Neuroactive steroids or neurosteroids are a new class of medications which appear to have anxiolytic and antidepressant effects and have received a great deal of attention over the past few years. Most of the neuroactive steroids currently under investigation as antidepressants are derivatives of allopregnanolone. In the human body, allopregnanolone is produced when the hormone progesterone is metabolized.
The first neurosteroid to generate a great deal of excitement was brexanolone which was approved by the FDA for the treatment of postpartum depression. Zuranolone, which is similar to brexanolone but can be administered orally, appears also to be effective for the treatment of postpartum depression. While most studies have focused on the use of allopregnanolone derivatives to treat reproductive hormone mediated mood disorders in women, neurosteroids may have a broader range of efficacy. For example, other studies have suggested that zuranolone may be effective for the treatment of (non-postpartum) depression in both men and women.
It is hypothesized that derivatives of allopregnanolone ameliorate anxiety and depressive symptoms by modulating GABAergic signaling and in turn the hypothalamic-pituitary-adrenal or HPA axis which mediates the body’s response to stress. It is hypothesized that targeting GABA-A receptor signaling using neuroactive steroids may be a novel approach to treating depressive disorders; however, further investigation is required to evaluate the utility of these neurosteroids beyond the treatment of postpartum depression.
Given the efficacy of these neurosteroid agents for the treatment of postpartum depression, many have speculated that derivatives of allopregnanolone may be effective for the treatment of other reproductive hormone-associated mood disorders, including premenstrual dysphoric disorder (PMDD) and menopausal depression.
In a new study, Dr. Marlene Freeman and colleagues at the Center for Women’s Mental Health is currently investigating the effectiveness of pregnenolone, another neurosteroid which is a derivative of progesterone, for the treatment of depression during the menopausal transition.
Pregnenolone is produced in the body and is involved in the synthesis and metabolism of other steroid hormones, including progestogens and estrogens. Pregnenolone is biologically active and modulates various neurotransmitter systems, including the endocannabinoid system. Its metabolite pregnenolone sulfate is similar to brexanolone and acts as a negative allosteric modulator of the GABA-A receptor and is also a positive allosteric modulator of the NMDA receptor.
Both preclinical and human data suggest that pregnenolone may be a promising treatment for depression. Dr. Freeman’s study will test the effectiveness of pregnenolone in women with menopausal depression. You can learn more about the study HERE.
