Long-term treatment with clozapine does not affect morning circulating levels of allopregnanolone and THDOC in patients with schizophrenia: a preliminary study.

Clozapine has been shown to acutely increase the rat brain and plasma concentrations of the neuroactive steroids 3a,5atetrahydroprogesterone (3a,5a-THP) or allopregnanolone and THDOC, 2 positive allosteric modulators of GABA-A receptors. Hence, it has been suggested that this effect could underlie the therapeutic efficacy of this drug, contributing to its atypical profile. So far, no study assessed whether the effects on neurosteroids reported in the experimental animal occur also in humans. Therefore, we measured plasma levels of 3a,5a-THP and THDOC in a sample of drug-resistant schizophrenic patients before and after 1, 2, 4, 6, 8, 12, and 24 weeks of clozapine administration (600 mg/d by the end of the 6th week). No significant changes in circulating concentrations of 3a,5a-THP and THDOC were observed in the course of clozapine administration in spite of the patients' good clinical response to the drug. These findings provide evidence, for the first time, that clozapine is not able to affect morning circulating levels of 3a,5a-THP and THDOC in humans. Therefore, although we cannot exclude that changes in neuroactive steroids could occur immediately after the daily administration of clozapine as in the experimental animal, our data support the view that the therapeutic efficacy of this atypical antipsychotic is not linked to changes in the baseline concentrations of peripheral 3a,5a-THP and THDOC.