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Background: Evidence-based data on prevalence and risk factors of suicidal intentions and behavior in dementia are as scarce as the data on assisted dying. The present literature review aimed on summarizing the current knowledge and provides a critical discussion of the results.Methods: A systematic narrative literature review was performed using Medline, Cochrane Library, EMBASE, PSYNDEX, PSYCINFO, Sowiport, and Social Sciences Citation Index literature.Results: Dementia as a whole does not appear to be a risk factor for suicide completion. Nonetheless some subgroups of patients with dementia apparently have an increased risk for suicidal behavior, such as patients with psychiatric comorbidities (particularly depression) and of younger age. Furthermore, a recent diagnosis of dementia, semantic dementia, and previous suicide attempts most probably elevate the risk for suicidal intentions and behavior. The impact of other potential risk factors, such as patient's cognitive impairment profile, behavioral disturbances, social isolation, or a biomarker based presymptomatic diagnosis has not yet been investigated. Assisted dying in dementia is rare but numbers seem to increase in regions where it is legally permitted.Conclusion: Most studies that had investigated the prevalence and risk factors for suicide in dementia had significant methodological limitations. Large prospective studies need to be conducted in order to evaluate risk factors for suicide and assisted suicide in patients with dementia and persons with very early or presymptomatic diagnoses of dementia. In clinical practice, known risk factors for suicide should be assessed in a standardized way so that appropriate action can be taken when necessary. [ABSTRACT FROM AUTHOR]

BackgroundCognitive inhibition deficits have previously been found in suicide attempters. This study examined the neural basis for these deficits in depressed patients with and without a history of suicidal behavior.MethodFunctional magnetic resonance imaging was used to measure brain activation during the Go/No-Go response inhibition task in 25 unmedicated and depressed middle-aged suicide attempters, 22 unmedicated depressed patient controls with no personal or family history of suicidal behavior, and 27 healthy controls. Whole-brain analyses were conducted with SPM12.ResultsSuicide attempters exhibited an elevated number of commission errors relative to both control groups. However, suicide attempters did not differ from patient controls in terms of brain activation for any contrast. Analyses showed a significant association between depression and brain activation in the left inferior frontal gyrus and medial thalamus during Go v. No-Go, and in the bilateral parietal cortex and left orbitofrontal cortex during No-Go v. baseline. These regions were correlated with psychological pain, suicidal ideation and global functioning. There was no association between brain activation and personal histories of suicidal act.ConclusionsOur study suggests that deficits in cognitive inhibition, in relation to the inferior frontal gyrus, thalamus, orbitofrontal cortex and parietal cortex, are related to the depressive state and not specifically to suicide vulnerability. We hypothesize that state-related deficits may add to trait-like cognitive impairments to facilitate suicidal acts. These different types of cognitive impairments may necessitate different therapeutic strategies for the prevention of suicide. [ABSTRACT FROM PUBLISHER]

Background Antisocial personality disorder (ASPD) is characterised by elevated impulsive aggression and increased risk for criminal behaviour and incarceration. Deficient activity of the monoamine oxidase A (MAOA) gene is suggested to contribute to serotonergic system dysregulation strongly associated with impulsive aggression and antisocial criminality. Aims To elucidate the role of epigenetic processes in altered MAOA expression and serotonin regulation in a population of incarcerated offenders with ASPD compared with a healthy non-incarcerated control population. Method Participants were 86 incarcerated participants with ASPD and 73 healthy controls. MAOA promoter methylation was compared between case and control groups. We explored the functional impact of MAOA promoter methylation on gene expression in vitro and blood 5-HT levels in a subset of the case group. Results Results suggest that MAOA promoter hypermethylation is associated with ASPD and may contribute to downregulation of MAOA gene expression, as indicated by functional assays in vitro, and regression analysis with whole-blood serotonin levels in offenders with ASPD. Conclusions These results are consistent with prior literature suggesting MAOA and serotonergic dysregulation in antisocial populations. Our results offer the first evidence suggesting epigenetic mechanisms may contribute to MAOA dysregulation in antisocial offenders. [ABSTRACT FROM AUTHOR]

Background. Suicidal behavior is frequently associated with a history of childhood abuse yet it remains unclear precisely how early life adversity may increase suicide risk later in life. As such, our aim was to examine whether lifetime trajectories of disruptiveness and anxiousness trait dysregulation explain the association between childhood adversity and suicidal behavior; and moreover, to test the potential modifying effects of mental disorders on these associations. Method. A sample of 1776 individuals from a prospective school-based cohort followed longitudinally for over 22 years was investigated. We tested the influence of disruptiveness and anxiousness trajectories from age 6 to 12 years on the association between childhood adversity (i.e. sexual and physical abuse) and history of suicide attempts (SA) using logistic regression models. Both adolescent externalizing and internalizing Axis I disorders and gender were tested as potential modifiers of these associations. Results. Four distinct longitudinal trajectories were identified for both disruptiveness and anxiousness. The high disruptiveness trajectory accounted for the association between childhood adversity and SA, but only for females. The high anxiousness trajectory also explained the association between adversity and SA; however, in this case it was not sex but mental disorders that influenced the potency of the mediating effect. More specifically, anxiousness fully explained the effect of adversity on SA in the presence of externalizing disorders, whereas in the absence of these disorders, this effect was significantly attenuated. Conclusions. This study provides evidence that both disruptiveness and anxiousness play an important role in explaining the relationship between childhood adversity and SA. [ABSTRACT FROM AUTHOR]

