Journal of Affective Disorders 170 (2015) 237–254

Contents lists available at ScienceDirect

Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Review

Risk factors for suicide in bipolar disorder: A systematic review Lucas da Silva Costa a,n, Átila Pereira Alencar a, Pedro Januário Nascimento Neto a, Maria do Socorro Vieira dos Santos a, Cláudio Gleidiston Lima da Silva b, Sally de França Lacerda Pinheiro b, Regiane Teixeira Silveira b, Bianca Alves Vieira Bianco b, Roberto Flávio Fontenelle Pinheiro Júnior c, Marcos Antonio Pereira de Lima c, Alberto Olavo Advincula Reis d, Modesto Leite Rolim Neto e a

Laboratório de Escrita Científica, Faculdade de Medicina, Universidade Federal do Cariri, UFCA, Barbalha, Ceará, Brazil 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 d Programa de Pós-Graduação em Saúde Pública, Faculdade de Saúde Pública, Universidade de São Paulo, USP, São Paulo, São Paulo, Brazil e Líder de Grupo de Pesquisa em Suicidologia, Universidade Federal do Ceará, UFC/Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq, Faculdade de Medicina, Universidade Federal do Cariri, UFCA, Barbalha, Ceará, Brazil b c

art ic l e i nf o

a b s t r a c t

Article history: Received 30 July 2014 Received in revised form 18 August 2014 Accepted 2 September 2014 Available online 16 September 2014

Background: Bipolar disorder confers the highest risk of suicide among major psychological disorders. The risk factors associated with bipolar disorder and suicide exist and are relevant to clinicians and researchers. Objective: The aim of the present study was to conduct a systematic review of articles regarding the suicide risk factors in bipolar disorder. Methods: A systematic review of articles on suicide risk factors in bipolar disorder, published from January 1, 2010 to April 05, 2014, on SCOPUS and PUBMED databases was carried out. Search terms were “Suicide” (medical subject headings [MeSH]), “Risk factors” (MeSH), and “Bipolar” (keyword). Of the 220 retrieved studies, 42 met the eligibility criteria. 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.

Keywords: Bipolar Suicide Risk factors

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Risk factors associated with sociodemographic components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

238 238 238 239 246

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

http://dx.doi.org/10.1016/j.jad.2014.09.003 0165-0327/& 2014 Elsevier B.V. All rights reserved.

238

L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

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

247 248 248 249 250 251 251 251 251 251

1. Introduction

We performed a qualitative systematic review of articles about suicide risk factors in bipolar affective disorder in previously chosen electronic databases. A search of the literature was conducted via PubMed and SCOPUS online databases in April 2014 and was limited to articles published from January 1, 2010 to April 6, 2014. The reason for limiting the search to 2010–2014 was that, during this period, there was an expansion of research into new types of comorbidities that influence the risk of suicide in Bipolar disorder, such as hopelessness, altitude and religiosity. Therefore, the Bipolar Affective Disorder and its association with suicide had greater relevance in the scientific community. Initially, the search terms browsed in SCOPUS database were

with the theme object of the present review. The search strategy and the retrieved articles were reviewed on two separate occasions to ensure adequate sampling. A similar search strategy was performed in the PubMed database, using the aforementioned terms and their correspondent terms. The article analysis followed previously determined eligibility criteria. We adopted the following inclusion criteria: Goldstein et al. (2012) references written in English; Goodwin and Jamison (2007) studies pertaining suicide risk factors in bipolar affective disorder; Eroglu et al., (2013) original articles with online accessible full text available in database SCOPUS, PubMed or CAPES (Higher Education Co-ordination Agency) Journal Portal (Periodicos.capes.gov.br, 2014), a virtual library linked to Brazil's Ministry of Education and subjected to content subscription; (Simon et al., 2007) articles that included in the title at least one combination of terms described in the search strategy; (Weissman et al., 1999) case reports, cohort studies, controlled clinical trials and case-control studies; Kheirabadi et al. (2012) articles that appear in more than one database will be included only once, giving priority to the SCOPUS database. Exclusion criteria were: Goldstein et al. (2012) studies that did not include the proposed topic; Goodwin and Jamison (2007) non-original studies, including editorials, reviews, prefaces, brief communications and letters to the editor. Then, each paper in the sample was read in entirety, and data elements were then extracted and entered into a matrix that included authors, journal, description of the study sample, and main findings. Some of the studies dealt not only with the risk factors associated with bipolar disorder, but also to the risk factors in other psychiatric disorders, such as schizophrenia and mood disorder; because the focus of this study was the risk factors associated with suicide in bipolar disorder, studies related to psychiatric disorders in general were not recorded or analyzed for this study. To provide a better analysis, the next phase involved comparing the studies and grouping. For heuristic reasons, the results regarding the studied subject into six categories: Risk factors associated with sociodemographic components; Risk factors associated with genetic components; Risk factors associated with Medicines and Drugs in general that interfere with bipolar disorder; Risk factors associated with Biological components; Risk factors associated with Psychological causes; and Risk factors associated with components of Religious 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. In addition to MeSH terms, we opted to add the keyword “bipolar” to the search strategy, because, despite not being included in the MeSH thesaurus, it is frequently used to describe studies that deal

Initially, the aforementioned search strategies resulted in 220 references. After browsing the title and abstract of the retrieved citations for eligibility based on study inclusion criteria, 178 articles were excluded and 42 articles were further retrieved and included

Bipolar disorder confers the highest risk of suicide among major psychological disorders (Goldstein et al., 2012; Goodwin and Jamison, 2007). Suicide attempts and completed suicide are significantly more common in patients with bipolar disorder when compared with the general population (Eroglu et al., 2013; Simon et al., 2007; Weissman et al., 1999). Bipolar spectrum disorders, especially recurrent depressive episodes, is the major risk of repeated suicide attempt and co-morbidity of another psychiatric disorders increase highly the risk of suicide reattempt (Kheirabadi et al., 2012). In particular, among mental disorders, bipolar disorder is one of the leading causes of suicidal behaviors and this is a major issue in the management of the disease. About 50% of patients with bipolar disorder will experience at least one suicide attempt (Jamison, 2000) and 11–19% will commit suicide (Goodwin and Jamison, 2007; Abreu et al., 2009; Angst et al., 2005; Harris and Barraclough, 1997; Parmentier et al., 2012). This study is based on the following research question: what is the main suicide risk factors associated with bipolar disorder? This issue has gained great impact in recent years with the establishment of new risk factors for suicide and bipolar disorder. Thus, this systematic review aims to present the main risk factors and compares them, since the applicant was disagreement among authors. Therefore, it is suggested, that further studies are needed in order to establish a stronger relationship between bipolar disorder and its risk factors that culminate in suicide.

2. Methods

L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

in the final sample Fig. 1). Articles from SCOPUS and PubMed database matched the inclusion criteria of the present study. Table 1 provides an overview of all studies included in the final sample and of all data elements used during the data analysis process. Study designs included one case report (Kerner et al., 2013), seven transversal studies (Goldstein et al., 2012; Kheirabadi et al., 2012; Undurraga et al., 2012; De Abreu et al., 2012; Algorta et al., 2011; Evans et al., 2012; Gomes et al., 2010), nineteen cohort studies (Parmentier et al., 2012; Huber et al., 2014; Ruengorn et al., 2012; Etain et al., 2013; Cassidy, 2011; Baldessarini et al., 2012; Bellivier et al., 2011; Sears et al., 2013; Jiménez et al., 2013; Leon et al., 2012; Finseth et al., 2012; Oquendo et al., 2010; Kenneson et al., 2013; Gilbert et al., 2011; Shabani et al., 2013; Pompili et al., 2012; Acosta et al., 2012; Song et al., 2012; Suttajit et al., 2013), and fifteen case-control studies (Eroglu et al., 2013; Antypa et al., 2013; Ryu et al., 2010; Manchia et al., 2013; Neves et al., 2010; Magno et al., 2011; Yoon et al., 2011; Arias et al., 2013; Clements et al., 2013; Pawlak et al., 2013; Kamali et al., 2012; de Moraes et al., 2013; Azorin et al., 2013; Dervic et al., 2011; Pawlak et al., 2013). The 42 studies were distributed into the previously determined six categories as follows: Risk factors associated with sociodemographic components (seven studies) (Huber et al., 2014; De Abreu et al., 2012; Ruengorn et al., 2012; Algorta et al., 2011; Cassidy, 2011; Antypa et al., 2013; Ryu et al., 2010); Risk factors associated with genetic components (six studies) (Manchia et al., 2013; Sears et al., 2013; Neves et al., 2010; Magno et al., 2011; Jiménez et al., 2013; Kerner et al., 2013); Risk factors associated with Medicines and Drugs in general that interfere with bipolar disorder (eight studies)

239

(Bellivier et al., 2011; Yoon et al., 2011; Leon et al., 2012; Arias et al., 2013; Clements et al., 2013; Finseth et al., 2012; Oquendo et al., 2010; Kenneson et al., 2013); Risk factors associated with Biological components (three studies) (Kamali et al., 2012; Evans et al., 2012; Gomes et al., 2010); Risk factors associated with Psychological causes (seven studies) (Parmentier et al., 2012; Shabani et al., 2013; Pompili et al., 2012; Acosta et al., 2012; Song et al., 2012; Suttajit et al., 2013; Stewart et al., 2009); and Risk factors associated with components of Religious and Spiritual (three studies) components (Azorin et al., 2013; Dervic et al., 2011; Pawlak et al., 2013). Among the 42 studies, 8 discussed about “suicide risk factors in Bipolar Affective disorder” — more broadly (Goldstein et al., 2012; Eroglu et al., 2013; Kheirabadi et al., 2012; Undurraga et al., 2012; Etain et al., 2013; Baldessarini et al., 2012; Pawlak et al., 2013; Gilbert et al., 2011), being refered in more than one category. The categorization of studies aims to a better organizational quality systematic review and it is not compulsory that each article must be referenced only in their respective category.

4. Discussion Bipolar disorder (BD) is a major public health concern worldwide, and is associated with significant morbidity and mortality (Kupfer, 2005). In addition to an increased rate of death by suicide, community and clinical studies indicate that bipolar patients usually present a broadrange of comorbid general medical conditions, which contribute

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 (2012) Psychiatry

A total of 413 youths (mean [SD] age, 12.6 [3.3] years) who received Of the 413 youths with bipolar disorder, 76 (18%) made at least 1 suicide attempt within 5 years of a diagnosis of bipolar I disorder (n¼244), bipolar II disorder study intake; of these, 31 (8% of the entire sample (n¼ 28), or bipolar disorder not otherwise specified (n¼141). 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. (2013)

Dusunen Adam

One hundred twenty two consecutive patients, from Bipolar Disorder Unit of Çukurova University, Faculty of Medicine, Department of Psychiatry, are included in this study.

Kheirabadi et al. (2012)

Iranian Journal of Epidemiology

Participants consisted of 703 individuals (424 of them were female) Bipolar spectrum disorders, unipolar depression and 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 et al. (2012)

European Psychiatry

In a sample of 652 euthymic bipolar patients, we assessed clinical features with the Diagnostic Interview for Genetics Studies (DIGS) and dimensional characteristics with questionnaires measuring impulsivity/hostility and affective lability/intensity.

Of the 652 subjects, 42.9% had experienced at least one suicide attempt. Lifetime history of suicidal behavior was associated with being a woman, a history of head injury, tobacco misuse and indicators of severity of bipolar disorder including early age at onset, high number of depressive episodes, positive history of rapid cycling, alcohol misuse and social phobia. Indirect hostility and irritability were dimensional characteristics associated with suicidal behavior in bipolar patients, whereas impulsivity and affective lability/intensity were not associated with suicidal behavior.

Huber et al. (2014)

Medical Hypotheses

Data were available for 16 states for the years 2005–2008, representing a total of 35,725 completed suicides in 922 U.S. counties.

Altitude was a significant, independent predictor of the altitude at which suicides occurred (F¼ 8.28, p ¼ 0.004 and Wald chi-square.¼ 21.67, p o 0.0001). Least squares means of altitude, independent of other variables, indicated that individuals with BD committed suicide at the greatest mean altitude. Moreover, the mean altitude at which suicides occurred in BD was significantly higher than in decedents whose mental health diagnosis was major depressive disorder (MDD), schizophrenia, or anxiety disorder.

