The role of substance use, smoking, and inflammation in risk for suicidal behavior.

BACKGROUND: Alcohol and substance use disorders are important predictors for suicidal behavior. However, the role of individual substances as proximal risk factors for suicidal behavior and the mechanisms through which substance use affect risk are not entirely clear. We examine whether the frequency of substance use and whether biological markers in the HPA axis and inflammatory pathways are associated with clinical risk factors of suicidal behavior of aggression, impulsivity, hopelessness, and poor sleep. METHODS: The sample consisted of psychiatric inpatients, aged 15-30 years, admitted for suicide attempt (n = 38), suicidal ideation (n = 40); and healthy controls (n = 37). We measured hair cortisol concentrations, glucocorticoid receptor (GR) sensitivity, stimulated production of interleukin- or IL-6, C-reactive protein, and mRNA expression of GR, SKA2, FKBP5, TNF-α, and IL-1ß. RESULTS: Smoking was associated with increased aggression [ß = 2.9, 95% CI (-0.03, 6), p = 0.05], impulsivity [ß = 3.1, 95% CI (1.6, 4.6), p < 0.001], and poor sleep [ß = 0.5, 95% CI (0.03, 0.95), p = 0.04] even after controlling for demographics and group. Similarly, TNF-α mRNA was associated with impulsivity [ß = 0.07, 95% CI (0.01, 0.1), p = 0.02] and hopelessness [ß = 0.03, 95% CI (0.004, 0.05), p = 0.03]. Smoking tobacco (r = 0.32, p < 0.001) was positively associated with TNF-α mRNA. LIMITATIONS: Study limitations include the cross-sectional design, retrospective assessment, and relatively small sample size. CONCLUSIONS: Future longitudinal studies are needed to test whether inflammatory markers mediate the relationships between smoking, clinical risk factors, and suicidal behavior; and to examine whether smoking cessation could reduce the risk for suicidal behavior in at-risk patients.

Blunted HPA axis activity prior to suicide attempt and increased inflammation in attempters.

BACKGROUND: Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation is associated with increased risk for suicidal behavior. However, it is not clear whether such dysregulation exists prior to or is a consequence of attempt. Studies also show an activation of inflammatory responses in suicidal behavior but often combine attempters with those with ideation. METHODS: The sample consisted of psychiatric inpatients, aged 15-30 years, admitted for suicide attempt (SA, n=38), inpatients admitted for suicidal ideation with no prior history of attempts (SI, n=40), and healthy controls (n=37). We compared SA, SI, and controls on hair cortisol concentrations (HCC), which provides retrospective levels of cortisol and thus prior to the attempt in SA. We also compared them on the expression of genes in the HPA axis and inflammatory pathways previously implicated in suicidal behavior (GR or NR3C1, SKA2, FKBP5, IL-1ß, TNF-α); plasma C-Reactive Protein (CRP); and cellular measures of glucocorticoid receptor (GR) sensitivity and stimulated production of IL-6. RESULTS: We found lower HCC [ß=-0.55, 95% CI (-0.96, -0.13), p=0.01, ES=-0.54] in first-time SA compared to SI and controls. In addition, SA showed lower GR or NR3C1 (α isoform) mRNA [ß=-5.11, 95% CI (-10.9, 0.73), p=0.09, ES=-0.46], higher CRP [ß=0.94, 95% CI (-0.004, 1.9), p=0.05, ES=0.60], and higher TNF-α mRNA [ß=26.4, 95% CI (7.7, 45.2), p=0.006, ES=0.73]. CONCLUSIONS: This is the first study to differentiate youth who attempt suicide from those with suicidal ideation on HCC and to show that low HCC precedes suicide attempt. Suicide attempters also showed a distinct biological profile on several markers in both the HPA axis and inflammatory pathways. Future longitudinal studies are needed to examine the ability of these biomarkers to predict suicidal behavior.