Abstract

Introduction

Bipolar disorder (BD) is strongly associated with the risk of suicidal behavior (SB), and 10 to 15% of BD patients eventually die by suicide.¹1. Novick DM, Swartz HA, Frank E. Suicide attempts in bipolar I and bipolar II disorder: a review and meta-analysis of the evidence. Bipolar Disord. 2010;12:1-9. SB is complex and multifactorial, resulting from the interaction of environmental and biological factors.²2. Turecki G, Ernst C, Jollant F, Labonte B, Mechawar N. The neurodevelopmental origins of suicidal behavior. Trends Neurosci. 2012;35:14-23. Among short- and long-term environmental risk factors for SB, childhood-maltreatment (CM) plays an important role. World Health Organization data show that 25% of all adults report having been physically abused as children³3. Worl Health Organization (WHO). Global status report on violence prevention [Internet]. 2014 [cited 2020 Apr 20]. http://www.who.int/violence_injury_prevention/violence/status_report/2014/report/report/en/
http://www.who.int/violence_injury_preve... and this prevalence is as high as 57% among BD patients.⁴4. Post RM, Altshuler L, Leverich G, Nolen W, Kupka R, Grunze H, et al. More stressors prior to and during the course of bipolar illness in patients from the United States compared with the Netherlands and Germany. Psychiatry Res. 2013;210:880-6. In fact, CM has serious lifelong effects on neurobiology (e.g., neuroinflammation) and is strongly associated with unfavorable clinical course and disease progression in BD.⁵5. Agnew-Blais J, Danese A. Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:342-9.,⁶6. Daruy-Filho L, Brietzke E, Lafer B, Grassi-Oliveira R. Childhood maltreatment and clinical outcomes of bipolar disorder. Acta Psychiatr Scand. 2011;124:427-34.

CM is generally defined by sustained or repeated exposure to events that usually involve a betrayal of trust.⁷7. De Bellis MD. Developmental traumatology: the psychobiological development of maltreated children and its implications for research, treatment, and policy. Dev Psychopathol. 2001;13:539-64. Active examples of CM include childhood sexual and physical abuse, and various forms of emotional abuse. Passive examples include emotional and physical neglect.⁸8. Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav. 2012;106:29-39. In this regard, strong evidence suggests that different types of adversity may contribute to SB in BD patients.⁵5. Agnew-Blais J, Danese A. Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:342-9.,⁶6. Daruy-Filho L, Brietzke E, Lafer B, Grassi-Oliveira R. Childhood maltreatment and clinical outcomes of bipolar disorder. Acta Psychiatr Scand. 2011;124:427-34. The impact depends on timing, type, and severity of exposure,⁹9. Teicher MH, Samson JA. Childhood maltreatment and psychopathology: a case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. Am J Psychiatry. 2013;170:1114-33. and has cumulative effects over time.¹⁰10. Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav. 2012;106:29-39.

11. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14:245-58.-¹²12. Jaworska-Andryszewska P, Rybakowski JK. Childhood trauma in mood disorders: neurobiological mechanisms and implications for treatment. Pharmacol Rep. 2018;71:112-20.

Despite considerable interest in this subject, efforts to better understand the interactions between CM and SB have been hampered by a lack of consensus regarding the definition and measurement of CM. This heterogeneity decreases the internal and external validity of the available evidence, thereby limiting its generalizability and potential clinical applications. Indeed, prior research has highlighted the need to examine the specific impact of childhood trauma subtypes on severe BD outcomes.¹³13. Aas M, Henry C, Andreassen OA, Bellivier F, Melle I, Etain B. The role of childhood trauma in bipolar disorders. Int J Bipolar Disord. 2016;4:2.

One potential solution to this problem is the systematic use of a validated and reliable questionnaire to obtain data that is replicable and generalizable across different contexts. Perhaps the most promising tool yet developed is the Childhood Trauma Questionnaire (CTQ),¹⁴14. Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, et al. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry. 1994;151:1132-6. which is the most widely used quantitative measure of CM. The CTQ is available in multiple languages,¹⁵15. Grassi-Oliveira R, Stein LM, Pezzi JC. Tradução e validação de conteúdo da versão em português do Childhood Trauma Questionnaire. Rev Saude Publica. 2006;40:249-55. has been validated in clinical and nonclinical settings,¹⁴14. Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, et al. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry. 1994;151:1132-6. and possesses excellent test-retest stability.¹⁴14. Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, et al. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry. 1994;151:1132-6. For these reasons, the CTQ is currently the front-runner for assessing CM – though each instrument has advantages and disadvantages, and newer instruments are being developed.¹⁶16. MacDonald K, Thomas ML, Sciolla AF, Schneider B, Pappas K, Bleijenberg G, et al. Minimization of childhood maltreatment is common and consequential: results from a large, multinational sample using the childhood trauma questionnaire. PloS One. 2016;11:e0146058.