Undurraga et al. (2012)

Journal of Clinical Psychiatry

Accordingly, we compared selected demographic and clinical factors for long-term association with nonlethal suicidal acts or ideation in 290 DSM-IV bipolar I (n¼ 204) and II (n¼ 86) disorder patients followed for a mean of 9.3 years at the University of Barcelona, using preliminary bivariate comparisons followed by multivariate logistic regression modeling.

Rates of suicidal ideation (41.5%) and acts (19.7%) were similarly prevalent with bipolar I and II disorders and somewhat more common among women. Factors significantly and independently associated with suicidal acts were determined by multivariate modeling and ranked in order of their strength of association: suicidal ideation, more mixed episodes, Axis II comorbidity, female sex, more antidepressant trials, rapid cycling, predominant lifetime depression, having been hospitalized, older onset, and longer delay of diagnosis.

De Abreu et al. Comprehensive Psychiatry (2012)

The prevalence of suicide attempt was 19.7% in the outpatient group. Lifetime history of suicidal 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.

One hundred eight patients with Diagnostic and Statistical Manual Patients with BD and previous suicide attempts had 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 ) Sample

Main findings

suicide attempts, 64 without previous suicide attempts) were studied.

World Health Organization's Quality of Life 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 (2012) Behavior Management

Medical files of 489 patients diagnosed with BD at Suanprung Psychiatric Hospital between October 2006 and May 2009 were reviewed.

Six statistically significant indicators associated with suicide attempts were included in the risk-scoring 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. (2011)

Bipolar Disorders

Participants were 138 youths aged 5–18years presenting to outpatient clinics with DSM-IV diagnoses of bipolar I disorder (n¼ 27), bipolar II disorder (n¼ 18), cyclothymic disorder (n¼ 48), and bipolar disorder not otherwise specified (n ¼45).

Twenty PBD patients had lifetime suicide attempts, 63 had past or current suicide ideation, and 55 were free of suicide ideation and attempts. Attempters were older than nonattempters. Suicide ideation and attempts were linked to higher depressive symptoms, and rates were even higher in youths meeting criteria for the mixed specifier proposed for DSM-5. Both suicide ideation and attempts were associated with lower youth QoL and poorer family functioning. Parent effects (with suicidality treated as outcome) and child effects (where suicide was the predictor of poor family functioning) showed equally strong evidence in regression models, even after adjusting for demographics.

Etain et al. (2013)

Journal of Clinical Psychiatry

587 patients with DSM-IV-defined bipolar disorder were recruited Multivariate analyses investigating trauma variables together showed that both emotional and sexual from France and Norway between 1996-2008 and 2007-2012, abuse were independent predictors of lower age at respectively. 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 LifeThreatening Behavior

The study cohort included 87 males and 70 females. Ninety-six were White and sixty-one were Black.

Gender, nicotine use, medical comorbidity, and history of alcohol and other drug abuse were not, although a trend was noted for a history of benzodiazepine abuse.

Blair-West et al. (1999)

Journal of Psychiatric Research

Data was collected from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. 3083 bipolar patients were included in this report, among these 140 (4.6%) had a suicide event (8 died by suicide and 132 attempted suicide).

The strongest predictor of a suicide event was a history of suicide attempt (hazard ratio¼ 2.60, pvalue o 0.001) in line with prior literature. Additional 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. (1996)

Yonsei Med J.

A total of 579 medical records were retrospectively reviewed.

The prevalence of suicide attempt was 13.1% in our 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. (1988)

Acta Psychiatrica Scandinavica

We tested factors for association with predominantly (Z 2:1) depressive vs. mania-like episodes with 928 DSM-IV type-I BPD subjects from five international sites.

Factors preliminarily associated with predominantdepression included: electroconvulsive treatment, longer latency-to-BPD diagnosis, first episode depressive or mixed, more suicide attempts, more Axis-II comorbidity, ever having mixed-states, ever

Authors

Journal

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 'predominantdepression' increased risk of suicidal acts from 2.4to 4.5-fold excess over predominant-maniahypomania, and suicidal risk was associated continuously with increasing proportions of depressive or mixed episodes.

Akiskal et al. (1995)

Bipolar Disorders

European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) is a two-year, prospective, observational study that enrolled 3,684 adult patients with bipolar disorder and initiated or changed oral treatment for an acute manic/mixed episode.

Of the 2,219 patients who provided data on their lifetime history of suicide attempts, 663 (29.9%) had a history of suicidal behavior (at least one attempt). Baseline factors associated with a history of suicidal behavior included female gender, a history of alcohol abuse, a history of substance abuse, young age at first treatment for a mood episode, longer disease duration, greater depressive symptom severity (HAMD-5 total score), current benzodiazepine use, higher overall symptom severity (CGI-BP: mania and overall score), and poor compliance.

McIntyre et al. (2008)

Bipolar disorders

We studied 737 families of probands with MAD with 4919 firstdegree relatives (818 affected, 3948 unaffected, and 153 subjects with no information available).

The estimated lifetime prevalence of suicidal behavior (attempted and completed suicides) in 737 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., (1978)

Journal of Affective Disorders

We used family-based association testing in a cohort of 130 multiplex bipolar pedigrees, comprising 795 individuals, to look for associations between suicidal behavior and 32 single nucleotide polymorphisms (SNPs) from across the genes brain-derived neurotrophic factor (BDNF), cholecystokinin (CCK) and the cholecystokinin beta-receptor (CCKBR).

We found associations (p r 0.05) between suicide attempt and 12 SNPs of CCKBR and five SNPs of BDNF. After correction for multiple testing, seven SNPs of CCKBR remained significantly associated. No association was found between CCK and suicidal behavior.

WHO (2011)

Journal of Affective Disorders

We evaluated 198 bipolar patients and 103 health controls, using a We found that 26.77% and 16.67% had a lifetime 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 et al. (2006)

Journal of Affective Disorders

TaqMan genotyping was used to detect FOXO3A SNPs in 273 BD patients and 264 control subjects.

Dwivedi et al. (2003)

European Polymorphisms at the IMPA1 (rs915, rs1058401 and rs2268432) Neuropsychopharmacology and IMPA2 (rs66938, rs1020294, rs1250171 and rs630110), INPP1 (rs3791809, rs4853694 and 909270), GSK3α (rs3745233) and GSK3β (rs334558, rs1732170 and rs11921360) genes were genotyped.

Three SNPs (rs1536057, rs2802292 and rs1935952) were associated with BD, but none was positively linked with suicidal behavior. Single SNP analyses showed that suicide attempters had higher frequencies of AA genotype of the rs669838-IMPA2 and GG genotype of the rs4853694INPP1gene compared to non-attempters. Results also revealed that T-allele carriers of the rs1732170GSK3β gene and A-allele carriers of the rs11921360GSK3β 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 ) Main findings

Authors

Journal

Sample

Polter et al. (2009)

Front Psychiatry

Here, we describe a family with four siblings, three affected females Our results support a new model for psychiatric 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. (2013)

Compr Psychiatry.

This study is based on the US Multiple Cause of Death public-use data files for 1999 to 2006. Secondary data analysis was conducted comparing decedents with unipolar/bipolar disorders and decedents with all other causes of death, based on the death records of 19,052,468 decedents in the Multiple Cause of Death data files who died at 15 years and older

Prevalence of comorbid SUDs was higher among unipolar and bipolar disorder deaths than that among all other deaths. Among unipolar and bipolar disorder deaths, comorbid SUDs were associated with elevated risks for suicide and other unnatural death in both men and women (prevalence ratios ranging 1.49–9.46, P o0.05). They also were associated with reductions in mean ages at death (ranging 11.7–33.8 years, Po 0.05). In general, these effects were much stronger for drug use disorders than for alcohol use disorders. Both SUDs had stronger effects on suicide among women, whereas their effects on other unnatural deaths were stronger among men.

Nilsson et al., (2002)

American Journal of Psychiatry

Analyses included 199 participants with bipolar disorder for whom 1077 time intervals were classified as either exposed to an antiepileptic (carbamazepine, lamotrigine, or valproate) or not exposed to an antiepileptic, an antidepressant, or lithium during 30 years of follow-up.

Participants who had more severe manic symptoms were more likely to receive antiepileptic drugs. Mixed-effects grouped-time survival models revealed no elevation in risk of suicide attempt or 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., (2008)

Mental Health and Substance Use: Dual Diagnosis

The sample consisted of 837 outpatients from Madrid, Spain. We compared 528 subjects with a lifetime diagnosis of alcohol abuse or dependence and 182 with other substance use disorders (SUDs) not involving alcohol.

It was considered that 76.1% of the alcohol addicts had a current dual diagnosis, the most prevalent being mood and anxiety disorders. Fifty-two percent had a personality disorder and most of them (81.6%) had other SUDs. 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. (2002)

Psychological Medicine

During the study period 1489 individuals with BD died by suicide, Compared to other primary diagnosis suicides, those 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 (2013) Psychiatry

The aim of the study was to look for suicide risk factors among sociodemographic and clinical factors, family history and stressful life events in patients with diagnosis of unipolar and bipolar affective disorder (597 patients, 563 controls).

In the bipolar and unipolar affective disorders sample, we observed an association between suicidal attempts and the following: family history of psychiatric disorders, affective disorders and psychoactive substance abuse/dependence; inappropriate guilt in depression; chronic insomnia and early onset of unipolar disorder. The risk of suicide attempt differs in separate age brackets (it is greater in patients under 45 years old). No difference in family history of suicide and suicide attempts; marital status; offspring; living with family; psychotic symptoms and irritability; and coexistence of personality disorder, anxiety disorder or substance abuse/dependence with affective disorder was observed in the groups of patients with and without suicide attempt in lifetime history.

Pawlak et al. (2013)

A total of 206 consecutive patients (mean age 42 715years; 54.9% women) with DSM-IV diagnosed BD-I (n¼140) and BD-II (n¼ 66) acutely admitted to a single psychiatric hospital department from November 2002 through June 2009 were included.

Ninety-three patients (45.1%) had a history of one or more serious suicide attempts. These constituted 60 (42.9%) of the BD-I patients and 33 (50%) of the BD-II patients (no significant difference). Lifetime suicide attempt was associated with a higher number of hospitalizations due to depression (po 0.0001),

Bipolar Disorders

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. (2009)

Journal of Clinical Psychiatry

1,643 individuals with a DSM-IV lifetime diagnosis of bipolar disorder were identified from 43,093 general-population respondents who were interviewed in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions.

More than half of the respondents (54%) who met criteria for bipolar disorder also reported alcohol use disorder. Bipolar individuals with comorbid alcohol 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., (2001)

Comprehensive Psychiatry

Using data collected from the National Comorbidity Survey Replication study, we identified 158 individuals with childhoodonset ( o13 years) or adolescent-onset (13-18 years) primary bipolar disorder (I, II or subthreshold).

Compared to adolescent-onset, people with childhood-onset bipolar disorder had increased likelihoods of attention deficit hyperactivity disorder (ADHD) (adjusted odds ratio¼2.81) and suicide attempt (aOR ¼3.61). Males were more likely than females to develop SUD, and did so at a faster rate. Hazard ratios of risk factors for SUD were: lifetime oppositional defiant disorder (2.048), any lifetime anxiety disorder (3.077), adolescent-onset bipolar disorder (1.653), and suicide attempt (15.424). SUD was not predicted by bipolar disorder type, family history of bipolar disorder, hospitalization for a mood episode, ADHD or conduct disorder.

Oquendo et al. (2010)

Journal of Clinical Psychiatry

We found that nonattempters reported significantly Participants included 67 adult inpatients and outpatients aged 18-60 years meeting DSM-IV criteria for bipolar disorder (bipolar I higher trait impulsivity scores on the Barratt Impulsiveness Scale compared to attempters (t and II disorders, bipolar disorder not otherwise specified). 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., (2005)

Journal of Affective Disorders

Salivary cortisol was collected for three consecutive days in 29 controls, 80 bipolar individuals without a history of suicide and 56 bipolar individuals with a past history of suicide. Clinical factors that affect salivary cortisol were also examined.