Abstract: Despite strong evidence for a role of biological factors in the etiology and pathology of suicide, the study of traditional neurotransmitter systems has been able to explain only a small proportion of the neurobiology of what is now recognized as a complex genetic trait. The use of microarrays to simultaneously examine the expression levels of thousands of gene transcripts has vastly expanded our capacity to detect the involvement of additional genes and pathways in suicidality, and has opened many new avenues for the discovery of the biological underpinnings of suicide completion. This review examines microarray studies which have been used to identify genes displaying altered expression in suicide completers, and highlights some of the important methodological considerations and metabolic pathways which have emerged from these analyses. [Copyright &y& Elsevier]

BACKGROUND: It is unclear whether the association between impulsive-aggressive behaviours and suicide exists across different ages.MethodVia psychological autopsy, we examined a total of 645 subjects aged 11-87 years who died by suicide. Proxy-based interviews were conducted using the SCID-I & SCID-II or K-SADS interviews and a series of behavioural and personality-trait assessments. Secondarily, 246 living controls were similarly assessed. RESULTS: Higher levels of impulsivity, lifetime history of aggression, and novelty seeking were associated with younger age of death by suicide, while increasing levels of harm avoidance were associated with increasing age of suicide. This effect was observed after accounting for age-related psychopathology (current and lifetime depressive disorders, lifetime anxiety disorders, current and lifetime substance abuse disorders, psychotic disorders and cluster B personality disorders). Age effects were not due to the characteristics of informants, and such effects were not observed among living controls. When directly controlling for major psychopathology, the interaction between age, levels of impulsivity, aggression and novelty seeking predicted suicide status while controlling for the independent contributions of age and these traits. CONCLUSIONS: Higher levels of impulsive-aggressive traits play a greater role in suicide occurring among younger individuals, with decreasing importance with increasing age. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Little is known about differential suicide profiles across the life trajectory. This study introduces the life-course method in suicide research with the aim of refining the longitudinal and cumulative assessment of psychosocial factors by quantifying accumulation of burden over time in order to delineate distinctive pathways of completed suicide.MethodThe psychological autopsy method was used to obtain third-party information on consecutive suicides. Life-history calendar analysis served to arrive at an adversity score per 5-year segment that was then cluster-analysed and correlated to define victim profiles. RESULTS: Two distinct life trajectories emerged: (1) individuals who experienced childhood traumas, developmental adversity and little protection were more likely to present concurrent psychiatric and Axis II disorders; and (2) individuals who experienced less adversity but seemed more reactive to later major difficulties. CONCLUSIONS: The life calendar approach presented here in suicide research adds to the identification of life events, distal and recent, previously associated with suicide. It also quantifies the burden of adversity over the life course, defining two distinct profiles that could benefit from distinct targeted preventive intervention. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Suicidal behaviors in young individuals represent an important public health problem. Understanding their natural history and relationships would therefore be of clinical and research value. In this study, we examined the natural histories of several suicidal behaviors and investigated two conceptual models of suicidality (dimensional and categorical) in the context of adolescent and adult-onset suicide attempts.MethodParticipants were members of a prospectively studied, representative, population-based school cohort followed since age 6 (n=3017) through mid-adolescence (n=1715) to their early twenties (n=1684). Outcome measures included suicidal ideation, attempts and completions. RESULTS: Approximately one in 500 individuals died by suicide. About 33% had suicidal ideas and 9.3% made at least one suicide attempt. Over half (4.9%) of the self-reported attempters made their first attempt before age 18. With the exception of current suicidal ideas, non-fatal suicidal behaviors were more prevalent in females. In general, parental and cross-sectional self-reports underestimated suicidality rates. Aikaike (AIC) and Bayesian (BIC) information criteria suggested the ordinal model, and dimensional conceptualization of suicide attempts of different onset age, to be more optimal than its multinomial/categorical counterpart (ordinal: AIC 567.55, BIC 635.67; multinomial: AIC 616.59, BIC 723.83). Both models, nevertheless, identified five common factors of relevance to suicidal diathesis: gender, disruptive disorders, childhood anxiousness and abuse, and suicidal thoughts. CONCLUSIONS: Non-fatal suicidal behaviors in adolescents and young adults are more common than suggested by cross-sectional studies and parental reports. The dimensional model may be more useful in explaining the relationship of suicide attempts of different age of onset. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Identification of factors that distinguish between ideators who act on their suicidal thoughts from those who do not is an important clinical and research objective.MethodWe examined correlates of suicide attempts in suicidal ideators, members of a French-Canadian, school-based cohort. Suicidal thoughts were evaluated in adolescence and early adulthood in the total sample of suicidal ideators, who were then stratified into subgroups consisting of persistent ideators, male ideators and female ideators. RESULTS: In addition to persistent suicidal ideas [odds ratios (ORs) 2.1-2.8], Axis I psychopathology, female gender and childhood sexual abuse (CSA) were the most consistent correlates of suicide attempts. Externalizing disorders were significant contributors in persistent ideators [drug misuse: OR 2.8, 95% confidence interval (CI) 1.1-6.9] and in male ideators in particular (disruptive disorders: OR 5.9, 95% CI 2.2-16.0). In women, psychiatric co-morbidity also had a significant effect (OR 1.6, 95% CI 1.1-2.1). CSA was of relevance in both women (OR 1.2, 95% CI 1.1-1.4) and persistent ideators (OR 1.3, 95% CI 1.1-1.5). Personality traits showed gender-specific contribution with affective instability (OR 1.1, 95% CI 1.01-1.1) and anxiousness (OR 1.3, 95% CI 1.1-1.7) contributing in men and disruptive aggression (OR 1.1, 95% CI 1.03-1.3) in women. CONCLUSIONS: Correlates of suicide attempts in suicidal ideators vary as a function of the persistence of suicidal ideas and gender. This heterogeneity across subgroups of suicidal ideators may be attributed, at least in part, to differences between the sexes, early environmental adversity, maladaptive personality, and psychiatric symptoms. Further exploration and continued prospective follow-up is necessary to examine these possibilities. [ABSTRACT FROM AUTHOR]