Furthermore, several studies (including meta-analysis) have suggested a strong association between CM and SB in BD.⁵5. Agnew-Blais J, Danese A. Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:342-9.,⁶6. Daruy-Filho L, Brietzke E, Lafer B, Grassi-Oliveira R. Childhood maltreatment and clinical outcomes of bipolar disorder. Acta Psychiatr Scand. 2011;124:427-34.,¹²12. Jaworska-Andryszewska P, Rybakowski JK. Childhood trauma in mood disorders: neurobiological mechanisms and implications for treatment. Pharmacol Rep. 2018;71:112-20.,¹³13. Aas M, Henry C, Andreassen OA, Bellivier F, Melle I, Etain B. The role of childhood trauma in bipolar disorders. Int J Bipolar Disord. 2016;4:2.,¹⁷17. Alloy LB, Abramson LY, Urosevic S, Walshaw PD, Nusslock R, Neeren AM. The psychosocial context of bipolar disorder: environmental, cognitive, and developmental risk factors. Clin Psychol Rev. 2005;25:1043-75.

18. Alloy LB, Abramson LY, Smith JM, Gibb BE, Neeren AM. Role of parenting and maltreatment histories in unipolar and bipolar mood disorders: mediation by cognitive vulnerability to depression. Clin Child Fam Psychol Rev. 2006;9:23-64.

19. Etain B, Henry C, Bellivier F, Mathieu F, Leboyer M. Beyond genetics: childhood affective trauma in bipolar disorder. Bipolar Disord. 2008;10:867-76.-²⁰20. Fisher HL, Hosang GM. Childhood maltreatment and bipolar disorder: a critical review of the evidence. Mind Brain. 2010;1:75-85. However, evidence is lacking on the association between various subtypes of CM and SB, particularly when more homogeneous concepts of maltreatment are used (e.g., the CTQ). For instance, although a meta-analysis by Agnew-Blais et al. addressed subtypes of trauma and unfavorable clinical outcomes in BD, they employed a broad approach to collect data on childhood trauma, which was extracted from different questionnaires across studies.⁵5. Agnew-Blais J, Danese A. Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:342-9. Therefore, deeper knowledge with a more narrow construct could guide future studies on this topic, such as explorations of the specific neurobiological consequences of childhood trauma on adult brains.²¹21. Heany SJ, Groenewold NA, Uhlmann A, Dalvie S, Stein DJ, Brooks SJ. The neural correlates of childhood trauma questionnaire scores in adults: a meta-analysis and review of functional magnetic resonance imaging studies. Dev Psychopathol. 2018;30:1475-85.

In this context, we hypothesize that BD patients who attempted suicide have higher childhood trauma in differential subtypes measured by CTQ than BD patients without SB. We sought to conduct 1) a review of studies on CM (physical and emotional negligence and physical, emotional, and sexual abuse) using the CTQ and 2) a meta-analysis aimed at clarifying the relationship between the type of CM experienced based on a standardized and uniform method, the CTQ, and vulnerability to SB in BD.

Methods

Literature search

A systematic literature search of MEDLINE, Embase, and PsycINFO databases was performed for human studies published until February 2019 in English or French. The Medical Subject Heading (MeSH) term “suicide” was combined with the MeSH terms “bipolar disorder,” and “child abuse (adult survivors of child abuse),” and with the Title/Abstract (TIAB) terms “CTQ,” “child abuse,” “child neglect,” “child maltreatment,” “childhood abuse,” “childhood maltreatment,” “sexual abuse,” “physical abuse,” “emotional abuse,” and “family conflict.” An iterative process was used to ensure that all relevant articles were obtained. Bibliographical references of the selected papers and existing reviews were manually searched to identify additional potential studies. In cases of overlapping datasets, the most recently published studies were chosen.

Study selection

Abstract selection was based on the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist,²²22. Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61:344-9. which describes items that should be included in reports of cohort studies. Abstracts identified through the literature search were independently evaluated by two reviewers (DD and SR-D) and were selected by consensus from all authors.

Studies that met the following inclusion criteria were included in this systematic review: 1) original articles published in an English or French language peer-reviewed journal; 2) that included CM assessment with the CTQ; 3) that included at least two groups of patients, of which at least one had a history of suicide attempt and who 4) have BD according to DSM criteria. A suicide attempt was defined as any act carried out with a certain intent to die, distinct from non-suicidal self-injury.²³23. Mann JJ. Neurobiology of suicidal behaviour. Nat Rev Neurosci. 2003;4:819-28. As pointed out, since the study of CM is highly affected by subjectivity and heterogeneity across publications, a number of studies²⁴24. Leverich GS, McElroy SL, Suppes T, Keck PE Jr, Denicoff KD, Nolen WA, et al. Early physical and sexual abuse associated with an adverse course of bipolar illness. Biol Psychiatry. 2002;51:288-97.