A past history of suicide was associated with a 7.4% higher bedtime salivary cortisol level in bipolar individuals. There was no statistical difference between non-suicidal bipolar individuals and controls in bedtime salivary cortisol and awakening salivary cortisol was not different between the three groups.

Yerevanian PLoS ONE et al., (2004)

We studied 27 bipolar subjects using the NEO-PI

We found positive associations between personality 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. (2012)

Acta Neuropsychiatrica

Two hundred fifty-five DSM-IV out-patients with bipolar disorder were consecutively recruited from the Bipolar Disorder Program at Hospital das Clínicas de Porto Alegre and the University Hospital at the Universidade Federal de Santa Maria, Brazil.

Over 30% of the sample was obese and over 50% had a history of suicide attempt. In the multivariate model, obese patients were nearly twice (OR ¼1.97, 95% CI: 1.06–3.69, p ¼ 0.03) as likely to have a history of suicide attempt(s).

Azorin et al. (2009)

Iranian Journal of Psychiatry and Behavioral Sciences

One hundred patients were followed for 2–42 months (mean: 20.6 7 12.5 months).

Only one patient attempted suicide during the follow-up period. 33% of the patients had history of 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 et al. (2011)

Comprehensive Psychiatry

Participants were 216 consecutive inpatients (97 men and 119 women) with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), BD who were admitted to the Sant'Andrea Hospital's psychiatric ward in Rome (Italy).

Patients with BD-II had higher scores on the BHS (9.78 7 5.37 vs. 6.87 7 4.69; t143.59 ¼  3.94; P o 0.001) than patients with BD-I. Hopelessness was associated with the individual pattern of temperament traits (i.e., the relative balance of hyperthymic vs. cyclothymic-irritable-anxiousdysthmic). 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. (2013)

Comprehensive Psychiatry

A sample of 102 outpatients with a diagnosis of bipolar disorder according to International Classification of Diseases, 10th Revision criteria during nonsyndromal stage were evaluated.

As compared with the nonsuicidal group, female sex, combined psychopharmacologic treatment, and 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 Mental Disease

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

Weinstock and Neuropsychiatric Disease Miller (2008) and Treatment

The data of 383 bipolar I disorder patients were included in the analyses.

Pompili et al. (2012)

Psicologia: Reflexao e Critica

The Iowa Gambling Task and the Conner's Continuous Performance A factorial analysis evaluated the adequacy of the instruments. Furthermore, a multiple regression Test evaluated impulsivity in 95 euthymic bipolar patients -42 analysis was done in order to develop a model to suicide attempters and 115 normal control participants. 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 Psychiatric Association (2003)

Journal of Affective Disorders

As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 234 (55.2%) could be classified as with high religious involvement (HRl), and 190 (44.8%) as with low religious involvement (LRl), on the basis of their ratings on the Duke Religious lndex (DRl).

Compared to LRl, HRl patients did not differ with respect to their religious affiliation but had a later age at onset of their affective illness with more hospitalizations, suicide attempts, associated hypomanic features, switches under antidepressant treatment, prescription of tricyclics, comorbid obsessive compulsive disorder, and family history of affective disorder in first-degree relatives.

A retrospective case control study of 149 depressed bipolar patients (DSM-III-R criteria) in a tertiary care university research clinic was conducted. Patients who reported religious affiliation were compared with 51 patients without religious affiliation in terms of sociodemographic and clinical characteristics and history of suicidal behavior.

Religiously affiliated patients had more children and more family-oriented social networks than nonaffiliated patients. As for clinical variables, religiously affiliated patients had fewer past suicide attempts, had fewer suicides in first-degree relatives, and were older at the time of first suicide attempt than unaffiliated patients. Furthermore, patients with religious affiliation had comparatively higher scores on the moral or religious objections to suicide subscale of the RFLI, lower lifetime aggression, and less comorbid alcohol and substance abuse and childhood abuse experience. After controlling for confounders, higher aggression scores (P¼ 0.001) and lower score on the moral or religious objections

Journal of Clinical World Health Organization Psychiatry (WHO) (2003)

The demographic/clinical variables significantly associated with the MINI suicide risk scores included age, number of overall previous episodes, the Young Mania Rating Scale score, the Montgomery Asberg Depression Rating Scale scores, and the Clinical Global Impression Severity of Illness Scale for Bipolar Disorder mania score, depression score, and overall score. The variables affecting the differences of suicide risk scores between or among groups were type of first mood episode, a history of rapid cycling, anxiety disorders, and alcohol use disorders.

246

L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

Table 1 (continued ) Authors

Journal

Main findings

Sample

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. (2013)

General Hospital Psychiatry

The aim of the study was looking for suicide risk factors among personality dimensions and value system in patients with diagnosis of unipolar and bipolar affective disorder (n¼ 189 patients, n¼ 101 controls).

to overall mortality rates (Angst et al., 2002; Roshanaei-Moghaddam and Katon, 2009). The risk of suicide for individuals with BD is approximately 60 times greater than that of the general population (Simon et al., 2007). Fifteen to twenty percent of individuals with BD complete suicide and up to 40% report at least one suicide attempt during their lifetime (Simon et al., 2007). The ratio of suicide attempts to completed suicides for the general population is 35:1, but for individuals with BD, the same ratio is 3:1 (Simon et al., 2007). In fact, it is estimated that BD may account for one-quarter of all completed suicides (American Psychiatric Association, 2013; Huber et al., 2014). However, unlike other authors included in this review, Undurraga et al., (2012) concluded that suicidal risk-factors found to be independent of bipolar disorder. This fact, as well as the different conclusions reached by the authors, which will be demonstrated below, exposes the need for further research. 4.1. Risk factors associated with sociodemographic components Quality of life seems to be associated with suicidal behaviors (i.e., suicidal ideation, suicide attempts, and complete suicide) in the general population and in psychiatric patients (De Abreu et al., 2012). A recent review showed that Quality of Life (QoL) is markedly impaired in patients with BD, even when they are clinically euthymic (De Abreu et al., 2012; Michalak et al., 2005). Also, stressful life event(s) was another preponderant factor predicting suicide attempts, and has played an important role in predicting suicide attempts among BD patients in many studies, particularly during depressive phases (Azorin et al., 2009; Ruengorn et al., 2012). De Abreu et al. (2012) hypothesized that patients with BD and previous suicide attempts would have worse QoL than patients with BD but no previous suicide attempts . It is possible that low QoL may reflect the existence of poor coping skills and inadequate social support, which in turn may increase the risk for suicide attempts (De Abreu et al., 2012). Further prospective studies are needed to clarify the causal and temporal relationships between low QoL and suicide attempts (De Abreu et al., 2012). Pediatric Bipolar Disorder (PBD), for example, is associated with substantially lower average QoL than found with many other major medical illnesses, and worse than other mental illnesses in youth except for major depression (Freeman et al., 2009; Algorta et al., 2011). Suicidality and lower youth QoL both were significantly associated with worse family functioning (Algorta et al., 2011). Poor family functioning, poor youth QoL, and mixed features will each make unique contributions to suicidality as an outcome variable (Algorta et al., 2011). Also, Etain et al. (2013)

The main limitations of the study are number of participants, lack of data about stressful life events and treatment with lithium. Novelty seeking and harm avoidance dimensions constituted suicide attempt risk factors in the group of patients with affective disorders. Protective role of cooperativeness was discovered. Patients with and without suicide attempt in lifetime history varied in self-esteem position in Value Survey.

demonstrated consistent associations between childhood trauma and more severe clinical characteristics in bipolar disorder . Moreover, family history of completed suicide had the highest odds ratio of significant findings. In previous reports in bipolar cohorts (Galfavy et al., 2006; Valtonen et al., 2006), family history of suicide was no different between bipolar patients with and without histories of attempts, although one study reported family history was predictive of earlier attempts (Galfavy et al., 2006; Cassidy, 2011). Also, the higher frequency of bipolar disorder family history in agitated depression suggests that a bipolar vulnerability may be required to obtain such clustering of hypomanic symptoms (Akiskal et al., 2005). Overall, findings support an association between family functioning and suicidality within families where youths have bipolar disorder (Miklowitz and Chang, 2008). Results suggest that it is plausible that the youth's illness may play an active role in disrupting family processes. Bipolar disorder may involve a potent combination of mood dysregulation and interpersonal processes where threats of harm — against oneself or another — may occur both impulsively and/or instrumentally (Algorta et al., 2011). In fact, bipolar disorder imparts the greatest risk for completed suicide among youth (Goldstein et al., 2012). With regard to age groups at risk for suicidal behavior, prior literature suggests that young-aged patients are at higher risk of suicide compared to older patients, in line with the finding of this report. Studies with depressed patients have shown that young patients report a higher number of suicide attempts (Blair-West et al., 1999; Antypa et al., 2013; Azorin et al., 2010). Although no association was found between age and suicide attempts (Azorin et al., 2009). Studies of adolescent suicide completers document the substantial contribution of parental depression to offspring suicide risk (Gould et al., 1996), even after accounting for the child's depressive severity (Brent et al., 1993). It is possible that familial depression contributes to offspring suicide risk via multiple avenues, including decreased familial support and increased conflict (Goldstein et al., 2012; Brent et al., 1994). Ryu et al. (2010) investigated the descriptive characteristics of suicide attempts and the risk factors for suicide attempts in Korean bipolar patients by assessing sociodemographic factors, clinical factors, and the methods of suicide attempts using retrospective reviews of medical records . Ryu et al. (2010) reviewed medical records of all 601 patients who were admitted to the psychiatric wards in one mental hospital and three general hospitals (Ryu et al., 2010). The 579 subjects who were included in the final analysis was comprised of 262 (45.3%) men and 317 (54.7%) women (Ryu et al., 2010). Ryu et al. (2010) found two significant risk factors associated. First, they found that patients with depressive first episodes appear to be higher in suicide attempters. Bipolar patients with

L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

a depressive episode at their initial admission or first episode tend to have a depressed mood at the next episode (Daban et al., 2006; Perugi et al., 2000). Moreover, 60% of suicide attempters with depressive episodes commit suicide at the first mood episode (Balázs et al., 2003). Prolonged exposure to depressive episodes might increase the risk of suicide attempts in bipolar patients and poor prognostic factor in suicide related behavior (Valtonen et al., 2006; Ryu et al., 2010). Second it was observed that bipolar II patients have a higher risk for suicide attempts. Bipolar II patients are known to have greater risk of suicide than bipolar I patients (Balázs et al., 2003; Arató et al., 1988). Bipolar II patients show a predominantly depressive mood, mood lability, and mixed nature (Akiskal et al., 1995; Benazzi 2007). Bipolar II patients are likely to have depressive or mixed episodes at hospital admission rather than bipolar I patients (Ryu et al., 2010). Also, there is a stronger continuous relationship of suicidal risk with the proportion of total recurrences that were depressive-or-mixed vs. depressive (Baldessarini et al., 2012). Baldessarini et al. (2012) has shown a strong association of predominant depression, especially with mixed-episodes included, with suicidal behavior. Furthermore, suicide attempts were observed in both males and females at similar rates. Moreover, females who attempted suicide were as likely to have attempted suicide by a more violent method as males (Cassidy, 2011). Although, it was observed that some authors categorized the female gender as a risk factor (Bellivier et al., 2011). Parmentier et al. (2012) observed that reported rates of suicide attempts among women with bipolar disorders are about twice as high as among men with bipolar disorders, suggesting greater lethality of suicide attempts in men (Parmentier et al., 2012; Suicidology AAo, 2000; Tondo et al., 2006). Ruengorn et al. (2012) proposed a risk-scoring scheme for suicide attempts in Thai patients with BD. Ruengorn et al. (2012) conducted a study at Suanprung Psychiatric Hospital, a total of 489 patients' medical files were reviewed and included in the final analysis. Results revealed that suicide attempters were younger, single, did not have children, and had little or very little social support. They reported experiencing more stressful life events, reported being depressed, had suffered from BD at an early age, had a family history of suicide, had previously attempted suicide, had previous suicidal ideation, alcohol use, and were prescribed antipsychotics, antidepressants, anxiolytics, and mood stabilizers (Ruengorn et al., 2012). Using multivariate logistic regression, the author found six indicators of suicide attempts: depressive episodes, previous suicide attempt(s), stressful life event(s), intermittent or poor medication adherence, and shorter duration of BD treatment. Psychotic symptom(s) provided an inverse association with suicide risk (Ruengorn et al., 2012). Moreover, the altitude was seen as a significant risk factor (Huber et al., 2014). Several biological theories may explain an altitude-suicide association. Dopamine and serotonin are neurotransmitters associated with pleasure, reward, and mood. Decreased levels of serotonin and increased levels of dopamine and norepinephrine associated with hypoxia at higher altitudes may lead to increased irritability, depression, and suicide (Huber et al., 2014; Trouvin et al., 1986; Jou et al., 2009). Converging lines of evidence also indicate that mitochondrial dysfunction plays a role in the pathophysiology of BD and may influence the severity of episodes (Scaglia, 2010; Quiroz et al., 2008; Kato, 2006). Studies of patients with mitochondrial disease show that both adults (Fattal et al., 2006, 2007) and children (Morava et al., 2010; Koene et al., 2009) have elevated rates of depressive symptoms. Metabolic stress due to hypoxia may have important considerations for individuals with BD. Hypoxia due to reduced oxygen partial pressure at higher altitudes may further decrease mitochondrial function in individuals with BD (McIntyre et al., 2008; Rezin et al., 2009). For these individuals, metabolic