BACKGROUND: Adults in their twenties appear to be at high risk for suicidal behaviors (SBs) and there is substantial evidence suggesting that certain personality traits may increase individual vulnerability to suicide. METHOD: We investigated relationships of personality traits with two SBs in a cohort (n=1140) of 21- to 24-year-old adults, representative of the general population of Quebec. Subjects were assessed using a series of structured diagnostic and personality trait questionnaires. Multivariate logistic regression analyses were employed to identify personality trait correlates of suicide-attempt history and serious suicidal ideation in the context of other known risk factors, such as psychopathology and experiences of childhood sexual and physical abuse. RESULTS: Traits of conduct problems contributed to both suicide attempts [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06] and suicidal ideation (OR 1.04, 95% CI 1.02-1.07), while identity problems (OR 1.10, 95% CI 1.07-1.13) and gender-moderated impulsivity contributed exclusively to suicidal ideation. CONCLUSIONS: Personality traits may make independent contributions to current suicidal ideation and previous suicide attempts in certain subgroups of suicidal individuals. In order to further explore their utility as markers of suicide risk and targets of intervention further investigation in clinical samples and other cultural and age groups is necessary. [ABSTRACT FROM AUTHOR]

Suicide and related behaviors are complex phenomena associated with different risk factors. While most individuals who display suicidal behavior do not have a history of early-life adversity, a significant minority does. In this symposium, Dr. Turecki will discuss results from his laboratory suggesting that early-life adversity increases risk of suicide by altering methylation patterns in discrete genetic loci. Stable gene expression resulting from these altered methylation patterns are likely to influence the development of stable emotional and behavioral phenotypes that, in turn, increase suicide risk. He will discuss recent data suggesting that these mechanisms are at play in the regulation of aggressive behavior. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about lithium therapy.

A letter to the editor is presented in response to an article published in the February 1989 issue, on the occurrence of bipolar disorder in response to brain stroke.

Background Suicidal behavior results from a complex interplay between stressful events and vulnerability factors, including neurocognitive alterations. Deficits in cognitive inhibition have previously been found in suicide attempters. Here, we examined the neural basis of these deficits in patients at-risk for suicide. Methods Functional magnetic resonance imaging was used to measure brain activation in 25 middle-aged depressed yet non-medicated suicide attempters (SA), 22 depressed patient controls with no personal or first-degree family history of suicidal behaviour (PC), and 27 healthy controls (HC) during the Go/No-Go response inhibition task. Results In whole brain exploration of No-Go versus Go inhibition contrast, SA show elevated activities in posterior cingulate gyrus compared to HC (Cluster FWE = 0.022). Further exploration of each individual condition against baseline (e.g. No-Go versus Baseline or Go versus Baseline) suggest this regional differences are mainly due to No-Go baseline comparison within each groups: namely, HC show a large reduced activities during No-Go blocks while PC and SA failed to show similar reductions comparing to baseline. Conclusion SA showed unique differentiated patterns of neural activity during Go-No-Go response inhibition differ from HC and PC mostly involving posterior cingulate gyrus. These findings indicate that suicide attempts during middle-aged are associated with abnormal activity in response inhibition neural circuitry. [ABSTRACT FROM AUTHOR]

Objective: There is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies in major depressive disorder (MDD)., Methods: In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10-20 mg daily for 8 weeks. Responders continued escitalopram while non-responders received adjunctive aripiprazole 2-10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers-C-reactive protein, interleukin (IL)-1β, IL-6, IL-17, interferon-gamma (IFN)-Γ, tumor necrosis factor (TNF)-α, and Chemokine C-C motif ligand-2 (CCL-2)-measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyzes to assess associations between inflammatory markers and treatment response., Results: Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16., Conclusion: Higher pre-treatment levels of IFN-Γ and CCL-2 were associated with non-response to escitalopram. Increasing levels of these pro-inflammatory markers may be associated with non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.