25. McIntyre RS, Soczynska JK, Mancini D, Lam C, Woldeyohannes HO, Moon S, et al. The relationship between childhood abuse and suicidality in adult bipolar disorder. Violence Vict. 2008;23:361-72.-²⁶26. Alvarez MJ, Roura P, Osés A, Foguet Q, Solà J, Arrufat FX. Prevalence and clinical impact of childhood trauma in patients with severe mental disorders. J Nerv Ment Dis. 2011;199:156-61. were excluded, despite their importance, due to not using the CTQ. After analysis of the titles and abstracts, the full articles were obtained for final review. The study selection process is shown in Figure 1.

Figure 1
Study selection process.

Of the 404 abstracts and records originally identified in previous systematic reviews, 13 met the inclusion criteria for this systematic review (Table 1). The quality of each study was assessed independently by two reviewers (DD and SRD) using the Crombie criteria adapted by Petticrew et al.²⁷27. Petticrew M, Roberts H. Systematic reviews in the social sciences: a practical guide. Oxford: Blackwell; 2006.

Although eligible and included in the systematic review (Table 1), five studies were not included in the meta-analysis because: 1) precise means and standard deviations (SD) were not available in the paper³⁵35. Li XB, Liu JT, Zhu XZ, Zhang L, Tang YL, Wang CY. Childhood trauma associates with clinical features of bipolar disorder in a sample of Chinese patients. J Affect Disord. 2014;168:58-63.; 2) they did not report CTQ scores for BD patients who attempted suicide vs. those who did not, and they did not report CTQ sub-scores²⁹29. Pavlova B, Perroud N, Cordera P, Uher R, Alda M, Dayer A, et al. Anxiety disorders and childhood maltreatment as predictors of outcome in bipolar disorder. J Affect Disord. 2018;225:337-41.; 3) only the most recent study of Janiri et al.²⁸28. Janiri D, De Rossi P, Kotzalidis GD, Girardi P, Koukopoulos AE, Reginaldi D, et al. Psychopathological characteristics and adverse childhood events are differentially associated with suicidal ideation and suicidal acts in mood disorders. Eur Psychiatry. 2018;53:31-6. was selected to prevent sample overlapping.³⁴34. Janiri D, Sani G, Danese E, Simonetti A, Ambrosi E, Angeletti G, et al. Childhood traumatic experiences of patients with bipolar disorder type I and type II. J Affect Disord. 2015;175:92-7. Of note, the second study performed a logistic regression to explore the association between childhood maltreatment and each BD severity indicator (i.e., unemployment, more than five lifetime depressive episodes, more than five lifetime manic episodes, history of psychotic symptoms, one or more hospitalizations for BD, and suicide attempts). Although requested, data could not be obtained directly from Janiri et al. about either study. Finally, two studies that used CTQ were excluded, one for not evaluating suicide behavior⁴⁵45. Innamorati M, Erbuto D, Venturini P, Fagioli F, Ricci F, Lester D, et al. Factorial validity of the Childhood Trauma Questionnaire in Italian psychiatric patients. Psychiatry Res. 2016;245:297-302. and the other for not addressing patients with major depressive disorder.⁴⁶46. Pompili M, Innamorati M, Lamis DA, Erbuto D, Venturini P, Ricci F, et al. The associations among childhood maltreatment, "male depression" and suicide risk in psychiatric patients. Psychiatry Res. 2014;220:571-8.

Data extraction and analyses

To extract data from the studies, a standardized form was used that included the authors, date of publication, study design, settings, study population, CM scale, definition of SB, and CTQ scores (mean and SD). CTQ scores and CTQ sub-scores were explored in at least three different studies.

Analyses were performed using Comprehensive Meta-Analyses version 2.0 and SPSS version 20. Two groups were compared: suicide attempters (patients with a history of suicide attempt) and patient controls (i.e., patients with no personal history of SB, but with a history of bipolar disorders).

We used a random-effects model to account for likely variations in true effect size between the included studies⁴⁷47. Riley RD, Higgins JP, Deeks JJ. Interpretation of random effects meta-analyses. BMJ. 2011;342:d549. and pooled Hedges’ g effect sizes for the subjects’ CTQ scores.⁴⁸48. Hedges LV, Olkin I. Statistical methods for meta-analysis. London: Academic Press; 1985. The obtained effect sizes are usually considered small if < 0.3, moderate if between 0.4-0.8, and large if > 0.8.⁴⁹49. Egger M, Davey Smith G, Altman D. Systematic reviews in health care: meta-analysis in context. London: BMJ Publishing Group; 2001.

Heterogeneity was assessed using the Q statistic and the I² index.⁵⁰50. Cooper H, Hedges LV, Valentine JC. The handbook of research synthesis and meta-analysis. New York: Russell Sage Foundation Publications; 2009. Values of p < 0.10 for the former and > 35% for the latter were deemed as indicative of study heterogeneity. Finally, we used funnel plots, Rosenthal’s fail-safe N⁵¹51. Rosenthal R. The file drawer problem and tolerance for null results. Psychol Bull. 1979;86:638-41. and Egger’s regression intercept⁵²52. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-34. to test for the presence of publication bias.⁵⁰50. Cooper H, Hedges LV, Valentine JC. The handbook of research synthesis and meta-analysis. New York: Russell Sage Foundation Publications; 2009.

