attempt and family history of suicide in general practice patients.
chiatry 19, 257–264. J. Affect. Disord. 149 (1–3), 350–354.
McIntyre, R.S., Soczynska, J.K., Mancini, D., et al., 2008. The relationship between Roshanaei-Moghaddam, B., Katon, W., 2009. Premature mortality from general
childhood abuse and suicidality in adult bipolar disorder. Violence Vict. 23 (3), medical illnesses among persons with bipolar disorder: a review. Psychiatr.
361–372. Serv. 60, 147–156.
McIntyre, R.S., Muzina, D.J., Kemp, D.E., et al., 2008. Bipolar disorder and suicide: Roy, A., Segal, N.L., 2001. Suicidal behavior in twins: a replication. J. Affect. Disord.
researchsynthesis and clinical translation. Curr. Psychiatry Rep. 10, 66–72. 66, 71–74.
Michalak, E.E., Yatham, L.N., Lam, R.W., 2005. Quality of life in bipolar disorder: a Ruengorn, C., Sanichwankul, K., Niwatananun, W., et al., 2012. A risk-scoring
review of the literature. Health Qual. Life Outcomes 15, 3–72. scheme for suicide attempts among patients with bipolar disorder in a Thai
Miklowitz, D.J., Chang, K.D., 2008. Prevention of bipolar disorder in at-risk children: patient cohort. Psychol. Res. Behav. Manage. 5, 37–45.
theoretical assumptions and empirical foundations. Dev. Psychopathol. 20, Rybakowski, J.K., Twardowska, K., 1999. The dexamethasone/corticotropinreleasing
881–897. hormone test in depression in bipolar and unipolar affective illness. J. Psychiatr.
Morava, E., Gardeitchik, T., Kozicz, T., et al., 2010. Depressive behavior in children Res. 33, 363–370.
diagnosed with a mitochondrial disorder. Mitochondrion 10, 528–533. Ryu, V., Jon, D.I., Cho, H.S., et al., 2010. Initial depressive episodes affect the risk of
Mykletun, A., Bjerkeset, O., Dewey, M., et al., 2007. Anxiety, depression, and cause- suicide attempts in Korean patients with bipolar disorder. Yonsei. Med. J. 51 (5),
specific mortality: the HUNT study. Psychosom. Med. 69, 323–331. 641–647.
Neves, F.S., Malloy-Diniz, L.F., Ma, Romano-Silva, et al., 2010. Is the serotonin Sajatovic, M., 2005. Bipolar disorder: disease burden. Am. J. Manag. Care 11,
transporter polymorphism (5-HTTLPR) a potential marker for suicidal behavior S80–S84.
in bipolar disorder patients? J. Affect. Disord. 125 (1-3), 98–102. Scaglia, F., 2010. The role of mitochondrial dysfunction in psychiatric disease. Dev.
Neves, F.S., Malloy-Diniz, L., Romano-Silva, M.A., et al., 2011. The role of BDNF Disabil. Res. Rev. 16, 136–143.
genetic polymorphisms in bipolar disorder with psychiatric comorbidities. Schmider, J., Lammers, C.H., Gotthardt, U., et al., 1995. Combined dexamethasone/
J. Affect. Disord. 131, 307–311. corticotropin-releasing hormone test in acute and remitted manic patients, in
Nilsson, L., Ahlbom, A., Farahmand, B.Y., et al., 2002. Risk factors in suicide in acute depression, and in normal controls: I. Biol. Psychiatry 38, 797–802.
epilepsy: a case-control study. Epilepsia 43, 644–651. Sears, C., Wilson, J., Fitches, A., et al., 2013. Investigating the role of BDNF and CCK
Oquendo, M.A., Currier, D., Liu, S., et al., 2010. Increased risk for suicidal behavior in system genes in suicidality in a familial bipolar cohort. J. Affect. Disord. 151 (2),
comorbid bipolar disorder and alcohol use disorders. J. Clin. Psychiatry 71 (7), 611–617.
902–909. Serretti, A., Drago, A., De, R.D., et al., 2009. Lithium pharmacodynamics and
Ösby, U., Brandt, L., Correia, N., et al., 2001. Excess mortality in bipolar and unipolar pharmacogenetics: focus on inositol mono phosphatase (IMPase), inositol
disorder in Sweden. Arch. Gen. Psychiatry 58, 844–850. poliphosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta).