Background: Prediction of treatment outcomes is a key step in improving the treatment of major depressive disorder (MDD). The Canadian Biomarker Integration Network in Depression (CAN-BIND) aims to predict antidepressant treatment outcomes through analyses of clinical assessment, neuroimaging, and blood biomarkers., Methods: In the CAN-BIND-1 dataset of 192 adults with MDD and outcomes of treatment with escitalopram, we applied machine learning models in a nested cross-validation framework. Across 210 analyses, we examined combinations of predictive variables from three modalities, measured at baseline and after 2 weeks of treatment, and five machine learning methods with and without feature selection. To optimize the predictors-to-observations ratio, we followed a tiered approach with 134 and 1152 variables in tier 1 and tier 2 respectively., Results: A combination of baseline tier 1 clinical, neuroimaging, and molecular variables predicted response with a mean balanced accuracy of 0.57 (best model mean 0.62) compared to 0.54 (best model mean 0.61) in single modality models. Adding week 2 predictors improved the prediction of response to a mean balanced accuracy of 0.59 (best model mean 0.66). Adding tier 2 features did not improve prediction., Conclusions: A combination of clinical, neuroimaging, and molecular data improves the prediction of treatment outcomes over single modality measurement. The addition of measurements from the early stages of treatment adds precision. Present results are limited by lack of external validation. To achieve clinically meaningful prediction, the multimodal measurement should be scaled up to larger samples and the robustness of prediction tested in an external validation dataset.

Background: Suicidal behavior is moderately heritable and a consequence of a combination of the diathesis traits for suicidal behavior and suicide-related major psychiatric disorders. Here, we sought to examine shared polygenic effects between various psychiatric disorders/traits and suicidal behavior and to compare the shared polygenic effects of various psychiatric disorders/traits on non-fatal suicide attempt and suicide death., Methods: We used our genotyped European ancestry sample of 260 non-fatal suicide attempters, 317 suicide decedents and 874 non-psychiatric controls to test whether polygenic risk scores (PRSs) obtained from large GWASs for 22 suicide-related psychiatric disorders/traits were associated with suicidal behavior. Results were compared between non-fatal suicide attempt and suicide death in a sensitivity analysis., Results: PRSs for major depressive disorder, bipolar disorder, schizophrenia, ADHD, alcohol dependence, sensitivity to environmental stress and adversity, educational attainment, cognitive performance, and IQ were associated with suicidal behavior (Bonferroni-corrected p < 2.5 × 10 -4 ). The polygenic effects of all 22 psychiatric disorders/traits had the same direction ( p for binomial tests = 4.8 × 10 -7 ) and were correlated (Spearman's ρ = 0.85) between non-fatal suicide attempters and suicide decedents., Conclusions: We found that polygenic effects for major psychiatric disorders and diathesis-related traits including stress responsiveness and intellect/cognitive function contributed to suicidal behavior. While we found comparable polygenic architecture between non-fatal suicide attempters and suicide decedents based on correlations with PRSs of suicide-related psychiatric disorders/traits, our analyses are limited by small sample size resulting in low statistical power to detect difference between non-fatal suicide attempt and suicide death.

Background: While childhood externalizing, internalizing and comorbid problems have been associated with suicidal risk, little is known about their specific associations with suicidal ideation and attempts. We examined associations between childhood externalizing, internalizing and comorbid problems and suicidal ideation (without attempts) and attempts by early adulthood, in males and females., Method: Participants were from the Quebec Longitudinal Study of Kindergarten Children, a population-based study of kindergarteners in Quebec from 1986 to 1988 and followed-up until 2005. We captured the co-development of teacher-rated externalizing and internalizing problems at age 6-12 using multitrajectories. Using the Diagnostic Interview Schedule administered at age 15 and 22, we identified individuals (1) who never experienced suicidal ideation/attempts, (2) experienced suicidal ideation but never attempted suicide and (3) attempted suicide., Results: The identified profiles were no/low problems (45%), externalizing (29%), internalizing (11%) and comorbid problems (13%). After adjusting for socioeconomic and familial characteristics, children with externalizing (OR 2.00, CI 1.39-2.88), internalizing (OR 2.34, CI 1.51-3.64) and comorbid (OR 3.29, CI 2.05-5.29) problems were at higher risk of attempting suicide ( v. non-suicidal) by age 22 than those with low/no problems. Females with comorbid problems were at higher risk of attempting suicide than females with one problem. Childhood problems were not associated with suicidal ideation. Externalizing (OR 2.01, CI 1.29-3.12) and comorbid problems (OR 2.28, CI 1.29-4.03) distinguished individuals who attempted suicide from those who thought about suicide without attempting., Conclusion: Childhood externalizing problems alone or combined with internalizing problems were associated with suicide attempts, but not ideation (without attempts), suggesting that these problems confer a specific risk for suicide attempts.