Ethics statement

This study was conducted in accordance with the Declaration of Helsinki and according to local and international standards.

Results

Systematic review

Table 1 summarizes the 13 studies²⁸28. Janiri D, De Rossi P, Kotzalidis GD, Girardi P, Koukopoulos AE, Reginaldi D, et al. Psychopathological characteristics and adverse childhood events are differentially associated with suicidal ideation and suicidal acts in mood disorders. Eur Psychiatry. 2018;53:31-6.,²⁹29. Pavlova B, Perroud N, Cordera P, Uher R, Alda M, Dayer A, et al. Anxiety disorders and childhood maltreatment as predictors of outcome in bipolar disorder. J Affect Disord. 2018;225:337-41.,³¹31. Cakir S, Tasdelen Durak R, Ozyildirim I, Ince E, Sar V. Childhood trauma and treatment outcome in bipolar disorder. J Trauma Dissociation. 2016;17:397-409.

32. Bernegger A, Kienesberger K, Carlberg L, Swoboda P, Ludwig B, Koller R, et al. Influence of sex on suicidal phenotypes in affective disorder patients with traumatic childhood experiences. PloS One. 2015;10:e0137763.

33. Mert DG, Kelleci M, Mizrak A, Semiz M, Demir MO. Factors associated with suicide attempts in patients with bipolar disorder type I. Psychiatr Danub. 2015;27:236-41.

34. Janiri D, Sani G, Danese E, Simonetti A, Ambrosi E, Angeletti G, et al. Childhood traumatic experiences of patients with bipolar disorder type I and type II. J Affect Disord. 2015;175:92-7.

35. Li XB, Liu JT, Zhu XZ, Zhang L, Tang YL, Wang CY. Childhood trauma associates with clinical features of bipolar disorder in a sample of Chinese patients. J Affect Disord. 2014;168:58-63.

36. Erten E, Funda Uney A, Saatcioglu O, Ozdemir A, Fistikci N, Cakmak D. Effects of childhood trauma and clinical features on determining quality of life in patients with bipolar I disorder. J Affect Disord. 2014;162:107-13.

37. Watson S, Gallagher P, Dougall D, Porter R, Moncrieff J, Ferrier IN, et al. Childhood trauma in bipolar disorder. Aust N Z J Psychiatry. 2014;48:564-70.

38. Etain B, Aas M, Andreassen OA, Lorentzen S, Dieset I, Gard S, et al. Childhood trauma is associated with severe clinical characteristics of bipolar disorders. J Clin Psychiatry. 2013;74:991-8.

39. Pompili M, Iliceto P, Innamorati M, Rihmer Z, Lester D, Akiskal HS, et al. Suicide risk and personality traits in physically and/or sexually abused acute psychiatric inpatients: a preliminary study. Psychol Rep. 2009;105:554-68.-⁴⁰40. Garno JL, Goldberg JF, Ramirez PM, Ritzler BA. Impact of childhood abuse on the clinical course of bipolar disorder. Br J Psychiatry. 2005;186:121-5.41. Hamilton M. Standardised assessment and recording of depressive symptoms. Psychiatr Neurol Neurochir. 1969;72:201-5.42. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-71.43. Osman A, Bagge CL, Gutierrez PM, Konick LC, Kopper BA, Barrios FX. The Suicidal Behaviors Questionnaire-Revised (SBQ-R): validation with clinical and nonclinical samples. Assessment. 2001;8:443-54.44. Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988;45:742-7.,⁵³53. Duarte DG, Neves Mde C, Albuquerque MR, Neves FS, Correa H. Sexual abuse and suicide attempt in bipolar type I patients. Braz J Psychiatry. 2015;37:180-2. included in the systematic literature review. The design of all identified studies was cross-sectional. The percentage of males ranged from 31.3 to 39.8%.

Overall, the main findings in patients suffering from BD were:

1. A higher rate of suicide attempts in those who experienced childhood abuse;

2. Higher total CTQ scores and higher CTQ sub-scores in suicide attempters compared to non-attempters.

Meta-analysis

A total of six studies were included, comprising 1,033 participants, of whom 379 were suicide attempters and 654 were patient controls.

Suicide attempters had significantly higher CTQ total scores, sexual abuse CTQ sub-scores, physical abuse CTQ sub-scores, emotional abuse CTQ sub-scores, physical neglect CTQ sub-scores, and emotional neglect CTQ sub-scores than patient controls (Figure 2), all representing moderate to small effect sizes.

Figure 2
Comparison of the Childhood Trauma Questionnaire (CTQ) total score (A), CTQ sexual abuse sub-score (B), CTQ physical abuse sub-score (C), CTQ emotional abuse sub-score (D), CTQ physical neglect sub-score (E), and CTQ emotional neglect sub-score (F) between suicide attempters and patient controls in bipolar patients. 95%CI = 95% confidence interval.