247

changes associated with hypoxia may lead to depression, instability of mood, and increased risk of suicide (Huber et al., 2014; Vaccari et al., 1978). 4.2. Risk factors associated with genetic components Suicide attempt was defined as an intentional self-inflicted injury with self-destructive intent (Manchia et al., 2013). Globally, approximately one million individuals commit suicide each year (WHO, 2011; Sears et al., 2013). Suicidal behavior is a matter of major concern in the management of BD patients for many reasons. First, their suicide rates are about 60 times higher than that observed in general population. Second, about one third to half of these patients will make at least one suicide attempt during their disease. Finally, their suicide acts have a higher lethality as suggested by a much lower ratio of attempted suicide (approximately 3:1) than in the general population (approximately 30:1) (Baldessarini et al., 2006; Neves et al., 2010). Although many data have suggested that BD confers a higher risk of suicide than other psychiatric illnesses (Sajatovic, 2005), few studies have yet been conducted to investigate the contribution of the genetic component (Magno et al., 2011). Genetic variation plays an important role in BD and suicide susceptibility. However, little is known about the genetic influence on the risk of suicide, particularly in BD patients (Magno et al., 2011). The liability to suicidal behavior is influenced by genetic factors (particularly family history of suicidal behavior and Major Affective Disorders) (Manchia et al., 2013). In addition, genetic determinants such as polymorphisms within the tryptophan hydroxylase 1 (TPH1; Gene ID 7166 in 11p15.3–p14) and the tryptophan hydroxylase 2 (TPH2; Gene ID 121278 in 12q21.1) genes were found to be associated with suicide attempts of high lethality and with completed suicides, respectively (Manchia et al., 2013; Galfalvy et al., 2009; Lopez et al., 2007). These findings are of interest considering the association between altered serotonin system function in the brain and suicide (Manchia et al., 2013). Neves et al. (2010) showed that serotonin polymorphism (5-HTTLPR; Gene ID 6532 in 17q11.2) is strongly associated with violent suicidal behavior in BD patients. Their results could be an important step to create a genetic tool for long-term suicide prediction (Neves et al., 2010). Biological markers, such as 5-HTTLPR (Gene ID 6532 in 17q11.2), could help for identification of potential suicide attempters (Neves et al., 2010). Several lines of evidence indicate that brain-derived neurotrophic factor (BDNF; Gene ID 627 in 11p13) is a good candidate gene for involvement in suicidal behavior. Post-mortem studies have shown that the expression of BDNF (Gene ID 627 in 11p13) is significantly reduced in individuals that have committed suicide, regardless of psychiatric diagnosis (Sears et al., 2013; Dwivedi et al., 2003; Karege et al., 2005). Moreover, an association between BDNF (Gene ID 627 in 11p13) gene and violent Suicide Attempt (SA) has been also detected in a sample of this patients (Neves et al., 2011; Jiménez et al., 2013). In addition, brain-derived neurotrophic factor (BDNF; Gene ID 627 in 11p13) and lithium, well known therapeutic drug in mood disorder (Fountoulakis et al., 2008), reduces FoxO3a (Gene ID 2309 in 6q21) transcriptional activity (Magno et al., 2011; Mao et al., 2007; Zhu et al., 2004). FoxO3a (Gene ID 2309 in 6q21) influences distinct behavioral processes linked to anxiety and depression. Recently, a study using a knockout (KO) mice model suggested that FoxO3a (Gene ID 2309 in 6q21) may be a transcriptional target for anxiety and mood disorder treatment (Magno et al., 2011; Polter et al., 2009). These data suggest that FOXO3A (Gene ID 2309 in 6q21) is a novel susceptibility locus for BD, but not for suicidal behavior in BD patients. These results may contribute to a better understanding of the BD genetics (Magno et al., 2011).

248

L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

Some evidence links phosphosinositol pathway to suicidal behavior (Jiménez et al., 2013). Jiménez et al. (2013) suggest that genetic variability at rs669838-IMPA2 (Gene ID 3613 in 18p11.2), rs4853694-INPP1 (Gene ID 3628 in 2q32), rs1732170- GSK3b (Gene ID 2932 in 3q13.3) and rs11921360-GSK3b (Gene ID 2932 in 3q13.3) genes is associated with a higher risk of attempting suicide in bipolar patients (Jiménez et al., 2013). It is known that at therapeutic concentrations, lithium immediately inhibits several enzymes, such as both isoenzymes (1 and 2) of inositolmonophosphatase (IMPA), inositolpolyphosphate-1 phosphatase (INPP1), phosphoglucomutase and glycogen synthasekinase-3b (GSK3b) (Jiménez et al., 2013; Quiroz et al., 2004; Serretti et al., 2009). The phosphoinositol pathway is associated with cellular activities such as metabolism, secretion, phototransduction, cell growth and differentiation (Jiménez et al., 2013; Serretti et al., 2009). The question remains how genetic risk factors contribute to the manifestation of bipolar disorder. If we could answer this question, early intervention and effective treatment could become a reality (Kerner et al., 2013). Heritable factors have important effect on susceptibility to suicidal behavior, which is supported by several studies showing that genetic polymorphisms play a role in suicide risk (Magno et al., 2011; Galfalvy et al., 2009; Magno et al., 2010; Roy and Segal, 2001). Strong heritability of bipolar disorder has been supported by many studies, but the identification of causal variants has been challenging (Kerner et al., 2013). 4.3. Risk factors associated with medicines and drugs in general that interfere with bipolar disorder Prevalence of comorbid substance use disorders was higher among unipolar and bipolar disorder deaths than that among all other deaths. Among unipolar and bipolar disorder deaths, comorbid substance use disorders were associated with elevated risks for suicide and other unnatural death in both males and females (Yoon et al., 2011). Antiepileptic drugs are approved for the treatment of epilepsy, bipolar disorder, and neuropathic pain. Each of these conditions is associated with an elevated risk of suicide (Simon et al., 2007; Christensen et al., 2007; Nilsson et al., 2002; Ratcliffe et al., 2008; Tsai et al., 2002; Leon et al., 2012). Alcohol addicts were associated with diagnoses of several types of personality disorder and bipolar disorder and presented a greater suicide risk than the subgroup of other substance use disorders (SUDs) (Arias et al., 2013). Personality disorder and alcohol dependence were the most common secondary diagnoses in the BD group (Clements et al., 2013). Twenty-five percent of persons consume alcohol prior to suicidal attempt (Raja and Azzoni, 2004). Leverich et al. (2003) also point to family history of abuse of medicinal drugs as a suicide risk factor (Leverich et al., 2003; Pawlak et al., 2013). The risk of suicidal behavior or ideation was significantly elevated in patients who received an antiepileptic compared with those who received placebo when no adjustments were made for trial differences (Leon et al., 2012). This warning was based on an U.S. Food and Drug Administration (FDA) examination of data from 199 randomized clinical trials of 11 antiepileptic medications (carbamazepine, divalproex, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, and zonisamide) (Leon et al., 2012). The role of antidepressants (AD) in suicide risk is important, and this has received much attention in recent years (McElroy et al., 2006). There is an association between the use of AD and a risk of acute manic switch in BD (Ghaemi et al., 2003), and McElroy et al. (2006) concluded that AD may induce suicidal intention by manic conversion in a subset of depressive presentations (Finseth et al., 2012). In general, these effects were much stronger for Drug Use Disorders (DUD) than for Alcohol Use Disorders (AUD). Both

substance use disorders had stronger effects on suicide among females, whereas their effects on other unnatural deaths were stronger among males (Yoon et al., 2011). According to the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) estimates, among individuals with 12-month unipolar depressive disorder, 14.1% had alcohol use disorders (AUD) and 4.6% had drug use disorders (DUD). These represented significantly elevated risks for the comorbid substance use disorders (Yoon et al., 2011; Hasin et al., 2005). In a sample consisted of 837 outpatients from Madrid, Spain. Arias et al., (2013) compared 528 subjects with a lifetime diagnosis of alcohol abuse or dependence and 182 with other substance use disorders (SUDs) not involving alcohol. The Mini International Neuropsychiatric Interview (MINI) was used to evaluate Axis I disorders and the Personality Disorder Questionnaire to evaluate personality disorders. It was considered that 76.1% of the alcohol addicts had a current dual diagnosis, the most prevalent being mood and anxiety disorders. Fifty-two percent had a personality disorder and most of them (81.6%) had other SUDs Compared to people with bipolar disorder alone, those who have bipolar disorder with comorbid SUD have an increased prevalence of suicide attempts (Sublette et al., 2009; Dalton et al., 2003; Lopez et al., 2001; Oquendo et al., 2010; Potash et al., 2000; Kenneson et al., 2013). Gilbert et al. (2011) identified the extremely difficult to predict suicidal behavior, even when comprehensive clinical information is available. However, empirical evidence has shown that people with mood disorders and/or substance use disorders experience excess mortality (Yoon et al., 2011; Amaddeo et al., 1995; Black et al., 1985; Bruce et al., 1994; Cuijpers and Smit, 2002; Harris and Barraclough, 1998; Hiroeh et al., 2001; Mykletun et al., 2007; Wulsin et al., 1999). Actually, only a few studies have examined the association between mood disorders and other causes of unnatural death (Black et al., 1985; Hiroeh et al., 2001; Mykletun et al., 2007; Gau and Cheng, 2004; Joukamaa et al., 2001; Ösby et al., 2001), despite the fact that individuals with mood disorders, especially those with bipolar disorder, are more likely to engage in fatal accidents due to impaired attention and concentration (Stahl, 2000) or to be victims of homicide due to affective psychoses (Yoon et al., 2011; Hiroeh et al., 2001). These findings suggest that abuse of alcohol or drugs could be considered as an important characteristic to identify subgroups at risk for suicidal behavior (Akiskal et al., 1995; Maremmani et al., 2007). Leverich et al. (2003) have found a correlation between suicidal behaviors and the family history of suicide attempts or committed suicides, as well as the family history of abuse of medicinal drugs (Leverich et al., 2003; Pawlak et al., 2013). Interventions to reduce suicide risk in bipolar disorder need to address the common and high risk comorbidity with alcohol use disorders (Oquendo et al., 2010). 4.4. Risk factors associated with biological components Altered functioning of the Hypothalamic-pituitary-adrenal (HPA) axis has been reported in suicidal behavior and in Bipolar Disorder (BD) (Daban et al., 2005; Mann, 2003). However, many studies of HPA axis function in bipolar disorder have not examined the potential effects of Suicidal Behavior (SB) (Cassidy et al., 1998; Cervantes et al., 2001; Cookson et al., 1985; Godwin, 1984; Linkowski et al., 1994; Rybakowski and Twardowska, 1999; Schmider et al., 1995) and studies of the association between HPA axis activity and suicidal behavior in varied diagnostic groups have had mixed results (Black et al., 2002; Coryell and Schlesser, 2001; Dahl et al., 1991; Duval et al., 2001; Jokinen and Nordström, 2008; Jokinen and Nordström, 2009; Jokinen et al., 2009; Lindqvist et al., 2008; Pfennig et al., 2005; Pitchot et al., 2008; Tripodianakis et al., 2000; Yerevanian et al., 2004; Kamali et al., 2012).