The present study examined the effect of early life stress (ELS) on the glucocorticoid receptor gene ( NR3C1 ) methylation, the associations between NR3C1 methylation and behavior problems, and the effect of the program Parents as Teachers (PAT) on NR3C1 methylation. Participants included 132 children, 72 assigned to the PAT intervention group and 60 to the PAT control group. Children were aged 3 years, and were living in psychosocially at-risk families. We assessed NR3C1 methylation of the NGFI-A binding regions of exon 1F via sodium bisulfite sequencing from saliva DNA. Results indicated that (a) children living in families receiving PAT had decreased methylation at one single cytosine-guanine dinucleotides (CpG) site; (b) current maternal depressive symptoms and parental disagreement were predictive of increased methylation of mean NGFI-A and three single CpG sites; and (c) increased methylation of mean NGFI-A and one single CpG site was significantly associated with increased internalizing and externalizing symptoms. In addition, mean NGFI-A was a mediator of the association between parental disagreement and a child's affective problems. These results suggest that PAT may contribute to preventing NR3C1 methylation in preschool children living in psychosocially at-risk situations, and confirm previous findings on the associations between ELS, NR3C1 methylation, and behavior problems.

Background: We aimed to identify groups of children presenting distinct perinatal adversity profiles and test the association between profiles and later risk of suicide attempt., Methods: Data were from the Québec Longitudinal Study of Child Development (QLSCD, N = 1623), and the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5734). Exposures to 32 perinatal adversities (e.g. fetal, obstetric, psychosocial, and parental psychopathology) were modeled using latent class analysis, and associations with a self-reported suicide attempt by age 20 were investigated with logistic regression. We investigated to what extent childhood emotional and behavioral problems, victimization, and cognition explained the associations., Results: In both cohorts, we identified five profiles: No perinatal risk, Poor fetal growth, Socioeconomic adversity, Delivery complications, Parental mental health problems (ALSPAC only). Compared to children with No perinatal risk, children in the Poor fetal growth (pooled estimate QLSCD-ALSPAC, OR 1.89, 95% CI 1.04-3.44), Socioeconomic adversity (pooled-OR 1.42, 95% CI 1.08-1.85), and Parental mental health problems (OR 1.74, 95% CI 1.27-2.40), but not Delivery complications, profiles were more likely to attempt suicide. The proportion of this effect mediated by the putative mediators was larger for the Socioeconomic adversity profile compared to the others., Conclusions: Perinatal adversities associated with suicide attempt cluster in distinct profiles. Suicide prevention may begin early in life and requires a multidisciplinary approach targeting a constellation of factors from different domains (psychiatric, obstetric, socioeconomic), rather than a single factor, to effectively reduce suicide vulnerability. The way these factors cluster together also determined the pathways leading to a suicide attempt, which can guide decision-making on personalized suicide prevention strategies.

Background: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools., Aims: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics., Method: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts., Results: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO., Conclusions: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Background: Multiple treatments are effective for major depressive disorder (MDD), but the outcomes of each treatment vary broadly among individuals. Accurate prediction of outcomes is needed to help select a treatment that is likely to work for a given person. We aim to examine the performance of machine learning methods in delivering replicable predictions of treatment outcomes., Methods: Of 7732 non-duplicate records identified through literature search, we retained 59 eligible reports and extracted data on sample, treatment, predictors, machine learning method, and treatment outcome prediction. A minimum sample size of 100 and an adequate validation method were used to identify adequate-quality studies. The effects of study features on prediction accuracy were tested with mixed-effects models. Fifty-four of the studies provided accuracy estimates or other estimates that allowed calculation of balanced accuracy of predicting outcomes of treatment., Results: Eight adequate-quality studies reported a mean accuracy of 0.63 [95% confidence interval (CI) 0.56-0.71], which was significantly lower than a mean accuracy of 0.75 (95% CI 0.72-0.78) in the other 46 studies. Among the adequate-quality studies, accuracies were higher when predicting treatment resistance (0.69) and lower when predicting remission (0.60) or response (0.56). The choice of machine learning method, feature selection, and the ratio of features to individuals were not associated with reported accuracy., Conclusions: The negative relationship between study quality and prediction accuracy, combined with a lack of independent replication, invites caution when evaluating the potential of machine learning applications for personalizing the treatment of depression.

Background: Network analysis (NA) conceptualizes psychiatric disorders as complex dynamic systems of mutually interacting symptoms. Major depressive disorder (MDD) is a heterogeneous clinical condition, and very few studies to date have assessed putative changes in its psychopathological network structure in response to antidepressant (AD) treatment., Methods: In this randomized trial with adult depressed outpatients (n = 151), we estimated Gaussian graphical models among nine core MDD symptom-domains before and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Networks were examined with the measures of cross-sectional and longitudinal structure and connectivity, centrality and predictability as well as stability and accuracy., Results: At baseline, the most connected MDD symptom-domains were fatigue-cognitive disturbance, whereas at week 8 they were depressed mood-suicidality. Overall, the most central MDD symptom-domains at baseline and week 8 were, respectively, fatigue and depressed mood; in contrast, the most peripheral symptom-domain across both timepoints was appetite/weight disturbance. Furthermore, the psychopathological network at week 8 was significantly more interconnected than at baseline, and they were also structurally dissimilar., Conclusion: Our findings highlight the utility of focusing on the dynamic interaction between depressive symptoms to better understand how the treatment with ADs unfolds over time. In addition, depressed mood, fatigue, and cognitive/psychomotor disturbance seem to be central MDD symptoms that may be viable targets for novel, focused therapeutic interventions.