Total CTQ between suicide attempters vs. patient controls

Suicide attempters had significantly higher CTQ total scores than patient controls, with a moderate effect size (Hedges’ g = -0.38, 95% confidence interval [95%CI] -0.52 to -0.24, z = -5.27, p < 0.001). The fail-safe N, i.e., the number of unpublished or missing null-findings that would be needed to render the results non-significant, was 35. Heterogeneity did not exceed that which was expected by chance (Q = 5.3; degrees of freedom [df] = 5; p = 0.37; I² = 6.3), implying that the variance among the effect sizes was not greater than expected by sampling error. The funnel plots were reasonably symmetrical, suggesting a low risk of publication bias, and the more conservative Egger’s regression intercept suggested no publication bias (online-only supplementary Figure S1). These results of funnel plots and Egger’s regression intercept were somewhat replicated in the CTQ subsets described below.

CTQ sexual abuse between suicide attempters vs. patient controls

Suicide attempters had significantly higher CTQ sexual abuse scores than patient controls, with a small effect size (Hedges’ g = -0.39, 95%CI -0.52 to -0.26, z = -5.9, p < 0.001). The fail-safe N was 45. Heterogeneity did not exceed that which was expected by chance (Q = 3.3; df = 5; p = 0.65; I² = 0).

CTQ physical abuse between suicide attempters vs. patient controls

Suicide attempters had significantly higher CTQ physical abuse scores than patient controls, with a small effect size (Hedges’ g = -0.26, 95%CI -0.39 to -0.13, z = -4.0, p = 0.001). The fail-safe N was 15. Heterogeneity did not exceed that which was expected by chance (Q = 3.46; df = 5; p = 0.6; I² = 0).

CTQ emotional abuse between suicide attempters vs. patient controls

Suicide attempters had significantly higher CTQ emotional abuse scores than patient controls, with a moderate effect size (Hedges’ g = -0.39, 95%CI -0.65 to -0.13, z = -2.88, p = 0.004). The fail-safe N was 11. Heterogeneity exceeded that which was expected by chance (Q = 14; df = 5; p = 0.016; I² = 64.2) at p < 0.05, implying that the variance among the effect sizes was greater than that expected by sampling error. The study by Janiri et al.²⁸28. Janiri D, De Rossi P, Kotzalidis GD, Girardi P, Koukopoulos AE, Reginaldi D, et al. Psychopathological characteristics and adverse childhood events are differentially associated with suicidal ideation and suicidal acts in mood disorders. Eur Psychiatry. 2018;53:31-6. was likely responsible for the heterogeneity. After excluding this study, the heterogeneity disappeared and the main results remained significant.

CTQ physical neglect between suicide attempters vs. patient controls

Suicide attempters had significantly higher CTQ physical neglect scores than patient controls, with a small effect size (Hedges’ g = -0.18, 95%CI -0.31 to -0.05, z = -2.79, p = 0.005). The fail-safe N was 6. Heterogeneity did not exceed that which was expected by chance (Q = 3.87; df = 5; p = 0.56; I² = 0).

CTQ emotional neglect between suicide attempters vs. patient controls

Suicide attempters had significantly higher CTQ emotional neglect scores than patient controls, with a small effect size (Hedges’ g = -0.27, 95%CI -0.43 to -0.11, z = -3.32, p = 0.001). The fail-safe N was 20. Heterogeneity did not exceed that which was expected by chance (Q = 2.23; df = 5; p = 0.28; I² = 19.82).

Discussion

To the best of our knowledge, this is the first meta-analysis on the association between CTQ subscale scores and vulnerability to SB in BD (type 1, 2, and not otherwise specified). Overall, we found that, compared to patient controls, individuals with BD who attempted suicide had more severe CM with significantly higher CTQ total scores and significantly higher CTQ sub-scores. Our meta-analysis of six BD studies confirmed a significant but small to moderate effect size of higher CTQ total and subscale scores among suicide attempters than patient controls. Given the effect sizes, emotional abuse, sexual abuse and emotional neglect might contribute more to SB in BD in comparison to physical trauma (abuse or neglect).

These findings suggest that CM may be related to increased vulnerability to SB in bipolar patients, which is congruent with longitudinal studies that have highlighted the association between CM and SB in bipolar diagnosis.⁵⁴54. Ernst C, Angst J, Foldenyi M. The Zurich Study. XVII. The Zurich Study. XVII. Sexual abuse in childhood. Frequency and relevance for adult morbidity data of a longitudinal epidemiological study. Eur Arch Psychiatry Clin Neurosci. 1993;242:293-300.

55. Leverich GS, Altshuler LL, Frye MA, Suppes T, Keck PE Jr, McElroy SL, et al. Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network. J Clin Psychiatry. 2003;64:506-15.

56. Brezo J, Paris J, Vitaro F, Hebert M, Tremblay RE, Turecki G. Predicting suicide attempts in young adults with histories of childhood abuse. Br J Psychiatry. 2008;193:134-9.

57. Enns MW, Cox BJ, Afifi TO, De Graaf R, Ten Have M, Sareen J. Childhood adversities and risk for suicidal ideation and attempts: a longitudinal population-based study. Psychol Med. 2006;36:1769-78.

