The transition to menopause, or perimenopause, represents the passage from reproductive to non-reproductive life. During the perimenopause, women experience irregular menstrual cycles, which reflect the large fluctuations in ovarian hormone secretion during this time. In addition, women may experience vasomotor symptoms, altered sleep patterns, changes in cognition, and depression. While hormone replacement therapy (HRT) has been used to manage physical symptoms associated with the menopausal depression, much less attention has been focused on the treatment of menopausal depression. Concerns regarding the long-term use of HRT have limited its use, and women experiencing depression in this setting typically use traditional antidepressants, most commonly serotonergic reuptake inhibitors. While these antidepressants do work for many women, there is a clear need to develop other interventions for women who cannot take or do not respond to serotonergic antidepressants.
Over the last few years we have heard a great deal about neurosteroids, also known as neuroactive steroids. This class of compounds are steroid hormones produced in the brain and endocrine tissues which can modulate neurotransmission. Animal studies have demonstrated that neurosteroids have a broad range of activities, including antidepressant, anxiolytic, sedative, analgesic, anticonvulsant, neuroprotective, and neuroproliferative effects.
While we have known about the neuroactive effects of steroids since the 1940s, it has been difficult to replicate the beneficial effects of naturally produced neurosteroids with similar compounds synthesized in the laboratory. There has recently been some progress, and several different neurosteroids have been tested as anticonvulsants and anesthetic agents; however, we have seen the most robust clinical findings with several different derivatives of allopregnanolone used as antidepressants. One of these allopregnanolone analogues, brexanolone, was approved by the FDA for the treatment of severe postpartum depression and is now being marketed as Zulresso (Sage Therapeutics). Another allopregnanolone derivative, zuranolone, has also been shown to be effective for 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. Allopregnanolone is produced by the human body as a byproduct of progesterone. While most previous research has focused on the mood-modulating effects of estrogen and have speculated that falling levels of estrogen trigger depressive symptoms in some women, other studies have suggested that shifting levels of allopregnanolone may play a role in the pathophysiology of reproductive hormone-associated mood disorders, including premenstrual dysphoric disorder (PMDD) and menopausal depression. In light of the positive results of brexanolone for postpartum depression, there has been considerable interest in exploring the effectiveness of similar neurosteroids in women with other types of reproductive hormone-associated mood disorders.
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.
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