Background: Youth who attempt suicide are more at risk for later mental disorders and suicide. However, little is known about their long-term socioeconomic outcomes., Aims: We investigated associations between youth suicide attempts and adult economic and social outcomes., Method: Participants were drawn from the Quebec Longitudinal Study of Kindergarten Children (n = 2140) and followed up from ages 6 to 37 years. Lifetime suicide attempt was assessed at 15 and 22 years. Economic (employment earnings, retirement savings, welfare support, bankruptcy) and social (romantic partnership, separation/divorce, number of children) outcomes were assessed through data linkage with government tax return records obtained from age 22 to 37 years (2002-2017). Generalised linear models were used to test the association between youth suicide attempt and outcomes adjusting for background characteristics, parental mental disorders and suicide, and youth concurrent mental disorders., Results: By age 22, 210 youths (9.8%) had attempted suicide. In fully adjusted models, youth who attempted suicide had lower annual earnings (average last 5 years, US$ -4134, 95% CI -7950 to -317), retirement savings (average last 5 years, US$ -1387, 95% CI -2982 to 209), greater risk of receiving welfare support (risk ratio (RR) = 2.05, 95% CI 1.39 to 3.04) and were less likely to be married/cohabiting (RR = 0.82, 95% CI 0.73 to 0.93), compared with those who did not attempt suicide. Over a 40-year working career, the loss of individual earnings attributable to suicide attempts was estimated at US$98 384., Conclusions: Youth who attempt suicide are at risk of poor adult socioeconomic outcomes. Findings underscore the importance of psychosocial interventions for young people who have attempted suicide to prevent long-term social and economic disadvantage.

Background: Low birth weight is associated with adult mental health, cognitive and socioeconomic problems. However, the causal nature of these associations remains difficult to establish owing to confounding., Aims: To estimate the contribution of birth weight to adult mental health, cognitive and socioeconomic outcomes using two-sample Mendelian randomisation, an instrumental variable approach strengthening causal inference., Method: We used 48 independent single-nucleotide polymorphisms as genetic instruments for birth weight (genome-wide association studies' total sample: n = 264 498) and considered mental health (attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), schizophrenia, suicide attempt), cognitive (intelligence) and socioeconomic (educational attainment, income, social deprivation) outcomes., Results: We found evidence for a contribution of birth weight to ADHD (OR for 1 s.d. unit decrease (~464 g) in birth weight, 1.29; 95% CI 1.03-1.62), PTSD (OR = 1.69; 95% CI 1.06-2.71) and suicide attempt (OR = 1.39; 95% CI 1.05-1.84), as well as for intelligence (β = -0.07; 95% CI -0.13 to -0.02) and socioeconomic outcomes, i.e. educational attainment (β = -0.05; 95% CI -0.09 to -0.01), income (β = -0.08; 95% CI -0.15 to -0.02) and social deprivation (β = 0.08; 95% CI 0.03-0.13). However, no evidence was found for a contribution of birth weight to the other examined mental health outcomes. Results were consistent across a wide range of sensitivity analyses., Conclusions: These findings support the hypothesis that birth weight could be an important element on the causal pathway to mental health, cognitive and socioeconomic outcomes.

Background: Suicide is a leading cause of mortality in youth, yet the course of suicide attempts is poorly documented. We explored the vulnerable transition from adolescence to emerging adulthood to identify group trajectories and risk factors., Methods: The National Longitudinal Survey of Children and Youth is a prospective representative cohort of Canadian children. We followed participants aged 7-11 years in 1994-95 to age 23 (2008-09). We modelled self-reported past-year suicide attempts (ages 12 to 23 years) using growth mixture models. We analysed risk factors from self- and parent-report questionnaires at pre-adolescence (ages 10-11) and early adolescence (ages 12-13) using multinomial logistic regressions. Analyses were adjusted for sample non-response and attrition., Results: In 2233 participants answering questions on teen and adult suicide attempts, we identified three trajectories: never attempted (96.0%), adolescence-limited (2.0%) and persisting into adulthood (2.0%). Adolescent girls aged 12-13 with depression/anxiety symptoms, and with mothers experiencing depression had higher risks of adolescence-limited than never-attempted [relative risk RR 9.27 (95% confidence interval: 1.73-49.82); 2.03 (1.02-3.32), for each standard deviation increase; 1.07 (1.00-1.15); respectively]. Preteen ADHD symptoms increased the risk of attempts persisting into adulthood as compared to never-attempted [RR 2.05 (1.29-3.28) for each standard deviation increase]. Suicide death of schoolmate/acquaintance increased risks of an adulthood trajectory as compared to never-attempted and adolescence-limited [RR 8.41 (3.04-23.27) and 6.63 (1.29-34.06), respectively]., Conclusion: In half the participants attempting suicide, attempts continued into adulthood. We stress the need for preventive strategies in early adolescence and differential clinical/educational interventions as identified for each trajectory.

