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.

Na(+)/H(+) exchanger in the regulation of platelet activation and paradoxical effects of cariporide.

Platelets are anucleated cell fragments derived from mature megakaryocytes and function in hemostasis when the endothelium is injured. Hemostasis involving platelets can be divided into four phases: adhesion, activation, secretion, and aggregation. Platelet activation requires a rise in intracellular Ca(2+) concentrations and results in both a morphological change and the secretion of platelet granule contents. Na(+)/H(+) exchanger isoform 1 (NHE1) regulates the intracellular pH (pHi) and the volume of platelets. In addition, NHE1 plays a large role in platelet activation. Thrombus generation involves NHE1 activation and an increase in [Ca(2+)]i, which results from NHE1-mediated Na(+) overload and the reversal of the Na(+)/Ca(2+) exchanger. Cariporide (HOE-642), a potent NHE1 inhibitor, has inhibitory effects on the degranulation of human platelets, the formation of platelet-leukocyte-aggregates, and the activation of the GPIIb/IIIa receptor (PAC-1). However, despite the demonstrated protection against myocardial infarction as mediated by cariporide in patients undergoing coronary artery bypass graft surgery, the EXPEDITION clinical trial revealed that cariporide treatment increased mortality due to thromboembolic stroke. These findings suggest that a better understanding of NHE1 and its effect on platelet function and procoagulant factor regulation is warranted in order to develop therapies using NHE inhibitors.