Steroid 5 alpha-Reductase as a Novel Therapeutic Target for Schizophrenia and Other Neuropsychiatric Disorders

The enzyme steroid 5 alpha-reductase (S5 alpha R) catalyzes the conversion of Delta(4)-3-ketosteroid precursors-such as testosterone, progesterone and androstenedione-into their 5 alpha-reduced metabolites. Although the current nomenclature assigns five enzymes to the S5 alpha R family, only the types 1 and 2 appear to play an important role in steroidogenesis, mediating an overlapping set of reactions, albeit with distinct chemical characteristics and anatomical distribution. The discovery that the 5 alpha-reduced metabolite of testosterone, 5 alpha-dihydrotestosterone (DHT), is the most potent androgen and stimulates prostatic growth led to the development of S5 alpha R inhibitors with high efficacy and tolerability. Two of these agents, finasteride and dutasteride, have received official approval for the treatment of benign prostatic hyperplasia and are being tested for prevention of prostate cancer. Finasteride is also approved for male-pattern alopecia and has been shown to induce very limited side effects. Over the last decade, converging lines of evidence have highlighted the role of 5 alpha-reduced steroids and their precursors in brain neurotransmission and behavioral regulation. Capitalizing on these premises, we and other groups have recently investigated the role of S5 alpha R in neuropsychiatric disorders. Our preliminary data suggest that S5 alpha R inhibitors may elicit therapeutic effects in a number of disorders associated with dopaminergic hyperreactivity, including psychotic disorders, Tourette syndrome and impulse control disorders. In the present article, we review emerging preclinical and clinical evidence related to these effects, and discuss some of the potential mechanisms underlying the role of S5 alpha R in the pathophysiology of mental disorders.