Background: Poor cognitive abilities and low intellectual quotient (IQ) are associated with an increased risk of suicide attempts and suicide mortality. However, knowledge of how this association develops across the life-course is limited. Our study aims to establish whether individuals who died by suicide by mid-adulthood are distinguishable by their child-to-adolescence cognitive trajectories., Methods: Participants were from the 1958 British Birth Cohort and were assessed for academic performance at ages 7, 11, and 16 and intelligence at 11 years. Suicides occurring by September 2012 were identified from linked national death certificates. We compared mean mathematics and reading abilities and rate of change across 7-16 years for individuals who died by suicide v. those still alive, with and without adjustment for potential early-life confounding factors. Analyses were based on 14 505 participants., Results: Fifty-five participants (48 males) had died by suicide by age 54 years. While males who died by suicide did not differ from participants still alive in reading scores at age 7 [effect size (g) = -0.04, p = 0.759], their reading scores had a less steep improvement up to age 16 compared to other participants. Adjustments for early-life confounding factors explained these differences. A similar pattern was observed for mathematics scores. There was no difference between individuals who died by suicide v. participants still alive on intelligence at 11 years., Conclusions: While no differences in tests of academic performance and IQ were observed, individuals who died by suicide had a less steep improvement in reading abilities over time compared to same-age peers.

Background: Recently, artificial intelligence-powered devices have been put forward as potentially powerful tools for the improvement of mental healthcare. An important question is how these devices impact the physician-patient interaction., Aims: Aifred is an artificial intelligence-powered clinical decision support system (CDSS) for the treatment of major depression. Here, we explore the use of a simulation centre environment in evaluating the usability of Aifred, particularly its impact on the physician-patient interaction., Method: Twenty psychiatry and family medicine attending staff and residents were recruited to complete a 2.5-h study at a clinical interaction simulation centre with standardised patients. Each physician had the option of using the CDSS to inform their treatment choice in three 10-min clinical scenarios with standardised patients portraying mild, moderate and severe episodes of major depression. Feasibility and acceptability data were collected through self-report questionnaires, scenario observations, interviews and standardised patient feedback., Results: All 20 participants completed the study. Initial results indicate that the tool was acceptable to clinicians and feasible for use during clinical encounters. Clinicians indicated a willingness to use the tool in real clinical practice, a significant degree of trust in the system's predictions to assist with treatment selection, and reported that the tool helped increase patient understanding of and trust in treatment. The simulation environment allowed for the evaluation of the tool's impact on the physician-patient interaction., Conclusions: The simulation centre allowed for direct observations of clinician use and impact of the tool on the clinician-patient interaction before clinical studies. It may therefore offer a useful and important environment in the early testing of new technological tools. The present results will inform further tool development and clinician training materials.

Theory of mind, the ability to represent the mental states of others, is an important social cognitive process, which contributes to the development of social competence. Recent research suggests that interactions between gene and environmental factors, such as oxytocin receptor gene (OXTR) polymorphisms and maternal parenting behavior, may underlie individual differences in children's theory of mind. However, the potential influence of DNA methylation of OXTR remains unclear. The current study investigated the roles of OXTR methylation, maternal behavior, and their statistical interaction on toddlers' early emerging theory of mind abilities. Participants included a community sample of 189 dyads of mothers and their 2- to 3-year-old children, whose salivary DNA was analyzed. Results indicated that more maternal structuring behavior was associated with better performance, on a battery of three theory of mind tasks, while higher OXTR methylation within exon 3 was associated with poorer performance. A significant interaction also emerged, such that OXTR methylation was related to theory of mind among children whose mothers displayed less structuring, when controlling for children's age, sex, ethnicity, number of child-aged siblings, verbal ability, and maternal education. Maternal structuring behavior may buffer the potential negative impact of hypermethylation on OXTR gene expression and function.

Background: Heritability of antisocial behaviour is estimated at approximately 50% and involves multiple genes.AimsTo investigate the cumulative genetic effects of 116 single nucleotide polymorphisms mapping to 11 candidate serotonergic genes and antisocial behaviours, in adolescence and in early adulthood., Method: Participants were 410 male members of the Quebec Longitudinal Study of Kindergarten Children, a population-based cohort followed up prospectively from age 6 to age 23. The serotonergic genes were selected based on known physiological processes and prior associations with antisocial behaviours. Antisocial behaviours were self-reported and assessed by using semi-structured interviews in adolescence and in adulthood., Results: Cumulative, haplotype-based contributions of serotonergic genes conferring risk and protection for antisocial behaviours were detected by using multilocus genetic profile risk scores (MGPRSs) and multilocus genetic profile protection scores (MGPPSs). Cumulatively, haplotype-based MGPRSs and MGPPSs contributed to 9.6, 8.5 and 15.2% of the variance in general delinquency in adolescence, property/violent crimes in early adulthood and physical partner violence in early adulthood, respectively., Conclusions: This study extends previous research by showing a cumulative effect of multiple haplotypes conferring risk and protection to antisocial behaviours in adolescence and early adulthood. The findings further support the relevance of concomitantly considering multiple serotonergic polymorphisms to better understand the genetic aetiology of antisocial behaviours. Future studies should investigate the interplay between risk and protective haplotype-based multilocus genetic profile scores with the environment., Declaration of Interest: I.O.-M. holds a Canada Research Chair in the developmental origins of vulnerability and resilience.

