Neurosteroids: mechanistic considerations and clinical prospects

Abstract

AbstractLike other classes of treatments described in this issue’s section, neuroactive steroids have been studied for decades but have risen as a new class of rapid-acting, durable antidepressants with a distinct mechanism of action from previous antidepressant treatments and from other compounds covered in this issue. Neuroactive steroids are natural derivatives of progesterone but are proving effective as exogenous treatments. The best understood mechanism is that of positive allosteric modulation of GABAA receptors, where subunit selectivity may promote their profile of action. Mechanistically, there is some reason to think that neuroactive steroids may separate themselves from liabilities of other GABA modulators, although research is ongoing. It is also possible that intracellular targets, including inflammatory pathways, may be relevant to beneficial actions. Strengths and opportunities for further development include exploiting non-GABAergic targets, structural analogs, enzymatic production of natural steroids, precursor loading, and novel formulations. The molecular mechanisms of behavioral effects are not fully understood, but study of brain network states involved in emotional processing demonstrate a robust influence on affective states not evident with at least some other GABAergic drugs including benzodiazepines. Ongoing studies with neuroactive steroids will further elucidate the brain and behavioral effects of these compounds as well as likely underpinnings of disease.