58. Fergusson DM, Boden JM, Horwood LJ. Exposure to childhood sexual and physical abuse and adjustment in early adulthood. Child Abuse Negl. 2008;32:607-19.-⁵⁹59. Sugaya L, Hasin DS, Olfson M, Lin KH, Grant BF, Blanco C. Child physical abuse and adult mental health: a national study. J Trauma Stress. 2012;25:384-92. Furthermore, three recent reviews have addressed the impact of CM in clinical outcomes of BD patients⁵5. Agnew-Blais J, Danese A. Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:342-9.,¹³13. Aas M, Henry C, Andreassen OA, Bellivier F, Melle I, Etain B. The role of childhood trauma in bipolar disorders. Int J Bipolar Disord. 2016;4:2.,⁶⁰60. Maniglio R. Prevalence of child sexual abuse among adults and youths with bipolar disorder: a systematic review. Clin Psychol Rev. 2013;33:561-73. and the neurobiological mechanisms of CM in mood disorders.¹²12. Jaworska-Andryszewska P, Rybakowski JK. Childhood trauma in mood disorders: neurobiological mechanisms and implications for treatment. Pharmacol Rep. 2018;71:112-20. Although the previously mentioned evidence, in conjunction with the results of the present review, point to an evident association between CM and SB in BD, we cannot affirm a causal mechanism or a cause-effect phenomenon.

The association between SB and CM is multifactorial and begins early in life. Parental figures, caregivers, and other close relatives provide social support during developmental stages, which is essential for healthy emotional regulation and stress resilience.⁶¹61. Labonte B, Turecki G. The epigenetics of suicide: explaining the biological effects of early life environmental adversity. Arch Suicide Res. 2010;14:291-310. The experience of repeated acts of maltreatment and negligence from such “protectors” signals an adverse environment that triggers epigenetic phenomena in key response systems, such as the serotonin transporter gene,¹²12. Jaworska-Andryszewska P, Rybakowski JK. Childhood trauma in mood disorders: neurobiological mechanisms and implications for treatment. Pharmacol Rep. 2018;71:112-20. the hypothalamic-pituitary-adrenal axis, and the serotonergic and sympathetic nervous systems,⁶²62. Bremner JD. Long-term effects of childhood abuse on brain and neurobiology. Child Adolesc Psychiatr Clin N Am. 2003;12:271-92.,⁶³63. Watts-English. T, Fortson BL, Gibler N, Hooper SR, De Bellis MD. The psychobiology of maltreatment in childhood. J Soc Issues. 2006;62:717-36. ultimately affecting the brain’s structure and function.⁶⁴64. Pechtel P, Pizzagalli DA. Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacology (Berl). 2011;214:55-70. For instance, the effect of childhood trauma on subcortical volumes in BD patients produces specific changes in grey matter volumes of the amygdala, hippocampus, and pre-frontal regions, which are key areas for emotional regulation and are involved in suicide attempts.¹²12. Jaworska-Andryszewska P, Rybakowski JK. Childhood trauma in mood disorders: neurobiological mechanisms and implications for treatment. Pharmacol Rep. 2018;71:112-20.,³⁰30. Duarte DG, Neves Me C, Albuquerque MR, de Souza-Duran FL, Busatto G, Corrêa H. Gray matter brain volumes in childhood-maltreated patients with bipolar disorder type I: a voxel-based morphometric study. J Affect Disord. 2016;197:74-80.,⁶⁵65. Janiri D, Sani G, Rossi P, Piras F, Iorio M, Banaj N, et al. Amygdala and hippocampus volumes are differently affected by childhood trauma in patients with bipolar disorders and healthy controls. Bipolar Disord. 2017;19:353-62. In individuals who have experienced CM, BD emerges earlier,²⁴24. Leverich GS, McElroy SL, Suppes T, Keck PE Jr, Denicoff KD, Nolen WA, et al. Early physical and sexual abuse associated with an adverse course of bipolar illness. Biol Psychiatry. 2002;51:288-97. with greater severity,³⁸38. Etain B, Aas M, Andreassen OA, Lorentzen S, Dieset I, Gard S, et al. Childhood trauma is associated with severe clinical characteristics of bipolar disorders. J Clin Psychiatry. 2013;74:991-8. greater comorbidity,⁶⁶66. Leverich GS, Post RM. Course of bipolar illness after history of childhood trauma. Lancet. 2006;367:1040-2. more suicidal behavior,⁴⁰40. Garno JL, Goldberg JF, Ramirez PM, Ritzler BA. Impact of childhood abuse on the clinical course of bipolar disorder. Br J Psychiatry. 2005;186:121-5.,⁵³53. Duarte DG, Neves Mde C, Albuquerque MR, Neves FS, Correa H. Sexual abuse and suicide attempt in bipolar type I patients. Braz J Psychiatry. 2015;37:180-2. and treatment resistance.⁵5. Agnew-Blais J, Danese A. Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:342-9.,⁴⁰40. Garno JL, Goldberg JF, Ramirez PM, Ritzler BA. Impact of childhood abuse on the clinical course of bipolar disorder. Br J Psychiatry. 2005;186:121-5. Nevertheless, these negative outcomes are likely not unique to BD, since recent investigations have shown that CM is associated with an increased risk of SB in patients with schizophrenia,⁶⁷67. Roy A. Reported childhood trauma and suicide attempts in schizophrenic patients. Suicide Life Threat Behav. 2005;35:690-3. alcoholism,⁶⁸68. Roy A. Distal risk factors for suicidal behavior in alcoholics: replications and new findings. J Affect Disord. 2003;77:267-71. personality disorders,⁶⁹69. Bierer LM, Yehuda R, Schmeidler J, Mitropoulou V, New AS, Silverman JM, et al. Abuse and neglect in childhood: relationship to personality disorder diagnoses. CNS Spectr. 2003;8:737-54. and substance abuse,⁷⁰70. Roy A. Relationship of childhood trauma to age of first suicide attempt and number of attempts in substance dependent patients. Acta Psychiatr Scand. 2004;109:121-5. as well in healthy volunteers.⁷¹71. Brown J, Cohen P, Johnson JG, Smailes EM. Childhood abuse and neglect: specificity of effects on adolescent and young adult depression and suicidality. J Am Acad Child Adolesc Psychiatry. 1999;38:1490-6.