Background: Cognitive inhibition deficits have previously been found in suicide attempters. This study examined the neural basis for these deficits in depressed patients with and without a history of suicidal behavior., Method: Functional magnetic resonance imaging was used to measure brain activation during the Go/No-Go response inhibition task in 25 unmedicated and depressed middle-aged suicide attempters, 22 unmedicated depressed patient controls with no personal or family history of suicidal behavior, and 27 healthy controls. Whole-brain analyses were conducted with SPM12., Results: Suicide attempters exhibited an elevated number of commission errors relative to both control groups. However, suicide attempters did not differ from patient controls in terms of brain activation for any contrast. Analyses showed a significant association between depression and brain activation in the left inferior frontal gyrus and medial thalamus during Go v. No-Go, and in the bilateral parietal cortex and left orbitofrontal cortex during No-Go v. baseline. These regions were correlated with psychological pain, suicidal ideation and global functioning. There was no association between brain activation and personal histories of suicidal act., Conclusions: Our study suggests that deficits in cognitive inhibition, in relation to the inferior frontal gyrus, thalamus, orbitofrontal cortex and parietal cortex, are related to the depressive state and not specifically to suicide vulnerability. We hypothesize that state-related deficits may add to trait-like cognitive impairments to facilitate suicidal acts. These different types of cognitive impairments may necessitate different therapeutic strategies for the prevention of suicide.

Background: The monoamine oxidase A (MAOA) gene has been shown to moderate the impact of maltreatment on antisocial behaviour. Replication efforts have, however, yielded inconsistent results., Aims: To investigate whether the interaction between the MAOA gene and violence is present across the full distribution of violence or emerges at higher levels of exposure., Method: Participants were 327 male members of the Québec Longitudinal Study of Kindergarten Children. Exposure to violence comprised retrospective reports of mother's and father's maltreatment, sexual and physical abuse. Conduct disorder and antisocial personality symptoms were assessed in semi-structured interviews and partner violence, property-violent crimes and arrest were self-reported., Results: Non-linear interactions between the MAOA gene and violence were detected, suggesting that the genetic moderation may come about once a certain level of violence is experienced., Conclusions: Future studies should investigate the mechanisms translating substantial violence exposure, which could, subsequently, trigger the expression of genetically based differences in antisocial behaviour., (© The Royal College of Psychiatrists 2016.)

Background: Most developmental studies on suicide do not take into account individual variations in suicide trajectories., Aims: Using a life course approach, this study explores developmental models of suicide trajectories., Method: Two hundred and fourteen suicides were assessed with mixed methods. Statistical analysis using combined discrete-time survival (DTS) and growth mixture modelling (GMM) generated various trajectories, and path analysis (Mplus) identified exogenous and mediating variables associated with these trajectories., Results: Two groups share common risk factors, and independently of these major risk factors, they have different developmental trajectories: the first group experienced a high burden of adversity and died by suicide in their early 20s; and the second group experienced a somewhat moderate or low burden of adversity before they took their own life. Structural equation modelling identified variables specific to the early suicide trajectory: conduct and behavioural difficulties, social isolation/conflicts mediated by school-related difficulties, the end of a love relationship, and previous suicide attempts., Conclusions: Psychosocial adversity between 10 and 20 years of age may warrant key periods of intervention., (Royal College of Psychiatrists.)

Background: Although childhood abuse is an important correlate of suicidality, not all individuals who were abused as children attempt suicide., Aims: To identify correlates and moderators of suicide attempts in adults reporting childhood physical abuse, contact sexual abuse, or both., Method: A French-Canadian, school-based cohort (n=1684) was prospectively followed., Results: The identity of the abuser moderated the relationship of abuse frequency and suicide attempts, with individuals abused by their immediate family being at highest risk. Although paternal education exhibited negative associations (OR=0.71, 95% CI 0.58-0.88), several externalising phenotypes had positive associations with suicide attempts: disruptive disorders (OR=3.10, 95% CI 1.05-9.15), conduct problems (OR=1.09, 95% CI 1.01-1.19) and childhood aggression (OR=1.41, 95% CI 1.08-1.83)., Conclusions: Characteristics of the abuser and abusive acts may be important additional indicators of risk for suicide attempts. Future research needs to employ developmental approaches to examine the extent and mechanisms by which childhood abuse contributes to the shared variance of suicidality, maladaptive traits and psychopathology.

Background: Psychiatric co-morbidity is thought to be an important problem in suicide, but it has been little investigated. This study aims to investigate patterns of co-morbidity in a group of male suicide completers., Method: One hundred and fifteen male suicide completers from the Greater Montreal Area and 82 matched community controls were assessed using proxy-based diagnostic interviews. Patterns of co-morbidity were investigated using latent class analysis., Results: Three subgroups of male suicide completers were identified (L2 = 171.62, df = 2012, P < 0.05). they differed significantly in the amount of co-morbidity (Kruskal-Wallis chi2 = 71.227, df = 2. P < 0.000) and exhibited different diagnostic profiles. Co-morbidity was particularly found in subjects with disorders characterized by impulsive and impulsive-aggressive traits, whereas subjects without those traits had levels of co-morbidity which were not significantly different from those of controls (chi2 = 8.17, df = 4, P = 0.086)., Conclusions: Suicide completers can be divided into at least three subgroups according to co-morbidity: a low co-morbidity group, a substance-dependent group and a group exhibiting childhood onset of psychopathology.