Osman, A., Bagge, C.L., Gutierrez, P.M., et al., 2001. The Suicidal Behaviors Curr. Med. Chem. 16, 1917–1948.
Questionnaire-Revised (SBQ-R): validation with clinical and nonclinical sam- Shabani, A., Teimurinejad, S., Koka, S., et al., 2013. Suicide risk factors in iranian
ples. Assessment 8 (4), 443–454. patients with bipolar disorder: A 21- month follow-up from BDPF study. Iran. J.
Parmentier, C., Etain, B., Yon, L., et al., 2012. Clinical and dimensional characteristics Psychiatry Behav. Sci. 7 (1), 16–23.
of euthymic bipolar patients with or without suicidal behavior. Eur. Psychiatry Simon, G.E., Bauer, M.S., Ludman, E.J., et al., 2007. Mood symptoms, functional
27 (8), 570–576. impairment and disability in people with bipolar disorder: specific effects of
Pasco, J., Jacka, F., Williams, L.J., et al., 2007. Leptin in depressed women: cross- mania and depression. J. Clin. Psychiatry 68, 1237–1245.
sectional and longitudinal data from an epidemiologic study. J. Affect. Disord. Simon, G.E., Hunkeler, E., Fireman, B., et al., 2007. Risk of suicide attempt and
107, 211–225. suicide death in patients treated for bipolar disorder. Bipolar Disord. 9,
Pawlak, J., Dmitrzak-Weglarz, M., Skibińska, M., et al., 2013. Suicide attempts and 526–530.
psychological risk factors in patients with bipolar and unipolar affective Sisask, M., et al., 2010. Is religiosity a protective factor against attempted suicide: a
disorder. Gen. Hosp. Psychiatry 35 (3), 309–313. crosscultural case–control study. Arch. Suicide Res. 14 (1), 44–55.
Pawlak, J., Dmitrzak-Weglarz, M., Skibińska, M., et al., 2013. Suicide attempts and Song, J.Y., Hy, Y.u., Kim, S.H., et al., 2012. Assessment of risk factors related to suicide
clinical risk factors in patients with bipolar and unipolar affective disorders. attempts in patients with bipolar disorder. J. Nerv. Ment. Dis. 200 (11), 978–984.
Gen. Hosp. Psychiatry 35 (4), 427–432. Stahl, S.M., 2000. Essential psychopharmacology of depression and bipolar dis- [homepage on the Internet]. 2014. Brasília: Higher Educa- order. Cambridge University Press, NewYork, NY.
tion Co-ordination Agency of Brazil‘s Ministry of Education; 2000. Available Stewart, C.D., Quinn, A., Plever, S., et al., 2009. Comparing cognitive behavior
from: 〈〉. (accessed 6.6.2014. therapy, problem solving therapy, and treatment as usual in a high risk
Perugi, G., Micheli, C., Akiskal, H.S., et al., 2000. Polarity of the first episode, clinical population. Suicide Life Threat Behav. 39 (5), 538–547.
characteristics, and course of manic depressive illness: a systematic retro- Sublette, M., Carballo, J.J., Moreno, C., et al., 2009. Substance use disorders and
spective investigation of 320 bipolar I patients. Compr Psychiatry. 41, 13–18. suicide attempts in bipolar subtypes. J. Psychiatry Res. 43 (3), 230–238.
Pfennig, A., Kunzel, H., Kern, N., et al., 2005. Hypothalamus-pituitary-adrenal Suicidology AAo. 2000. American Association of Suicidology [AAS]. Offical 1998
systemregulation and suicidal behavior in depression. Biol. Psychiatry 57, statistics.
336–342. Suttajit, S., Paholpak, S., Choovanicvong, S., et al., 2013. Correlates of current suicide
Pitchot, W., Scantamburlo, G., Pinto, E., et al., 2008. Vasopressin–neurophysin and risk among Thai patients with bipolar I disorder: findings from the Thai Bipolar
DST in major depression: relationship with suicidal behavior. J. Psychiatr. Res. Disorder Registry. Neuropsychiatry Dis. Treat. 9, 1751–1757.
