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Background: Suicidal behaviour aggregates in families, and the hypothalamic-pituitary-adrenal (HPA) axis and noradrenergic dysregulation may play a role in suicide risk. It is unclear whether stress dysregulation is a heritable trait of suicide or how it might increase risk. We investigated stress reactivity of the autonomic nervous system and the HPA axis in suicide predisposition and characterized the effect of this dysregulation on neuropsychologic function., Methods: In this family-based study of first-degree relatives (n = 14) of suicide completers and matched controls with no family or personal history of suicidal behaviour (n = 14), participants underwent the Trier Social Stress Test (TSST). We used salivary α-amylase and cortisol levels to characterize stress reactivity and diurnal variation. We administered a series of neuropsychologic and executive function tests before and after the TSST., Results: Despite normal diurnal variation, relatives of suicide completers exhibited blunted cortisol and α-amylase TSST reactivity. Although there were no baseline differences in conceptual reasoning, sustained attention or executive function, the relatives of suicide completers did not improve on measures of inhibition upon repeated testing after TSST. Secondary analyses suggested that these effects were related to suicide vulnerability independent of major depression., Limitations: The sample size was small, and the design prevents us from disentangling our findings from the possible traumatic consequences of losing a relative by suicide., Conclusions: Blunted stress response may be a trait of suicide risk, and impairment of stress-induced executive function may contribute to suicide vulnerability.

Objective: There is substantial evidence suggesting that suicide aggregates in families. However, the extent of overlap between the liability to suicide and psychiatric disorders, particularly major depressive disorder, remains an important issue. Similarly, factors that account for the familial transmission of suicidal behavior remain unclear. Thus, through direct and blind assessment of first-degree relatives, the authors conducted a family study of suicide by examining three proband groups: probands who committed suicide in the context of major depressive disorder, living depressed probands with no history of suicidal behavior, and psychiatrically normal community comparison probands., Method: Participants were 718 first-degree relatives from 120 families: 296 relatives of 51 depressed probands who committed suicide, 185 relatives of 34 nonsuicidal depressed probands, and 237 relatives of 35 community comparison subjects. Psychopathology, suicidal behavior, and behavioral measures were assessed via interviews., Results: The relatives of probands who committed suicide had higher levels of suicidal behavior (10.8%) than the relatives of nonsuicidal depressed probands (6.5%) and community comparison probands (3.4%). Testing cluster B traits as intermediate phenotypes of suicide showed that the relatives of depressed probands who committed suicide had elevated levels of cluster B traits; familial predisposition to suicide was associated with increased levels of cluster B traits; cluster B traits demonstrated familial aggregation and were associated with suicide attempts among relatives; and cluster B traits mediated, at least in part, the relationship between familial predisposition and suicide attempts among relatives. Analyses were repeated for severity of attempts, where cluster B traits also met criteria for endophenotypes of suicide., Conclusions: Familial transmission of suicide and major depression, while partially overlapping, are distinct. Cluster B traits and impulsive-aggressive behavior represent intermediate phenotypes of suicide.

Several lines of evidence suggest that suicide may have, in part, a genetic predisposition. In this study, we identified a family with high rates of suicidal behavior and assessed brain gene expression levels in the proband. A neuronally-expressed solute carrier for glutamine (Sodium-coupled neutral amino acid transporter 1 (SNAT1), also known as solute carrier family 38, member 1 (SLC38A1)) was identified as severely decreased across all brain regions. Follow-up analysis by semi-quantitative polymerase chain reaction (qPCR) and Western blot confirmed the reduction of SNAT1. We categorized the SNAT1 gene in human brain, cloned the gene promoter and assessed in silico the expression pattern of SNAT1 in >25 tissues from human. Complete DNA sequencing of the SNAT1 gene was performed in the family and 276 controls. The family was homozygous for rare alleles which suggests a possible association between low expression of SNAT1 and suicidal behavior.