L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

The HPA axis has been examined using a number of methods. Basal cortisol secretion has been measured with 24 h urinary cortisol secretion and serum or salivary cortisol levels. The feedback and suppression mechanisms of the HPA axis have been investigated with the dexamethasone suppression test (DST) (Kamali et al., 2012) or the dexamethasone/corticotropin-releasing hormone (DEX/CRH) challenge test (Carroll et al., 1981; Heuser et al., 1994). Kamali et al. (2012) examined HPA axis activity as a trait marker for bipolar disorder and suicide by measuring salivar cortisol in a bipolar cohort with a history of suicide and compares it with non-suicidal bipolar individuals and unaffected controls. Kamali et al., (2012) hypothesis was that those with bipolar disorder would have elevated basal salivary cortisol compared to unaffected controls, and that the suicidal bipolar individuals (defined by a lifetime history of attempted suicide) would have higher levels of salivary cortisol compared to those with no history of suicidal behavior and unaffected controls. A total of 185 individuals participated in the study and provided at least one salivary cortisol sample. The majority (152 individuals) were enrolled in the Prechter Longitudinal Study. One subject subsequently retracted their consent, the salivary samples from one subject were missing at time of analysis, the saliva volume from two individuals was insufficient for analysis and three individuals did not complete enough of the diagnostic interview to reach a diagnosis. Of the remaining 178, 118 (66.3%) had a diagnosis of bipolar I, 14 (7.9%) had bipolar II with recurrent depression, 7 (3.9%) had schizoaffective disorder—bipolar type, 8 (4.5%) had other affective diagnosis (depressive disorder NOS, MDD, Bipolar II with single depressive episode), 2 (1.1%) had only non-affective diagnoses (alcohol abuse and dependence) and 29 (16.3%) were unaffected controls. For the purpose of this study, those with bipolar I, bipolar II with recurrent depression and schizoaffective disorder bipolar type were grouped together as the bipolar group (N ¼139) and were categorized based on reported suicide history obtained during the Diagnostic Interview for Genetic Studies (DIGS) (Kamali et al., 2012). Kamali et al., (2012) found elevated bedtime salivary cortisol in bipolar individuals with a history of suicide attempts compared to nonsuicidal bipolar individuals. Secondary analysis of the intensity of suicidal behavior and level of bedtime cortisol indicated a positive correlation, with the highest cortisol levels reported in individuals that had made a past serious suicide attempt. The difference in bedtime salivary cortisol between suicidal and nonsuicidal bipolar individuals remained significant even after controlling for age and sex, body mass index (BMI), smoking status, childhood sexual abuse, medications, mood state at time of sampling and several clinical factors related to course and severity of illness (substance use disorders, chronicity of illness, rapid cycling, mixed states, years of illness, age of onset, anxiety and psychosis). This is a strong indicator that their finding is related to the presence of a past history of suicidality and not related to severity of illness, mood state, or demographic confounders. The presence of this finding during different mood states and also in the euthymic state indicates that hyperactivity of the HPA axis is a biological marker related to suicidality in bipolar disorder and warrants more detailed investigation (Kamali et al., 2012). The difference between bipolar participants with and without suicidal behavior was only 0.05 μg/dl. Currently, the test has low sensitivity and specificity in detecting individuals with suicidal history in practical clinical applications. However, the observation of a sustained correlation between increasing suicidality and cortisol levels while controlling for confounding clinical and biological factors clearly indicates the relevance of HPA axis abnormalities in this potentially lethal clinical condition (Kamali et al., 2012).

249

Several potential risk factors have been linked to suicidal behavior. Two of these include personality factors and Polyunsaturated fatty acids (PUFA) serum levels. It is unknown whether PUFA serum levels are associated with personality factors and if these may interact to affect suicidal behavior (Evans et al., 2012). Supplementation with the long-chain n-3 (n-3) fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), either as stand alone or adjunctive therapies have shown efficacy in the treatment of bipolar disorder (Evans et al., 2012). Epidemiological studies have pointed to an association between n-3 and n-6 dietary intake and lifetime prevalence of bipolar disorder. Populations that consume greater long-chain n-3 s and less long chain n-6 s have a lower incidence of bipolar disease (Evans et al., 2012; Hibbeln et al., 2006). N-3 intake inversely associates with violent behavior and suicidality, Evan et al. hypothesize that serum levels of the long chain n-3 s, DHA and EPA, may positively associate with personality factors that may be protective against suicide behavior and/or negatively associate with personality factors that, themselves, associate with increased risk of suicide behavior (Evans et al., 2012). Several studies suggest that BD patients' previous suicide attempt(s) may indicate that they are more than 50% more likely to go on to complete suicide (Ruengorn et al., 2012; Tsai et al., 2002; Isometsa et al., 1994). Identifying metabolic or dietary factors that influence factors associated with psychiatric illness may provide a path to improving therapeutic tools. Evans et al. found associations between lipid profiles and suicidal history in bipolar subjects (Evans et al., 2012). These data further support a link between essential fatty acid metabolism and mood disorders. While the current pilot study is an observational, cross-sectional study, it raises important questions regarding potential causative roles for lipid profiles in regulating personality phenotypes that may impact the treatment of bipolar disorder. Nevertheless, the fact that personality factors, promoted as trait markers in bipolar disorder are not entirely stable (Barnett and Huang, 2010) and longer-term longitudinal studies are necessary to examine the relationship between personality traits and fatty acid profiles. Evans et al., (2012) Of significant interest is the co-occurrence of metabolic disturbances in bipolar disorder, particularly obesity (Gomes et al., 2010). Gomes, et al. find adds to the notion that obesity is a correlate of severity in patients with bipolar disorder. Obese patients usually have more markers of illness severity, such as more previous affective episodes (Fagiolini et al., 2002) and suicide attempts (Fagiolini et al., 2004; Fagiolini et al., 2005; Wang et al., 2006). Recent data have stressed common features in the underlying pathophysiology of obesity and bipolar disorder. Leptin, a key hormone in regulation of adiposity has been shown to be positively associated with risk for depression in a prospective study (Pasco et al., 2007). Disturbances in metabolic pathways such as insulin-mediated glucose homeostasis, overactivation of the hypothalamic–pituitary–adrenal axis, dysregulated immune and inflammatory processes and adipocytokines profiles are present in both conditions (Gomes et al., 2010; McIntyre et al., 2007). 4.5. Risk factors associated with psychological causes BD is a frequent and chronic psychiatric disorder associated with an increase in all-cause mortality (Ösby et al., 2001; McIntyre and Konarski, 2004; McIntyre et al., 2008). In particular, among mental disorders, BD is one of the leading causes of suicidal behaviors and this is a major issue in the management of the disease (Parmentier et al., 2012). Mixed-states and well as depressions are strongly associated with suicidal behavior in patients with BD (Algorta et al., 2011; Baldessarini et al., 2012; Azorin et al., 2009; Pompili et al., 2009; Baldessarini et al., 2010; Undurraga et al., 2011).

250

L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

Bipolar disorder is strongly associated with suicidal ideations, attempts and commissions (Shabani et al., 2013). Cyclothymic temperament may influence suicide risk on multiple levels, from determining emotional reactivity in stressful situations at the level of the personality, through determining illness and illness course characteristics, to influencing within-episode dynamics (Rihmer et al., 2013). There are also no previous studies investigating the role of possible mediating factors, such as hopelessness, in the association between affective temperaments and suicidal behavior. Because it is well known that patients with BD-II are at a higher risk for attempting and completing suicide (Pompili et al., 2009; Rihmer and Pestality, 1999) and that hopelessness has been found to be a good predictor of suicidal behavior (Beck et al., 1990; Akiskal, 2007), understanding the relationship between these factors, and the possibly differential association of these factors, in patients with BD-I and BD-II disorders would give us better insight in to the nature of the emergence of suicidal behavior (Pompili et al., 2012). The finding of hopelessness as the most important variable when compared with depression is consistent with the nature of these psychopathological features (Acosta et al., 2012). A recent meta-analysis revealed that previous suicide attempts and hopelessness were the main risk factors for suicide, and that early onset, depressive symptoms, and family history of suicide were the main risk factors for nonfatal suicide related behavior (Ryu et al., 2010; Hawton et al., 2005). We cannot dismiss the possibility that hopelessness may also, at least in part, represent a consequence of a more severe course of illness, especially those with lifetime depressive burden, and predispose to suicidality from that perspective as well (Acosta et al., 2012). Hopelessness about the future in suicidal individuals is a multi-faceted construct but lack of positive future thinking is more important than presence of negative future thinking (Fountoulakis et al., 2012). Patients with bipolar disorder have recurrent fluctuating mood episodes with functional impairment, (Weinstock and Miller, 2008) which might induce chronic distress and increase suicide related behaviors (Ryu et al., 2010; MacKinnon et al., 2003). Because suicide and suicidal behaviors are the result of a combination of individual risk factors, precipitating stressors, and current disease features, the prediction of a suicide attempt for a given patient on the basis of risk factors statistically associated with suicide or suicide attempts in populations of patients with bipolar disorder is difficult (Song et al., 2012). For Pompili et al. not only the absolute elevations of each temperament may be associated with psychopathological symptoms but also that the individual pattern of temperaments may be associated with a higher suicidal risk (Pompili et al., 2012). However, what we so far know about the risk factors associated with suicidal thinking and behavior in bipolar disorder has overwhelmingly been derived by studying individuals who are in the “acute” phase of their disorder (Acosta et al., 2012). Many studies have investigated clinical characteristics associated with suicidal behavior. Gender has been associated with suicidal behavior in BD: men have a 4-fold greater risk for suicide than women (Suicidology AAo, 2000; American Psychiatric Association, 2003; World Health Organization WHO, 2003). Relative to the risk in the general population, BD is associated with an increased risk of suicidal behavior in women and a higher lethality in men (Parmentier et al., 2012). In particular, careful evaluation and effective management of bipolar depression among patients with mood disorder during major depressive episodes is necessary to prevent suicide attempts in bipolar disorder (Ryu et al., 2010). While suicidal ideation and a history of attempted suicide are among the most important risks for suicide (Osman et al., 2001; Kuo et al., 2001), only a few studies have taken into account both suicidal ideas and attempts in assessing the risk factors (Suttajit et al., 2013). The characteristics

associated with suicidal behavior in patients with BD may stimulate the development of specific therapeutic strategies; these may include emotional and hostility regulation and problem-solving therapies or specific treatment of comorbid social phobia or addiction (Parmentier et al., 2012; Gray and Otto, 2001; Stewart et al., 2009). Suicide prevention strategies are currently based on screening for the numerous risk factors (de Moraes et al., 2013). 4.6. Risk factors associated with components of religious and spiritual components Religiosity and Spirituality are important aspects to identify groups at risk of suicide in BD. However, there is a lack of studies on their impact on bipolar disorder and little is known about them (Azorin et al., 2013). Dervic et al. (2011) related higher score on the moral or religious objections to suicide subscale of the Reason for Living Inventory (RFLI) with fewer suicidal acts in depressed bipolar patients. The strength of this association was comparable to that of aggression scores and suicidal behavior, and had an independent effect. A possible protective role of moral or religious objections to suicide deserves consideration in the assessment and treatment of suicidality in bipolar disorder. In this study (Dervic et al., 2011), patients who reported religious affiliation were compared with 51 patients without religious affiliation in terms of sociodemographic and clinical characteristics and history of suicidal behavior. The results were patients with religious affiliation had comparatively higher scores on the moral or religious objections to suicide subscale of the RFLI, lower lifetime aggression, and less comorbid alcohol and substance abuse and childhood abuse experience (Dervic et al., 2011). In another hand, Azorin et al. (2013) identified another point of view. In their sample, Compared to Low Religious Involvement (LRI), High Religious Involvement (HRI) patients did not differ with respect to their religious affiliation but had a later age at onset of their affective illness with more hospitalizations, suicide attempts, associated hypomanic features, switches under antidepressant treatment, prescription of tricyclics, comorbid obsessive compulsive disorder, and family history of affective disorder in firstdegree relatives. The following independent variables were associated with religious involvement: age, depressive temperament, mixed polarity of first episode, and chronic depression. The study concluded that in depressive patients belonging to the bipolar spectrum, high religious involvement associated with mixed features may increase the risk of suicidal behavior, despite the existence of religious affiliation. The current study (Azorin et al., 2013) may help understand some potential negative effects of religious involvement in depressive patients belonging to the bipolar spectrum. First of all, their findings may be in line with the hypothesis of Cruz et al. (2010) that higher levels of distress as such caused by mixed episodes and/or chronic depression, would prompt patients to seek relief from religion, and therefore increase the frequency of their religious behaviors. However, it could be that, once depressed, HRI patients become the victims of their religious commitment and that, in this case, religion exerts harmful effects on health. Actually, for an individual with depressive temperament characterized by a rigid duty - orientation of his behavior, which distinguishes itself by an overidentification with what is normatively expected or by a meticulous fulfillment of social norms (Tellenbach, 1974), experiencing hypomanic social desinhibition may hardly be assimilated in his usual way of life. This “egodystonic” experience could therefore appear to consciousness under the form of obsessive thoughts such as the “fear of committing a sin” or an “excessive guilt” and give rise to compulsive religious behaviors, such as those found in our HRI patients. In those cases,

L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

it is likely that religious involvement may aggravate their guilt feelings or the sinful character of their hypomanic experiences, enhancing thereby the suicidal tendencies. This may contribute to explain why in the case of some mixed depressive patients, religiosity is unlikely to be associated with less suicidal behavior (Azorin et al., 2013). The last study (Pawlak et al., 2013) confirms what Dervic et al. analyzed, affirming that subjective sense of religious involvement may play a protective role in some communities (Sisask et al., 2010). Patients, who have not declared their commitment to any religion, undertook suicidal attempts significantly more often and had more relatives, who had died of suicide, in comparison with those involved in religion (Dervic et al., 2004).

