Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia.

The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoid-related genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development.

Trait emotion regulation strategies and diurnal cortisol profiles in healthy adults.

OBJECTIVE: Experimental studies have shown that 2 emotion regulation strategies-suppression and reappraisal-are associated with differential profiles of physiological activation in response to a stress test. The present study aims to add to those findings by investigating whether individual differences in trait emotion regulation strategies are associated with diurnal cortisol patterns in a naturalistic context. METHOD: A sample of 46 men and women from the Midlife in the United States II (MIDUS II) study completed the Emotion Regulation Questionnaire (ERQ) and provided 4 salivary cortisol samples per day over 4 consecutive days. Trait reappraisal and suppression were tested as predictors of 3 cortisol parameters averaged across days: cortisol awakening response (CAR), diurnal cortisol slope (DCS), and area under the curve with respect to ground (AUCg). RESULTS: Higher scores on the suppression scale were associated with more physiological activation, as indicated by steeper CAR and flatter DCS. Suppression was not associated with AUCg, and reappraisal was not predictive of any cortisol parameter. CONCLUSIONS: Individual differences in suppression, but not reappraisal, were linked to greater cortisol activation in this naturalistic study. These preliminary results add to a growing body of findings that link suppression to adverse psychological and physiological profiles. (PsycINFO Database Record