Simon N. Young

Depression related to interferon-alpha (IFN-α) is common, may reduce adherence, and can be treatment limiting. HIV-HCV coinfected persons experience lower sustained virologic response rates and commonly have psychiatric comorbidities, thus they may benefit from prevention of depression. The aim of the study was to determine whether prophylactic citalopram can increase HCV treatment adherence and reduce the incidence of moderate depression in HIV-HCV coinfected patients initiating PEG-IFN-α/ribavirin therapy. This was an investigator-initiated Canadian multicenter randomized, double-blind placebo-controlled trial. HIV-HCV coinfected patients were randomized in a 1:1 ratio to receive citalopram or placebo 3 weeks prior to starting PEG-IFN-α2b/ribavirin, stratified by study center and HCV genotype. The protocol design permitted the comparison of prophylaxis with the treatment of emergent depression. The primary outcomes were adherence (assessed through questionnaire and returned medication) and time to moderate depression measured by Beck Depression Inventory-II (BDI- II) score greater than 15, confirmed 2 weeks apart. Seventy-six patients (36 citalopram/40 placebo) were randomized. Overall adherence was high, ranging from 95% (week 12) to 91% (week 48). There was no difference between arms with respect to mean or median adherence at any study time point. Cumulative incidence of moderate depression did not differ significantly by group (log rank P = .32). The hazard ratio for moderate depression was 0.81 (95% CI, 0.26 to 2.54) for citalopram compared with placebo when adjusted for baseline BDI-II score. A strategy of prophylactic citalopram compared to treatment of emergent depression was not associated with higher adherence or a reduction in treatment-limiting depression nor did it significantly reduce depressive symptoms among HIV-HCV coinfected persons during treatment for HCV.

3,4‐Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long‐term neurotoxic effects. In this study, positron emission tomography with the tracer alpha‐[¹¹C]methyl‐l‐tryptophan (¹¹C‐AMT) was used to compare human brain serotonin (5‐HT) synthesis capacity in 17 currently drug‐free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional ¹¹C‐AMT trapping and characteristics of MDMA use were also examined. MDMA polydrug users exhibited lower normalized ¹¹C‐AMT trapping in pre‐frontal, orbitofrontal, and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized ¹¹C‐AMT trapping in MDMA users was also observed, mainly in the brainstem and in frontal and temporal areas. Normalized ¹¹C‐AMT trapping in the brainstem and pre‐frontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use. Although the possibility of pre‐existing 5‐HT alterations pre‐disposing people to use MDMA cannot be ruled out, regionally decreased 5‐HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5‐HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms. image Animal studies showed that MDMA (3,4‐methylenedioxymethamphetamine, ecstasy) exposure alters brain serotonin neurotransmission. Whether these effects are permanent is unknown. The present human study found that, compared to controls, young adult MDMA users had lower serotonin synthesis in parts of the frontal cortex, and greater serotonin synthesis in other regions, including the brainstem. The strength of these effects correlated with severity of use. The findings may indicate that MDMA can be neurotoxic but the brain may also have the capacity to regenerate, depending on the specific brain region. Longitudinal studies are needed to test the clinical relevance of these findings.

Associations between impulsivity and interpersonal behaviours have rarely been examined, even though impulsivity may disrupt the flow of social interactions. For example, it is unknown to what extent the commonly used B arratt I mpulsiveness S cale ( BIS ‐11) predicts impulsive behaviour in social situations, and how behaving impulsively during interpersonal encounters might influence levels of quarrelsomeness and agreeableness. In this study, 48 healthy working individuals completed the BIS ‐11 and recorded their behaviour in social situations using event‐contingent recording. Record forms included items representing quarrelsome, agreeable, and impulsive behaviours. BIS ‐11 motor impulsiveness scores predicted impulsive behaviour in social situations. Impulsive behaviour was associated, in different interactions, with both agreeableness and quarrelsomeness. Behaving impulsively in specific interactions was negatively associated with agreeableness in participants with higher BIS ‐11 motor impulsiveness and positively associated with agreeableness in participants with lower BIS ‐11 motor impulsiveness. Impulsive quarrelsome behaviour may cause interpersonal problems. Impulsive agreeable behaviour may have positive effects in individuals with low trait impulsivity. The idea that there are between‐person differences in the effects of state impulsivity on the flow of social interaction deserves further study.

Increasing serotonin decreases quarrelsome behaviours and enhances agreeable behaviours in humans. Antidepressants, even those whose primary action is not on serotonin, seem to increase serotonin function. We suggest that antidepressants act in part by effects on social behaviour, which leads to a gradual improvement in mood. We review the evidence supporting the idea that anti-depressants may be moving behaviour from quarrelsome to agreeable. The more positive social responses of interaction partners would initiate a cycle of more positive social behaviour, and this iterative process would result in a clinically significant improvement in mood.

Recent research indicates that suicide rates are elevated in those living at higher altitudes in both the United States and South Korea. A possible mechanism that was proposed is metabolic stress associated with hypoxia. This commentary discusses these results, and also the association between elevated suicide rates and other conditions associated with hypoxia (smoking, chronic obstructive pulmonary disease and asthma). Tryptophan hydroxylase may not normally be saturated with oxygen, so mild hypoxia would decrease serotonin synthesis. Low brain serotonin is known to be associated with suicide. Thus, the commentary proposes and discusses the hypothesis that decreased brain serotonin synthesis associated with hypoxia is a mechanism that may contribute to suicide in conditions causing hypoxia. Finally the commentary proposes various studies that could test aspects of this hypothesis.