42, 684–688. Tellenbach, 1974. Melancholie; Problemgeschichte; Endogenit ̈ at, Typologie, Patho-
Polter, A., Yang, S., Zmijewska, A.A., et al., 2009. Forkhead box, class O transcription genese, Klinik. Springer, Berlin.
factors in brain: regulation and behavioral manifestation. Biol. Psychiatry 65, Tondo, L., Albert, M.J., Baldessarini, R.J., 2006. Suicide rates in relation to health care
150–159. access in the United States: an ecological study. J. Clin. Psychiatry 67 (4),
Pompili, M., Rihmer, Z., Innamorati, M., et al., 2009. Assessment and treatment of 517–523.
suicide risk in bipolar disorders. Expert Rev. Neurother. 9, 109–136. Tripodianakis, J., Markianos, M., Sarantidis, D., et al., 2000. Neurochemical variables
Pompili, M., Rihmer, Z., Akiskal, H., et al., 2012. Temperaments mediate suicide risk in subjects with adjustment disorder after suicide attempts. Eur. Psychiatry 15,
and psychopathology among patients with bipolar disorders. Compr. Psychiatry 190–195.
53 (3), 280–285. Trouvin, J.H., Prioux-Guyonneau, M., Cohen, Y., et al., 1986. Rat brain monoamine
Pompili, M., Rihmer, Z., Akiskal, H., et al., 2012. Temperaments mediate suicide risk metabolism and hypobaric hypoxia: a new approach. Gen. Pharmacol. 17,
and psychopathology among patients with bipolar disorders. Compr. Psychiatry 69–73.
53 (3), 280–285. Tsai, S.Y., Kuo, C.J., Chen, C.C., et al., 2002. Risk factors for completed suicide in
Potash, J.B., Kane, H.S., Chiu, Y.-F., et al., 2000. Attempted suicide and alcoholism in bipolar disorder. J. Clin. Psychiatry 63, 469–476.
bipolar disorder: clinical and familial relationships. Am. J. Psychiatry 157, Undurraga, J., Baldessarini, R.J., Valentı´, M., et al., 2011. Dissimilar suicidal risk
2048–2050. factors in bipolar I and II disorders. J. Clin. Psychiatry.
Quiroz, J.A., Gould, T.D., Manji, H.K., et al., 2004. Molecular effects of lithium. Mol. Undurraga, J., Baldessarini, R.J., Valenti, M., et al., 2012. Suicidal risk factors in
Interv. 4, 259–272. bipolar I and II disorder patients. J. Clin. Psychiatry 73 (6), 778–782.
Quiroz, J.A., Gray, N.A., Kato, T., et al., 2008. Mitochondrially mediated plasticity in Vaccari, A., Brotman, S., Cimino, J., et al., 1978. Adaptive changes induced by high
the pathophysiology and treatment of bipolar disorder. Neuropsychopharma- altitude in the development of brain monoamine enzymes. Neurochem. Res. 3,
cology 33, 2551–2565. 295–311.
254 L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

Valtonen, H.M., Suominen, K., Mantere, O., et al., 2006. Prospective study of risk Wulsin, L.R., Vaillant, G.E., Wells, V.E., 1999. A systematic review of the mortality of
factors for attempted suicide among patients with bipolar disorder. Bipolar depression. Psychosom. Med. 61, 6–17.
Disord. 8 (5 Pt 2), 576–585. Yerevanian, B., Feusner, J., Koek, R., et al., 2004. The dexamethasone suppression
WHO, 2011. Causes of Death 2008: Data Sources and Methods Department of test as a predictor of suicidal behavior in unipolar depression. J. Affect. Disord.
Health Statistics and Informatics. World Health Organization, Geneva. 83, 103.
Wang, P.W., Sachs, G.S., Zarate, C.A., et al., 2006. Overweight and obesity in bipolar Yoon, Y.H., Chen, C.M., Moss, H.B., 2011. Effect of comorbid alcohol and drug use
disorders. J. Psychiatr. Res. 40, 762–764. disorders on premature death among unipolar and bipolar disorder decedents
Weinstock, L.M., Miller, I.W., 2008. Functional impairment as a predictor of short- in the United States, 1999–2006. Compr. Psychiatry 52 (5), 453–464.
term symptom course in bipolar I disorder. Bipolar Disord. 10, 437–442. Zhu, W., Bijur, G.N., Styles, N.A., et al., 2004. Regulation of FOXO3a by brainderived
Weissman, M.M., Bland, R.C., Canino, G., et al., 1999. Prevalence of suicide ideation neurotrophic factor in differentiated human SH SY5Y neuroblastoma cells.
and suicide attempts in nine countries. Psychol. Med. 29, 9–17.
Brain Res. Mol. Brain Res. 126, 45–56.
World Health Organization (WHO). International suicide rates. 2003.