Effects of Antipsychotic Drugs on Neuroactive Steroids Brain and Plasma Levels in Humans and Animals: A Systematic Review of the Literature

Objectives: The present study aims to review systematically the studies that investigated the effects of antipsychotic drugs on neuroactive steroids brain and plasma levels in animal and human studies

Methods: We conducted a review of the Medline databases, including articles published in English, Spanish and French, describing the results of controlled original animal and human studies that evaluated the effects of antipsychotics on brain and plasma neuroactive steroids levels.

Results: It was identified 291 studies through our search strategy. Of these studies, we selected 20, with one more study included after further searching throughout the reference list. Of these 21 studies, eight studies evaluated neuroactive steroids levels in humans, and 13 were animal studies. The antipsychotic used in the studies were: haloperidol, sulpiride, clozapine, olanzapine, risperidone, quetiapine and aripiprazol. Among the neuroactive steroids evaluated, we found studies evaluating levels of progesterone, allopregnanolone, DHEA, DHEA-S, TDHOC, pregnenolone and 3a,5a-THP. The human studies demonstrated diverse and non-conclusive alterations on the plasma levels of progesterone, no changes on allopregnanolone and TDHOC levels after clozapine use. Among the animal studies, nine of these evaluated progesterone levels, with no changes in three studies, and increased plasma levels in six studies. The same researchers in two studies investigated pregnenolone brain levels in rats, showing that clozapine and olanzapine acutely increased the levels of pregnenolone in rats. Four studies evaluating allopregnanolone showed increased brain levels after the use of olanzapine and clozapine. No changes with haloperidol or risperidone. The only animal study that investigated DHEA/DHEA-S levels, showed that clozapine decreased brain levels of DHEA-S, unlike haloperidol. Increased TDHOC levels after use of clozapine were observed in the only study that measured this neuroactive steroid. Two studies from the same group showed increased brain levels of 3a,5a-THP after olanzapine use.

Conclusion: The antipsychotic effects observed on neuroactive steroids levels reinforce their potential role in the pathophysiology of mental disorders, particularly schizophrenia. In the case of progesterone, the studies are in sufficient number to demonstrate the effect of antipsychotic on changes in their levels in animal but human studies. For the other neuroactive steroids, the inconclusive data points to the need for more well designed studies.