72. Dube SR, Anda RF, Felitti VJ, Chapman DP, Williamson DF, Giles WH. Childhood abuse, household dysfunction, and the risk of attempted suicide throughout the life span: findings from the adverse childhood experiences study. JAMA. 2001;286:3089-96.-⁷³73. Nelson EC, Heath AC, Madden PA, Cooper ML, Dinwiddie SH, Bucholz KK, et al. Association between self-reported childhood sexual abuse and adverse psychosocial outcomes: results from a twin study. Arch Gen Psychiatry. 2002;59:139-45.

Among all subtypes of CM, we found that emotional abuse; sexual abuse and emotional neglect might have a greater contribution to SB in BD. These findings are in line with studies by Etain et al.,³⁸38. Etain B, Aas M, Andreassen OA, Lorentzen S, Dieset I, Gard S, et al. Childhood trauma is associated with severe clinical characteristics of bipolar disorders. J Clin Psychiatry. 2013;74:991-8.,⁷⁴74. Etain B, Lajnef M, Henry C, Aubin V, Azorin JM, Bellivier F, et al. Childhood trauma, dimensions of psychopathology and the clinical expression of bipolar disorders: a pathway analysis. J Psychiatr Res. 2017;95:37-45. which show that emotional abuse is closely related to worse clinical outcomes in BD, including SB. In addition, sexual abuse seems to be a strong predictor for suicide.⁶6. Daruy-Filho L, Brietzke E, Lafer B, Grassi-Oliveira R. Childhood maltreatment and clinical outcomes of bipolar disorder. Acta Psychiatr Scand. 2011;124:427-34.,²⁰20. Fisher HL, Hosang GM. Childhood maltreatment and bipolar disorder: a critical review of the evidence. Mind Brain. 2010;1:75-85. Although in this present study we found a lower magnitude of effect between physical trauma (abuse or neglect) and SB, this type of trauma does seem to have an important role in SB among individuals with BD.¹³13. Aas M, Henry C, Andreassen OA, Bellivier F, Melle I, Etain B. The role of childhood trauma in bipolar disorders. Int J Bipolar Disord. 2016;4:2. This could be mediated by drug abuse⁵⁸58. Fergusson DM, Boden JM, Horwood LJ. Exposure to childhood sexual and physical abuse and adjustment in early adulthood. Child Abuse Negl. 2008;32:607-19.,⁷⁵75. Aas M, Etain B, Bellivier F, Henry C, Lagerberg T, Ringen A, et al. Additive effects of childhood abuse and cannabis abuse on clinical expressions of bipolar disorders. Psychol Med. 2014;44:1653-62. and gender effect, since physical abuse is more frequently reported in males and sexual abuse in females.⁷⁶76. Fisher H, Morgan C, Dazzan P, Craig TK, Morgan K, Hutchinson G, et al. Gender differences in the association between childhood abuse and psychosis. Br J Psychiatry. 2009;194:319-25. Unfortunately, only a small number of studies have addressed emotional and physical neglect.³⁸38. Etain B, Aas M, Andreassen OA, Lorentzen S, Dieset I, Gard S, et al. Childhood trauma is associated with severe clinical characteristics of bipolar disorders. J Clin Psychiatry. 2013;74:991-8. Finally, the frequency and presence of more than one sub-type of trauma have a direct relationship with suicide attempts in BD.⁴⁰40. Garno JL, Goldberg JF, Ramirez PM, Ritzler BA. Impact of childhood abuse on the clinical course of bipolar disorder. Br J Psychiatry. 2005;186:121-5.

