Due to a growing body of research, the connection between mental health and perimenopause is becoming clearer, namely its impact on mood and the onset of depression and anxiety. However, despite focused efforts in scientific research, this connection is still largely unexplored in the pharmaceutical space.

Perimenopause refers to the stage of menopausal transition when an irregularity in the menstrual cycle symptoms may arise before the last menstrual bleed. Medical interventions typically recommended during this stage include drugs to treat depression and hormone  replacement therapies (HRT).

While these are currently the go-to approach, they fail to support all women during perimenopause. Scientists are now looking at drugs to help address mood changes during perimenopause that fill this gap.

Mental health during perimenopause

“An under-recognised entity” is what one research study called perimenopausal depression. “Several studies on different cohorts of women have shown that the menopause transition is associated with a worsening of mood and an increase in the risk for major depression,” says Dr. Nanette Santoro, professor of Obstetrics and Gynecology at The University of Colorado.

As per one 2018 study, perimenopause is associated with an increased risk of experiencing greater symptoms of depression. Despite these findings, “Not much is known for sure regarding this link”, says Patrick Raynal, PhD, research director at Inserm, the Université de Toulouse-Jean Jaurès.

Data has also indicated that women are at higher risk of worsening anxiety while transitioning into menopause, Santoro says. Moreover, experiencing anxiety during perimenopause has also been found to be strongly connected with menopausal symptoms, and that poor sleep was more associated with anxiety than depression. While some of this risk is heightened for those with a history of pre-existing depression or anxiety, Santoro says, “it can be new in onset for some women and, therefore, particularly disruptive”.

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Science drives new developments in medications

Specific drug-based treatments for symptoms of anxiety and depression during perimenopause are largely unexamined. Instead, researchers are studying existing drugs to gauge their applicability in treating mood changes and reducing anxiety and depression resulting from perimenopause.

Scientists analysing depression during and after perimenopause have found that antidepressants are a potential treatment for moderate to severe symptoms. In 2018, guidelines by the North American Menopause Society, and others, recommended selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) as front-line medications for depression during perimenopause.

HRT, or systemic estrogen therapy, is also a leading medication to treat perimenopausal symptoms. Research suggests estrogen has antidepressant effects in perimenopausal women, particularly those with concomitant vasomotor symptoms. However, as per the 2018 guidelines, data on estrogen plus progestin is “sparse and inconclusive”.

Moreover, women with various existing conditions cannot take hormone therapies, and SSRIs and SNRIs may not always be effective. In this backdrop, some companies have taken to studying drugs approved drugs specifically for women undergoing perimenopause.

In 2019, Sage Therapeutics’ drug Zulresso received FDA approval to treat postpartum depression. Zulresso contains brexanolone, which is chemically identical to allopregnanolone, as per the drug’s label. It remains to be seen if this approach could also work for perimenopause. “We are doing better with postpartum depression than perimenopausal women,” says Santoro.  

An ongoing four-year study at Brigham and Women’s Hospital, is now exploring how the allopregnanolone affects behaviour and neurobiology that may underlie perimenopausal depression. With an estimated completion date of May 2026, the study strives to utilise the endocrine biology of perimenopause to explain the behavioural and neurobiological features of depression in perimenopausal women.

The National Institute of Mental Health (NIMH) is exploring the causes of and treatment for perimenopausal depression. The Institute’s behavioural endocrinology branch highlights the need for new treatments for these mood changes during perimenopause. For example, NIMH is leading a study to evaluate LY500307, which was previously being developed by Eli Lilly for treating schizophrenia.

Managing symptoms during perimenopause

“Our level of knowledge is not sufficient to propose specific treatments for managing symptoms of anxiety or depression due to perimenopause,”says Raynal. “If the conditions are mild, hormone therapy may help,” says Santoro. However, seeing a psychiatrist and exploring traditional pharmacotherapy for these conditions is often recommended, which she says is effective.

Importantly, studies often do not distinguish between perimenopausal and postmenopausal women, says Raynal.“More research is needed, both in larger samples and longitudinal design, to confirm findings specifically in perimenopausal women,” he adds. Unravelling the specific changes of menopause that impact the brain would be most helpful in designing more targeted treatment, Santoro highlights.