Background 5-HT1A autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating 5-HT signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C(-1019)G) in the human 5-HT1A gene (HTR1A) represents one potential source of such inter-individual variability. Both in vitro and in vivo the -1019G blocks transcriptional repression leading to increased autoreceptor expression. Thus, the -1019G may contribute to relatively decreased 5-HT signaling at postsynaptic forebrain target sites via increased negative feedback. Objectives & Design To use imaging genetics to evaluate the effects of HTR1A C(-1019)G on amygdala reactivity in 89 healthy adults and employ path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that the -1019G, which potentially results in decreased 5-HT signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety. Results Consistent with prior findings, the -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism impacting 5-HT signaling, namely the 5-HTTLPR. While there were no direct genotype effects on trait anxiety, the HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity. Conclusions Our findings further implicate relatively increased 5-HT signaling, associated with genetic variation mediating increased 5-HT1A autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation impacts emergent behavioral processes related to psychiatric disease risk indirectly by biasing the response of underlying neural circuitries.

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The cortico-limbic system is critically involved in emotional responses and resulting adaptive behaviors. Within this circuit, complementary regions are believed to be involved in either the appraisal or the regulation of affective state. However, the respective contribution of these bottom-up and top-down mechanisms during emotion processing remains to be clarified. We used a new functional magnetic resonance imaging (fMRI) paradigm varying 3 parameters: emotional valence, emotional congruency, and allocation of attention, to distinguish the functional variation in activity and connectivity between amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Bottom-up appraisal of negative compared with positive stimuli led to a greater amygdala response and stronger functional interaction between amygdala and both dorsal ACC and DLPFC. Top-down resolution of emotional conflict was associated with increased activity within ACC and higher functional connectivity between this structure, and both the amygdala and DLPFC. Finally, increased top-down attentional control caused greater engagement of the DLPFC, accompanied by increased connectivity between DLPFC and dorsal ACC. This novel task provides an efficient tool for exploring bottom-up and top-down processes underlying emotion and may be particularly helpful for investigating the neurofunctional underpinnings of psychiatric disorders.

Studies conducted so far suggest that clozapine is the treatment of choice for schizophrenic patients who are refractory to treatment, display violent behaviors, or who are at high risk of suicide. However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe. Experience with clozapine should therefore be included in the education of future physicians.

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Adjustment Disorders With Anxiety (ADWA) account for almost 10% of psychologically motivated consultations in primary care. The aim of this double-blind randomised parallel group study was to compare (non-inferiority test) the efficacies of etifoxine, a non-benzodiazepine anxiolytic drug, and lorazepam, a benzodiazepine, for ADWA outpatients followed by general practitioners. 191 outpatients (mean age: 43, female: 66%) were assigned to receive etifoxine (50 mg tid) or lorazepam (0.5-0.5-1 mg /day) for 28 days. Efficacy was evaluated on days 7 and 28 of the treatment. The main efficacy assessment criterion was the Hamilton Rating Scale for Anxiety score (HAM-A) on Day 28 adjusted to Day 0. The anxiolytic effect of etifoxine was found not inferior to that of lorazepam (HAM-A score decrease: 54.6% vs 52.3%, respectively, p=0.0006). The two drugs were equivalent on Day 28. However, more etifoxine recipients responded to the treatment (HAM-A score decreased by >or=50%, p=0.03). Clinical improvement (based on Clinical Global Impression scale CGI, Social Adjustment Scale Self-Report SAS-SR, and Sheehan scores) was observed in both treatment arms, but more etifoxine patients improved markedly (p=0.03) and had a marked therapeutic effect without side effects as assessed by CGI, p=0.04. Moreover, 1 week after stopping treatment, fewer patients taking etifoxine experienced a rebound of anxiety, compared to lorazepam (1 and 8, respectively, p=0.034).

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