Regarding the impact of our findings on the severity of SB and, ultimately, on clinical practice, current evidence suggests that in BD patients, CM is associated with a higher number and earlier onset of suicide attempts, comorbid substance misuse, and overall worse bipolar outcomes, including more hospitalizations.⁵5. Agnew-Blais J, Danese A. Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:342-9.,⁶6. Daruy-Filho L, Brietzke E, Lafer B, Grassi-Oliveira R. Childhood maltreatment and clinical outcomes of bipolar disorder. Acta Psychiatr Scand. 2011;124:427-34.,¹²12. Jaworska-Andryszewska P, Rybakowski JK. Childhood trauma in mood disorders: neurobiological mechanisms and implications for treatment. Pharmacol Rep. 2018;71:112-20.,¹³13. Aas M, Henry C, Andreassen OA, Bellivier F, Melle I, Etain B. The role of childhood trauma in bipolar disorders. Int J Bipolar Disord. 2016;4:2.,¹⁷17. Alloy LB, Abramson LY, Urosevic S, Walshaw PD, Nusslock R, Neeren AM. The psychosocial context of bipolar disorder: environmental, cognitive, and developmental risk factors. Clin Psychol Rev. 2005;25:1043-75.

18. Alloy LB, Abramson LY, Smith JM, Gibb BE, Neeren AM. Role of parenting and maltreatment histories in unipolar and bipolar mood disorders: mediation by cognitive vulnerability to depression. Clin Child Fam Psychol Rev. 2006;9:23-64.

19. Etain B, Henry C, Bellivier F, Mathieu F, Leboyer M. Beyond genetics: childhood affective trauma in bipolar disorder. Bipolar Disord. 2008;10:867-76.-²⁰20. Fisher HL, Hosang GM. Childhood maltreatment and bipolar disorder: a critical review of the evidence. Mind Brain. 2010;1:75-85. Collectively, current evidence suggests that CM is a potential marker for identifying BD patients at high risk of unfavorable clinical outcomes and disease progression, and thereby vulnerable to SB.⁵5. Agnew-Blais J, Danese A. Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:342-9. Thus, risk stratification in BD treatment could lead to the development of targeted treatment strategies.

The basis for valid stratification comes from the homogeneity of the collected data and the assessment of corresponding variables. Aside from the studies included in our systematic review, there is no uniformity for assessing CM and its potential association between BD and SB. Inherent challenges in assessing complex concepts like CM have resulted in a variety of heterogeneous definitions (i.e., childhood abuse, trauma, adversities, and early stress) and an even greater variety of instruments – over 40.⁷⁷77. Roy CA, Perry JC. Instruments for the assessment of childhood trauma in adults. J Nerv Ment Dis. 2004;192:343-51. Thus, to minimize discrepancies, the use of similar clinical interviews and validated questionnaires should be encouraged. Although the CTQ is not clearly superior to other available tools, its widespread use in research and its reliability (and validity) make it a promising instrument for professionals in research practice.⁷⁰70. Roy A. Relationship of childhood trauma to age of first suicide attempt and number of attempts in substance dependent patients. Acta Psychiatr Scand. 2004;109:121-5. However, as a drawback, the CTQ does not provide data on the timing of the trauma during neurodevelopment, which has been suggested to be of particular importance in first psychotic episode, for example.⁷⁸78. Alameda L, Ferrari C, Baumann PS, Gholam-Rezaee M, Do KQ, Conus P. Childhood sexual and physical abuse: age at exposure modulates impact on functional outcome in early psychosis patients. Psychol Med. 2015;45:2727-36.

This systematic review and meta-analysis has some limitations that should be considered when interpreting the results. The most common limitation in meta-analyses is the combination of heterogeneous studies and the inclusion of poor-quality trials, consequently increasing the risk of publication bias. Nonetheless, these concerns were addressed in the present study by assessing both publication bias and heterogeneity, as well as by the use of a standard questionnaire (the CTQ), which increased internal validity, generalizability, and significantly reduced heterogeneity. The present meta-analysis included six studies, therefore potentially overcoming the drawback of the small number of studies used in some analyses, which inadequately increases the effect size.⁷⁹79. Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14:365-76. The studies did not differentiate CTQ scores across subsets of the population, such as those with low vs. high-lethality suicide attempts and/or those with violent vs. non-violent suicide attempts. Due to the lack of data, we could not explore the effect of CM on specific types of BD (e.g., BD type 1). Since CM was evaluated retrospectively among the studies included in this systematic review and meta-analysis, inferences on cause and effect cannot be made, and memory bias must be considered. Finally, we ruled out the effects of several variables (e.g., age and the severity of depressive and mania symptoms at the time of assessment), although the association between CM and SB in bipolar populations should be further investigated.

In conclusion, our findings suggest that CM severity and subtypes (especially emotional abuse, sexual abuse, and emotional neglect) could contribute to the development of SB in individuals with BD. These findings also highlight the importance of recognizing maltreatment as an etiological risk factor that must be evaluated in psychiatric consultations, particularly with BD patients. This is crucial to developing science-based preventive psychiatry and designing effective therapeutic regimens.

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