5. Conclusion The results of the studies in the literature show that the risk factors associated with bipolar disorder and suicide exist and are relevant to clinicians and researchers, whereas knowledge of such influence better diagnosis and prognosis of BD cases involving suicide risk. Notwithstanding the differences in some points of the studies, research becomes important to maintain the high quality of knowledge of the disorder and its peculiarities, seeking improved quality of life for people suffering from bipolar disorder. Role of funding source We have no foundation source.

Conflict of interest Mr. Costa, Mr. Alencar, Mr. Nascimento and Drs. Maria do Socorro, Cláudio, Sally, Regiane, Bianca, Roberto, Marcos Antonio, Alberto and Modesto have no conflicts of interest or financial ties to report.

Acknowledgments The authors of this review would like to thank the support of the Suicidology Research Group, Federal University of Ceará (UFC/Brazil)/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil) and the Laboratório de Escrita Científica (LABESCI/Brazil)—Medical School of Federal University of Cariri (UFCA/Brazil).

References Abreu, L.N., Lafer, B., Baca-Garcia, E., et al., 2009. Suicidal ideation and suicide attempts in bipolar disorder type I: an update for the clinician. Rev. Bras. Psiquiatr. 31 (3), 271–280. 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 53 (8), 1103–1109. Akiskal, H., 2007. Targeting suicide preventing to modifiable risk factors: has bipolar II been overlooked? Acta Psychiatr. Scand. 116 (6), 395–402. Akiskal, H.S., Maser, J.D., Zeller, P.J., et al., 1995. Switching from unipolar‘ to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch. Gen. Psychiatry 52, 114–123. Akiskal, H.S., Benazzi, F., Perugi, G., et al., 2005. Agitated “unipolar” depression reconceptualized as a depressive mixed state: Implications for the antidepressant-suicide controversy. J. Affect. Disord. 85 (3), 245–258. Algorta, G.P., Youngstrom, E.A., Frazier, T.W., et al., 2011. Suicidality in pediatric bipolar disorder: predictor or outcome of family processes and mixed mood presentation? Bipolar Disord. 13 (1), 76–86. Amaddeo, F., Bisoffi, G., Bonizzato, P., et al., 1995. Mortality among patients with psychiatric illness. A ten-year case register study in an area with a communitybased system of care. Br. J. Psychiatry 166, 783–788. American Psychiatric Association, 2003. Practice guideline for the assessment and treatment of patients with suicidal behaviors. Am. J. Psychiatry 160 (Suppl. 11), S1–S60. American Psychiatric Association, 2013. Diagnostic and statistical manual of mental Disorders, 5th ed. American Psychiatric Association, Arlington, VA (DSM-5). Angst, F., Stassen, H.H., Clayton, P.J., et al., 2002. Mortality of patients with mood disorders: follow-up over 34–38 years. J. Affect. Disord. 68, 167–181. Angst, J., Angst, F., Gerber-Werder, R., et al., 2005. Suicide in 406 mood-disorder patients with and without long-term medication: a 40 to 44 years' follow- up. Arch. Suicide Res. 9 (3), 279–300.

251

Antypa, N., Antonioli, M., Serretti, A., 2013. Clinical, psychological and environmental predictors of prospective suicide events in patients with Bipolar Disorder. J. Psychiatr. Res. 47 (11), 1800–1808. Arató, M., Demeter, E., Rihmer, Z., et al., 1988. Retrospective psychiatric assessment of 200 suicides in Budapest. Acta Psychiatr. Scand. 77, 454–456. 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. Health Subst. Use: Dual Diagn. 6 (4), 339–350. Azorin, J.-M., Kaladijan, A., Fakra, E., et al., 2013. Religious involvement in major depression: protective or risky behavior? The relevance of bipolar spectrum. J. Affect Disord. 150 (3), 753–759. Azorin, J.M., Kaladjian, A., Adida, M., et al., 2009. Risk factors associated with lifetime suicide attempts in bipolar I patients: findings from a French national Cohort. Compr. Psychiatry 50 (2), 115–120. 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– European mania in bipolar longitudinal evaluation of medication. BMC Psychiatry 9, 33–40. Azorin, J.M., Kaladjian, A., Adida, M., et al., 2009. Risk factors associated with 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 Cohort of major depressive patients: characteristics of attempters and nonattempters. J. Affect Disord. 123 (1–3), 87–94. 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 depressive episodes and of bipolar II diagnoses. J. Affect Disord. 76, 113–119. Baldessarini, R.J., Pompili, M., Tondo, L., 2006. Suicide in bipolar disorder: risks and management. CNS Spectr. 11, 465–471. 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. 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 Psychiatr. Scand. 125 (4), 293–302. 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 and ultimate suicide: a replication with psychiatric outpatients. Am. J. Psychiatry 147, 190–195. 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. Benazzi, F., 2007. Bipolar disorder–focus on bipolar II disorder and mixed depression. Lancet 369, 935–945. Black, D., Monahan, P., Winokur, G., 2002. The relationship between DST results and suicidal behavior. Ann. Clin. Psychiatry 14, 83–88. Black, D.W., Warrack, G., Winokur, G., 1985. Excess mortality among psychiatric patients. The Iowa record-linkage study. J. Am. Med. Assoc. 253, 58–61. Blair-West, G.W., Cantor, C.H., Mellsop, G.W., et al., 1999. Lifetime suicide risk in major depression: sex and age determinants. J. Affect. Disord. 55, 171e8. Brent, D.A., Perper, J.A., Moritz, G., et al., 1993. Stressful life events, psychopathology, and adolescent suicide: a case control study. Suicide Life Threat. Behav. 23 (3), 179–187. 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 data in the New haven epidemiologic catchment area study. Am. J. Psychiatry 151, 716–721. Carroll, B.J., Feinberg, M., Greden, J.F., et al., 1981. A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. Arch. Gen. Psychiatry 38, 15–22. Cassidy, F., 2011. Risk factors of attempted suicide in bipolar disorder. Suicide Life Threat. Behav. 41 (1), 6–11. Cassidy, F., Ritchie, J.C., Carroll, B.J., 1998. Plasma dexamethasone concentration and cortisol response during manic episodes. Biol. Psychiatry 43, 747–754. Cervantes, P., Gelber, S., Kin, F.N., et al., 2001. Circadian secretion of cortisol in bipolar disorder. J. Psychiatry Neurosc. 26, 411–416. Christensen, J., Vestergaard, M., Mortensen, P.B., et al., 2007. Epilepsy and risk of suicide: a population-based case-control study. Lancet Neurol. 6, 693–698. Clements, C., Morriss, R., Jones, S., et al., 2013. Suicide in bipolar disorder in a national English sample, 1996–2009: frequency, trends and characteristics. Psychol. Med. 43 (12), 2593–2602. Cookson, J.C., Silverstone, T., Williams, S., et al., 1985. Plasma cortisol levels in mania: associated clinical ratings and changes during treatment with haloperidol. Br. J. Psychiatry 146, 498–502. Coryell, W., Schlesser, M., 2001. The dexamethasone suppression test and suicide prediction. Am. J. Psychiatry 2001 (158), 748. Cruz, M., Pincus, H.A., Welsh, D.E., et al., 2010. The relationship between religious involvement and clinical status of patients with bipolar disorder. Bipolar Disord. 12, 68–76. Cuijpers, P., Smit, F., 2002. Excess mortality in depression: a meta-analysis of community studies. J. Affect. Disord. 72, 227–236. de Moraes, P.H.P., Neves, F.S., Vasconcelos, A.G., et al., 2013. Relationship between neuropsychological and clinical aspects and suicide attempts in euthymic 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 bipolar disorder. Psychiatric Clin N. Am. 28, 469–480. Daban, C., Colom, F., Sanchez-Moreno, J., et al., 2006. Clinical correlates of firstepisode polarity in bipolar disorder. Compr. Psychiatry 47, 433–437. Dahl, R.E., Ryan, N.D., Puig-Antich, J., et al., 1991. 24-hour cortisol measures in adolescents with major depression: a controlled study. Biol. Psychiatry 1991 (30), 25–36. Dalton, J.E., Cate-Carter, T.D., Mundo, E., et al., 2003. Suicide risk in bipolar patients: the role of co-morbid substance use disorders. Bipolar Disord. 5, 58–61. De Abreu, L.N., Nery, F.G., Harkavy-Friedman, J.M., et al., 2012. Suicide attempts are associated with worse quality of life in patients with bipolar disorder type I. Compr. Psychiatry 53 (2), 125–129. Dervic, K., et al., 2004. Religious affiliation an suicide attempt. Am. J. Psychiatry 161 (12), 2303–2308. Dervic, K., Carballo, J.J., Baca-Garcia, E., et al., 2011. Moral or religious objections to suicide may protect against suicidal behavior in bipolar disorder. J. Clin. Psychiatry 72 (10), 1390–1396. Duval, F., Mokrani, M.C., Correa, H., et al., 2001. Lack of effect of HPA axis hyperactivity on hormonal responses to d-fenfluramine in major depressed patients: implications for pathogenesis of suicidal behavior. Psychoneuroendocrinology 26, 521–537. Dwivedi, Y., Rizavi, H.S., Conley, R.R., et al., 2003. Altered gene expression of brainderived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch. Gen. Psychiatry 60 (8), 804–815. Eroglu, M.Z., Karakus, G., Tamam, L., 2013. Bipolar disorder and suicide. Dusunen Adam. 26 (2), 139–147. Etain, B., Aas, M., Andreassen, O.A., et al., 2013. Childhood trauma is associated with severe clinical characteristics of bipolar disorders. J. Clin. Psychiatry 74 (10), 991–998. Evans, S.J., Prossin, A.R., Harrington, G.J., et al., 2012. Fats and factors: lipid profiles associate with personality factors and suicidal history in bipolar subjects. PLoS One 7 (1), e29297. Fagiolini, A., Frank, E., Houck, P.R., et al., 2002. Prevalence of obesity and weight change during treatment in patients with bipolar I disorder. J. Clin. Psychiatry 63, 528–533. Fagiolini, A., Kupfer, D.J., Rucci, P., et al., 2004. Suicide attempts and ideation in patients with bipolar I disorder. J. Clin. Psychiatry 65, 509–514. Fagiolini, A., Frank, E., Scott, J.A., et al., 2005. Metabolic syndrome in bipolar disorder: findings from the Bipolar Disorder Center for Pennsylvanians. Bipolar Disord. 7, 424–430. Fattal, O., Budur, K., Vaughan, A.J., et al., 2006. Review of the literature on major mental disorders in adult patients with mitochondrial diseases. Psychosomatics 47, 1–7. Fattal, O., Link, J., Quinn, K., et al., 2007. Psychiatric comorbidity in 36 adults with mitochondrial cytopathies. CNS Spectr. 12, 429–438. Finseth, P.I., Morken, G., Andreassen, O.A., et al., 2012. Risk factors related to lifetime suicide attempts in acutely admitted bipolar disorder inpatients. Bipolar Disord. 14 (7), 727–734. Fountoulakis, K.N., Grunze, H., Panagiotidis, P., et al., 2008. Treatment of bipolar depression: an update. J. Affect. Disord. 109, 21–34. Fountoulakis, K.N., Pantoula, E., Siamouli, M., et al., 2012. Development of the Risk Assessment Suicidality Scale (RASS): a population-based study. J. Affect. Disord. 138 (3), 449–457. Freeman, A.J., Youngstrom, E.A., Michalak, E., et al., 2009. Quality of life in pediatric bipolar disorder. Pediatrics 123, e446–e452. Galfalvy, H., Huang, Y.Y., Oquendo, M.A., et al., 2009. Increased risk of suicide attempt in mood disorders and TPH1 genotype. J. Affect. Disord. 115, 331–338. Galfavy, H., Oquendo, M.A., Carballo, J.J., et al., 2006. Clinical predictors of suicidal acts after major depression in bipolar disorder: a prospective study. Bipolar Disord. 8 (5 Pt 2), 586–595. Gau, S.S., Cheng, A.T., 2004. Mental illness and accidental death. Case-control psychological autopsy study. Br. J. Psychiatry 185, 422–428. Ghaemi, S.N., Hsu, D.J., Soldani, F., et al., 2003. Antidepressants in bipolar disorder: the case for caution. Bipolar Disord. 5, 421–433. Gilbert, A.M., Garno, J.L., Braga, R.J., et al., 2011. Clinical and cognitive correlates of suicide attempts in bipolar disorder: Is suicide predictable? J. Clin. Psychiatry 72 (8), 1027–1033. Godwin, C.D., 1984. The dexamethasone suppression test in acute mania. J. Affect. Disord. 7, 281–286. Goldstein, T.R., Ha, W., Axelson, D.A., et al., 2012. Predictors of prospectively examined suicide attempts among youth with bipolar disorder. Arch. Gen. Psychiatry 69 (11), 1113–1122. Gomes, F.A., Kauer-Sant‘Anna, M., Magalhães, P.V., et al., 2010. Obesity is associated with previous suicide attempts in bipolar disorder. Acta Neuropsychiatr. 22 (2), 63–67. Goodwin, F.K., Jamison, K.R., 2007. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. Oxford University Press, New York, NY. Gould, M.S., Fisher, P., Parides, M., et al., 1996. Psychosocial risk factors of child and adolescent completed suicide. Arch. Gen. Psychiatry 53 (12), 1155–1162. Gray, S.M., Otto, M.W., 2001. Psychosocial approaches to suicide prevention: applications to patients with bipolar disorder. J. Clin. Psychiatry 62 (Suppl. 25), S56–S64. Harris, E.C., Barraclough, B., 1997. Suicide as an outcome for mental disorders. A metaanalysis. Br. J. Psychiatry 170, 205–228. Harris, E.C., Barraclough, B., 1998. Excess mortality of mental disorder. Br. J. Psychiatry 173, 11–53.

