clozapine and tetrahydrodeoxycorticosterone

Clozapine has been shown to acutely increase the rat brain and plasma concentrations of the neuroactive steroids 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-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 3alpha,5alpha-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 3alpha,5alpha-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 3alpha,5alpha-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 3alpha,5alpha-THP and THDOC.

Topics: Adult; Analysis of Variance; Circadian Rhythm; Clozapine; Desoxycorticosterone; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pregnanolone; Prospective Studies; Schizophrenia

The extrapyramidal side effects of typical antipsychotics, which are induced to a markedly reduced extent by clozapine, have been linked to a dysfunction of central gamma-aminobutyric acid (GABA)-mediated neurotransmission. The effects of clozapine on the brain concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, AP) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC), two potent and endogenous positive allosteric modulators of GABA-mediated chloride current intensities at GABA(A) receptors, were compared with those of the typical antipsychotic haloperidol. A single administration of clozapine (1.25-20 mg/kg, IP), but not of haloperidol (0.1 or 0.5 mg/kg, IP), induced dose- and time-dependent increases in the concentrations of progesterone, AP, and THDOC in the cerebral cortex and striatum of rats. Clozapine (at 10 mg/kg, but not at lower doses) also increased the concentrations of these steroids as well as that of corticosterone in plasma in intact rats, but failed to increase the cortical concentrations of AP and THDOC in adrenalectomized-orchidectomized rats. An acute challenge with clozapine (10 mg/kg), administered 48 h after the termination of daily treatment with the same dose for 19 days, still increased the cortical concentrations of progesterone, AP, and THDOC. These results suggest that the clozapine-induced increases in neuroactive steroid concentrations in the brain may contribute to the atypical pharmacological profile of this antipsychotic drug.

Topics: Adrenalectomy; Animals; Antipsychotic Agents; Brain Chemistry; Clozapine; Desoxycorticosterone; Haloperidol; Male; Neurotransmitter Agents; Orchiectomy; Progesterone; Rats; Rats, Sprague-Dawley; Steroids