Hasin, D.S., Goodwin, R.D., Stinson, F.S., et al., 2005. Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch. Gen. Psychiatry 62, 1097–1106. Hawton, K., Sutton, L., Haw, C., et al., 2005. Suicide and attempted suicide in bipolar disorder: a systematic review of risk factors. J. Clin. Psychiatry 66, 693–704. Heuser, I., Yassouridis, A., Holsboer, F., 1994. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J. Psychiatr. Res. 28 (341–356), 138. Hibbeln, J.R., Nieminen, L.R., Blasbalg, T.L., et al., 2006. Healthy intakes of n-3 and n6 fatty acids: estimations considering worldwide diversity. Am. J. Clin. Nutr. 83, 1483S–1493S. Hiroeh, U., Appleby, L., Mortensen, P.B., et al., 2001. Death by homicide, suicide, and other unnatural causes in people with mental illness: a population- based study. Lancet 358, 2110–2112. Huber, R.S., Coon, H., Kim, N., et al., 2014. Altitude is a risk factor for completed suicide in bipolar disorder. Med. Hypotheses 82 (3), 377–381. Isometsa, E.T., Henriksson, M.M., Aro, H.M., et al., 1994. Suicide in bipolar disorder in Finland. Am J Psychiatry. 151 (7), 1020–1024. Jamison, K.R., 2000. Suicide and bipolar disorder. J. Clin. Psychiatry 61 (Supp l9), S47–S51. Jiménez, E., Arias, B., Mitjans, M., et al., 2013. Genetic variability at IMPA2, INPP1 and GSK3b increases the risk of suicidal behavior in bipolar patients. Eur. Neuropsychopharmacol. 23 (11), 1452–1462. Jokinen, J., Nordström, P., 2008. HPA axis hyperactivity as suicide predictor in elderly mood disorder inpatients. Psychoneuroendocrinology 33, 1387. Jokinen, J., Nordström, P., 2009. HPA axis hyperactivity and attempted suicide in young adult mood disorder inpatients. J. Affective Disord. 2009 (116), 117. Jokinen, J., Nordström, A., Nordström, P., 2009. CSF 5-HIAA and DST nonsuppression–orthogonal biologic risk factors for suicide in male mood disorder inpatients. Psychiat. Res. 165, 96. Jou, S.H., Chiu, N.Y., Liu, C.S., 2009. Mitochondrial dysfunction and psychiatric disorders. Chang Gung. Med. J. 32, 370–379. Joukamaa, M., Heliövaara, M., Knekt, P., et al., 2001. Mental disorders and causespecific mortality. Br. J. Psychiatry 179, 498–502. Kamali, M., Saunders, E.F.H., Prossin, A.R., et al., 2012. Associations between suicide attempts and elevated bedtime salivary cortisol levels in bipolar disorder. J. Affect. Disord. 136 (3), 350–358. Karege, F., Vaudan, G., Schwald, M., et al., 2005. Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Mol. Brain Res. 136 (1–2), 29–37. Kato, T., 2006. The role of mitochondrial dysfunction in bipolar disorder. Drug News Perspect. 19, 597–602. Kenneson, A., Funderburk, J.S., Maisto, S.A., 2013. Risk factors for secondary substance use disorders in people with childhood and adolescent-onset bipolar disorder: opportunities for prevention. Compr. Psychiatry 54 (5), 439–446. Kerner, B., Rao, A.R., Christensen, B., et al., 2013. Rare genomic variants link bipolar disorder with anxiety disorders to CREB-regulated intracellular signaling pathways. Front Psychiat. 4, 154. Kheirabadi, G.R., Hashemi, S.J., Akbaripour, S., et al., 2012. Risk factors of suicide reattempt in patients admitted to khorshid hospital, Isfahan, Iran, 2009. Iran. J. Epidemiology. 8 (3), 39–46. Koene, S., Kozicz, T.L., Rodenburg, R.J., et al., 2009. Major depression in adolescent children consecutively diagnosed with mitochondrial disorder. J. Affect. Disord. 114, 327–332. Kuo, W.H., Gallo, J.J., Tien, A.Y., 2001. Incidence of suicide ideation and attempts in adults: the 13-year follow-up of a community sample in Baltimore, Maryland. Psychol. Med. 31 (7), 1181–1191. Kupfer, D.J., 2005. The increasing medical burden in bipolar disorder. J. Am. Med. Assoc. 293, 2528–2530. Leon, A.C., Solomon, D.A., Li, C., et al., 2012. Antiepileptic drugs for bipolar disorder and the risk of suicidal behavior: a 30-year observational study. Am. J. Psychiatry 169 (3), 285–291. Leverich, G.S., et al., 2003. Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network. J. Clin. Psychiatry 64 (5), 506–515. Lindqvist, D., Isaksson, A., Trskman-Bendz, L., et al., 2008. Salivary cortisol and suicidal behavior—a follow-up study. Psychoneuroendocrinology 33, 1061. Linkowski, P., Kerkhofs, M., Van Onderbergen, A., et al., 1994. The 24-hour profiles of cortisol, prolactin, and growth hormone secretion in mania. Arch. Gen. Psychiatry 51, 616–624. Lopez, D.L., Brezo, J., Rouleau, G., et al., 2007. Effect of tryptophan hydroxylase-2 gene variants on suicide risk in major depression. Biol. Psychiatry 62, 72–80. Lopez, P., Mosquera, F., deLeon, J., et al., 2001. Suicide attempts in bipolar patients. J. Clin. Psychiatry 62, 963–966. MacKinnon, D.F., Zandi, P.P., Gershon, E., et al., 2003. Rapid switching of mood in families with multiple cases of bipolar disorder. Arch. Gen. Psychiatry 60, 921–928. Magno, L.A., Miranda, D.M., Neves, F.S., et al., 2010. Association between AKT1 but not AKTIP genetic variants and increased risk for suicidal behavior in bipolar patients. Genes Brain Behav. 9, 411–418. Magno, L.A.V., Santana, C.V.N., Rezende, V.B., et al., 2011. Genetic variations in FOXO3A are associated with Bipolar Disorder without confering vulnerability for suicidal behavior. J. Affect. Disord. 133 (3), 633–637. Manchia, M., Hajek, T., O‘Donovan, C., et al., 2013. Genetic risk of suicidal behavior in bipolar spectrum disorder: analysis of 737 pedigrees. Bipolar Disord. 15 (5), 496–506.

L.d.S. Costa et al. / Journal of Affective Disorders 170 (2015) 237–254

Mann, J.J., 2003. Neurobiology of suicidal behavior. Nat. Rev. Neurosci. 4, 819. Mao, Z., Liu, L., Zhang, R., et al., 2007. Lithium reduces FoxO3a transcriptional activity by decreasing its intracellular content. Biol. Psychiatry 62, 1423–1430. Maremmani, I., Pani, P.P., Canoniero, S., et al., 2007. Is the bipolar spectrum the psychopathological substrate of suicidality in heroin addicts? Psychopathology 40 (5), 269–277. McElroy, S.L., Kotwal, R., Kaneria, R., et al., 2006. Antidepressants and suicidal behavior in bipolar disorder. Bipolar Disord. 8, 596–617. McIntyre, R.S., Konarski, J.Z., 2004. Bipolar disorder: a national health concern. CNS Spectr. 9 (11 Suppl 12), S6–S15. McIntyre, R.S., Soczynska, J.K., Konarski, J.Z., et al., 2007. Should depressive syndromes be reclassified as "metabolic syndrome type II"? Ann. Clin. Psychiatry 19, 257–264. McIntyre, R.S., Soczynska, J.K., Mancini, D., et al., 2008. The relationship between childhood abuse and suicidality in adult bipolar disorder. Violence Vict. 23 (3), 361–372. McIntyre, R.S., Muzina, D.J., Kemp, D.E., et al., 2008. Bipolar disorder and suicide: researchsynthesis and clinical translation. Curr. Psychiatry Rep. 10, 66–72. Michalak, E.E., Yatham, L.N., Lam, R.W., 2005. Quality of life in bipolar disorder: a review of the literature. Health Qual. Life Outcomes 15, 3–72. Miklowitz, D.J., Chang, K.D., 2008. Prevention of bipolar disorder in at-risk children: theoretical assumptions and empirical foundations. Dev. Psychopathol. 20, 881–897. Morava, E., Gardeitchik, T., Kozicz, T., et al., 2010. Depressive behavior in children diagnosed with a mitochondrial disorder. Mitochondrion 10, 528–533. Mykletun, A., Bjerkeset, O., Dewey, M., et al., 2007. Anxiety, depression, and causespecific mortality: the HUNT study. Psychosom. Med. 69, 323–331. Neves, F.S., Malloy-Diniz, L.F., Ma, Romano-Silva, et al., 2010. Is the serotonin transporter polymorphism (5-HTTLPR) a potential marker for suicidal behavior in bipolar disorder patients? J. Affect. Disord. 125 (1-3), 98–102. Neves, F.S., Malloy-Diniz, L., Romano-Silva, M.A., et al., 2011. The role of BDNF genetic polymorphisms in bipolar disorder with psychiatric comorbidities. J. Affect. Disord. 131, 307–311. Nilsson, L., Ahlbom, A., Farahmand, B.Y., et al., 2002. Risk factors in suicide in epilepsy: a case-control study. Epilepsia 43, 644–651. Oquendo, M.A., Currier, D., Liu, S., et al., 2010. Increased risk for suicidal behavior in comorbid bipolar disorder and alcohol use disorders. J. Clin. Psychiatry 71 (7), 902–909. Ösby, U., Brandt, L., Correia, N., et al., 2001. Excess mortality in bipolar and unipolar disorder in Sweden. Arch. Gen. Psychiatry 58, 844–850. Osman, A., Bagge, C.L., Gutierrez, P.M., et al., 2001. The Suicidal Behaviors Questionnaire-Revised (SBQ-R): validation with clinical and nonclinical samples. Assessment 8 (4), 443–454. Parmentier, C., Etain, B., Yon, L., et al., 2012. Clinical and dimensional characteristics of euthymic bipolar patients with or without suicidal behavior. Eur. Psychiatry 27 (8), 570–576. Pasco, J., Jacka, F., Williams, L.J., et al., 2007. Leptin in depressed women: crosssectional and longitudinal data from an epidemiologic study. J. Affect. Disord. 107, 211–225. Pawlak, J., Dmitrzak-Weglarz, M., Skibińska, M., et al., 2013. Suicide attempts and psychological risk factors in patients with bipolar and unipolar affective disorder. Gen. Hosp. Psychiatry 35 (3), 309–313. Pawlak, J., Dmitrzak-Weglarz, M., Skibińska, M., et al., 2013. Suicide attempts and clinical risk factors in patients with bipolar and unipolar affective disorders. Gen. Hosp. Psychiatry 35 (4), 427–432. Periodicos.capes.gov.br [homepage on the Internet]. 2014. Brasília: Higher Education Co-ordination Agency of Brazil‘s Ministry of Education; 2000. Available from: 〈http://www.periodicos.capes.gov.br/〉. (accessed 6.6.2014. Perugi, G., Micheli, C., Akiskal, H.S., et al., 2000. Polarity of the first episode, clinical characteristics, and course of manic depressive illness: a systematic retrospective investigation of 320 bipolar I patients. Compr Psychiatry. 41, 13–18. Pfennig, A., Kunzel, H., Kern, N., et al., 2005. Hypothalamus-pituitary-adrenal systemregulation and suicidal behavior in depression. Biol. Psychiatry 57, 336–342. Pitchot, W., Scantamburlo, G., Pinto, E., et al., 2008. Vasopressin–neurophysin and DST in major depression: relationship with suicidal behavior. J. Psychiatr. Res. 42, 684–688. Polter, A., Yang, S., Zmijewska, A.A., et al., 2009. Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation. Biol. Psychiatry 65, 150–159. Pompili, M., Rihmer, Z., Innamorati, M., et al., 2009. Assessment and treatment of suicide risk in bipolar disorders. Expert Rev. Neurother. 9, 109–136. Pompili, M., Rihmer, Z., Akiskal, H., et al., 2012. Temperaments mediate suicide risk and psychopathology among patients with bipolar disorders. Compr. Psychiatry 53 (3), 280–285. Pompili, M., Rihmer, Z., Akiskal, H., et al., 2012. Temperaments mediate suicide risk and psychopathology among patients with bipolar disorders. Compr. Psychiatry 53 (3), 280–285. Potash, J.B., Kane, H.S., Chiu, Y.-F., et al., 2000. Attempted suicide and alcoholism in bipolar disorder: clinical and familial relationships. Am. J. Psychiatry 157, 2048–2050. Quiroz, J.A., Gould, T.D., Manji, H.K., et al., 2004. Molecular effects of lithium. Mol. Interv. 4, 259–272. Quiroz, J.A., Gray, N.A., Kato, T., et al., 2008. Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 33, 2551–2565.

253

Raja, M., Azzoni, A., 2004. Suicide attempts: differences between unipolar and bipolar patients and among groups with different lethality risk. J. Affect. Disord. 82 (3), 437–442. Ratcliffe, G.E., Enns, M.W., Belik, S.L., et al., 2008. Chronic pain conditions and suicidal ideation and suicide attempts: an epidemiologic perspective. Clin. J. Pain 24, 204–210. Rezin, G.T., Amboni, G., Zugno, A.I., et al., 2009. Mitochondrial dysfunction and psychiatric disorders. Neurochem. Res. 34, 1021–1029. Rihmer, Z., Pestality, P., 1999. Bipolar II disorder and suicidal behavior. Psychiatr. Clin. N. Am. 22 (667–73), ix–x. Rihmer, Z., Gonda, X., Torzsa, P., et al., 2013. Affective temperament, history of suicide attempt and family history of suicide in general practice patients. J. Affect. Disord. 149 (1–3), 350–354. Roshanaei-Moghaddam, B., Katon, W., 2009. Premature mortality from general medical illnesses among persons with bipolar disorder: a review. Psychiatr. Serv. 60, 147–156. Roy, A., Segal, N.L., 2001. Suicidal behavior in twins: a replication. J. Affect. Disord. 66, 71–74. Ruengorn, C., Sanichwankul, K., Niwatananun, W., et al., 2012. A risk-scoring scheme for suicide attempts among patients with bipolar disorder in a Thai patient cohort. Psychol. Res. Behav. Manage. 5, 37–45. Rybakowski, J.K., Twardowska, K., 1999. The dexamethasone/corticotropinreleasing hormone test in depression in bipolar and unipolar affective illness. J. Psychiatr. Res. 33, 363–370. Ryu, V., Jon, D.I., Cho, H.S., et al., 2010. Initial depressive episodes affect the risk of suicide attempts in Korean patients with bipolar disorder. Yonsei. Med. J. 51 (5), 641–647. Sajatovic, M., 2005. Bipolar disorder: disease burden. Am. J. Manag. Care 11, S80–S84. Scaglia, F., 2010. The role of mitochondrial dysfunction in psychiatric disease. Dev. Disabil. Res. Rev. 16, 136–143. Schmider, J., Lammers, C.H., Gotthardt, U., et al., 1995. Combined dexamethasone/ corticotropin-releasing hormone test in acute and remitted manic patients, in acute depression, and in normal controls: I. Biol. Psychiatry 38, 797–802. Sears, C., Wilson, J., Fitches, A., et al., 2013. Investigating the role of BDNF and CCK system genes in suicidality in a familial bipolar cohort. J. Affect. Disord. 151 (2), 611–617. Serretti, A., Drago, A., De, R.D., et al., 2009. Lithium pharmacodynamics and pharmacogenetics: focus on inositol mono phosphatase (IMPase), inositol poliphosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta). Curr. Med. Chem. 16, 1917–1948. Shabani, A., Teimurinejad, S., Koka, S., et al., 2013. Suicide risk factors in iranian patients with bipolar disorder: A 21- month follow-up from BDPF study. Iran. J. Psychiatry Behav. Sci. 7 (1), 16–23. Simon, G.E., Bauer, M.S., Ludman, E.J., et al., 2007. Mood symptoms, functional impairment and disability in people with bipolar disorder: specific effects of mania and depression. J. Clin. Psychiatry 68, 1237–1245. Simon, G.E., Hunkeler, E., Fireman, B., et al., 2007. Risk of suicide attempt and suicide death in patients treated for bipolar disorder. Bipolar Disord. 9, 526–530. Sisask, M., et al., 2010. Is religiosity a protective factor against attempted suicide: a crosscultural case–control study. Arch. Suicide Res. 14 (1), 44–55. Song, J.Y., Hy, Y.u., Kim, S.H., et al., 2012. Assessment of risk factors related to suicide attempts in patients with bipolar disorder. J. Nerv. Ment. Dis. 200 (11), 978–984. Stahl, S.M., 2000. Essential psychopharmacology of depression and bipolar disorder. Cambridge University Press, NewYork, NY. Stewart, C.D., Quinn, A., Plever, S., et al., 2009. Comparing cognitive behavior therapy, problem solving therapy, and treatment as usual in a high risk population. Suicide Life Threat Behav. 39 (5), 538–547. Sublette, M., Carballo, J.J., Moreno, C., et al., 2009. Substance use disorders and suicide attempts in bipolar subtypes. J. Psychiatry Res. 43 (3), 230–238. Suicidology AAo. 2000. American Association of Suicidology [AAS]. Offical 1998 statistics. Suttajit, S., Paholpak, S., Choovanicvong, S., et al., 2013. Correlates of current suicide risk among Thai patients with bipolar I disorder: findings from the Thai Bipolar Disorder Registry. Neuropsychiatry Dis. Treat. 9, 1751–1757. Tellenbach, 1974. Melancholie; Problemgeschichte; Endogenit ̈ at, Typologie, Pathogenese, Klinik. Springer, Berlin. Tondo, L., Albert, M.J., Baldessarini, R.J., 2006. Suicide rates in relation to health care access in the United States: an ecological study. J. Clin. Psychiatry 67 (4), 517–523. Tripodianakis, J., Markianos, M., Sarantidis, D., et al., 2000. Neurochemical variables in subjects with adjustment disorder after suicide attempts. Eur. Psychiatry 15, 190–195. Trouvin, J.H., Prioux-Guyonneau, M., Cohen, Y., et al., 1986. Rat brain monoamine metabolism and hypobaric hypoxia: a new approach. Gen. Pharmacol. 17, 69–73. Tsai, S.Y., Kuo, C.J., Chen, C.C., et al., 2002. Risk factors for completed suicide in bipolar disorder. J. Clin. Psychiatry 63, 469–476. Undurraga, J., Baldessarini, R.J., Valentı´, M., et al., 2011. Dissimilar suicidal risk factors in bipolar I and II disorders. J. Clin. Psychiatry. Undurraga, J., Baldessarini, R.J., Valenti, M., et al., 2012. Suicidal risk factors in bipolar I and II disorder patients. J. Clin. Psychiatry 73 (6), 778–782. Vaccari, A., Brotman, S., Cimino, J., et al., 1978. Adaptive changes induced by high altitude in the development of brain monoamine enzymes. Neurochem. Res. 3, 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 factors for attempted suicide among patients with bipolar disorder. Bipolar Disord. 8 (5 Pt 2), 576–585. WHO, 2011. Causes of Death 2008: Data Sources and Methods Department of Health Statistics and Informatics. World Health Organization, Geneva. Wang, P.W., Sachs, G.S., Zarate, C.A., et al., 2006. Overweight and obesity in bipolar disorders. J. Psychiatr. Res. 40, 762–764. Weinstock, L.M., Miller, I.W., 2008. Functional impairment as a predictor of shortterm symptom course in bipolar I disorder. Bipolar Disord. 10, 437–442. Weissman, M.M., Bland, R.C., Canino, G., et al., 1999. Prevalence of suicide ideation and suicide attempts in nine countries. Psychol. Med. 29, 9–17. World Health Organization (WHO). International suicide rates. 2003.

Wulsin, L.R., Vaillant, G.E., Wells, V.E., 1999. A systematic review of the mortality of depression. Psychosom. Med. 61, 6–17. Yerevanian, B., Feusner, J., Koek, R., et al., 2004. The dexamethasone suppression test as a predictor of suicidal behavior in unipolar depression. J. Affect. Disord. 83, 103. Yoon, Y.H., Chen, C.M., Moss, H.B., 2011. Effect of comorbid alcohol and drug use disorders on premature death among unipolar and bipolar disorder decedents in the United States, 1999–2006. Compr. Psychiatry 52 (5), 453–464. Zhu, W., Bijur, G.N., Styles, N.A., et al., 2004. Regulation of FOXO3a by brainderived neurotrophic factor in differentiated human SH SY5Y neuroblastoma cells. Brain Res. Mol. Brain Res. 126, 45–56.

Risk factors for suicide in bipolar disorder: a systematic review.

Bipolar disorder confers the highest risk of suicide among major psychological disorders. The risk factors associated with bipolar disorder and suicid...
822KB Sizes 0 Downloads 7 Views