Prioritizing Treatments for Mood Disorders in Perimenopause

PARIS — Mood disorders are a burdensome symptom that many women have as menopause approaches. Dr Gabriel André, a gynecologist-obstetrician in Strasbourg, France, and Vice-President of GEMVi, provided insights on these disorders at the Santé Paris Femmes 2024 congress.

Hormonal Fluctuation

For most women, perimenopause, which typically occurs between ages 40 and 50 years, is a vulnerable period accompanied by many unpleasant symptoms such as irregular cycles, breast tenderness, hot flashes, and mood disorders. This observation especially holds true for individuals who have had mood disorders while taking birth control, are highly sensitive to premenstrual syndrome, or have had postpartum depression, said André. If a continuous state of sadness persists for more than 15 days, it should be addressed by a psychiatrist or psychotherapist, he added. Moreover, the gynecologist has a crucial role to play. “The challenge is that menopausal symptoms overlap with those of depression,” said André.

Women with the previously mentioned risk factors are strongly sensitive to hormonal changes. “Perimenopause is nothing but a hormonal fluctuation. The vulnerability window needs to be acknowledged,” said André. Indeed, several studies have shown that during perimenopause, women have more significant mood fluctuations, which tend to normalize over time.

An 8-week study of women with a mean age of 48 years who were in perimenopause and had untreated depressive symptoms revealed an “association between the severity of the depressive score and the fluctuation of estradiol levels,” said André. “The absence of progesterone, being in anovulation, also exacerbates the depressive score.”

Hormone Therapy and Antidepressants

So, which treatments should be prioritized? “The brain contains estrogen and progesterone receptors. Regarding depressive disorders, there are two pathways. They are the serotonergic, where estrogens are active in boosting serotonin at all levels, and a somewhat newer and increasingly popular pathway: That of gamma-aminobutyric acid (GABA),” said André.

Can menopausal hormone therapy (MHT) help improve depressive symptoms? A Canadian study involved around 170 women with an average age of 50 years who were experiencing perimenopause or early menopause with depressive symptoms. It compared patients seen by a doctor and given antidepressants, hormone therapy, or both. “What’s interesting is that when you combine hormone therapy and antidepressants, you see a significant interaction,” said André. While in France, “we are not used to combining the two; in Canada, psychiatrists and gynecologists handle this well.”

What About Progestogens?

It has been demonstrated that androgenic progestogens are detrimental to the brain. A study showed that combining dienogest and estradiol continuously was much more effective. “It’s much better for the brain,” said André.

Furthermore, in treating a patient with mood disorders, the expert advised against increasing estrogen doses to counteract a deficiency. This, on the contrary, would worsen depressive symptoms in the second half of the cycle with sequential treatment. “Choosing the right estrogen level is critical; the highest level is not necessarily the best.

“MHT should be administered transdermally, ideally with a continuous, combined protocol to avoid fluctuations. In addition, the estradiol dose is often excessive, and if a woman does not respond well to treatment, rather than increasing it, it is better to decrease it, which is an important concept,” said André.

Moreover, it has been proven that natural progesterone benefits the brain and mood by addressing anxiety and depression symptoms.

What About GABA?

If a microprogestin is administered, drospirenone should be more seriously considered for a better effect on GABA. Regarding mental well-being, it is now understood that GABA takes precedence over serotonin. “It’s the primary inhibitory neurotransmitter of the CNS [central nervous system],” said André. “When present in sufficient levels in the body, one can experience a state of calm and well-being, whereas in its absence, feelings of anxiety and agitation prevail. There are 19 possible combinations of GABA receptors; some are beneficial, some are not. Particularly, it does not work with certain nonsteroidal progestogens, androgenic progestogens, hormonal fluctuation.…”

Natural progesterone may counteract the benefits of estradiol. Finding the optimal dose to be within the right range of allopregnanolone is not always easy. If there is too much or too little, it will not work, André warned. You may even end up with a completely opposite paradoxical effect.

Intermittent treatment can also be suggested. When treating a patient who is definitively in menopause, as mood disorders diminish over time, attention should be shifted to other symptoms such as vasomotor syndromes, sleep, and libido, which will significantly impact mood. “Mood disorders are part of the risk-benefit ratio when a patient questions whether it is time to stop treatment,” said André.

“In any case, it is also essential to refer the patient to a psychiatrist if the depression goes beyond hormonal changes. However, ketogenic diets, physical activities, and maintaining social life are also recommended,” he concluded.

Emerging Therapies

New nonhormonal therapies that affect the hypothalamus’ thermoregulation center, such as fezolinetant (a neurokinin 3 receptor inhibitor) or elinzanetant (a selective antagonist of neurokinin 1 and 3 receptors), seem to reduce the frequency and severity of moderate to severe vasomotor symptoms associated with menopause. These effects were demonstrated in the phase 3 trials SKYLIGHT 1 and OASIS 1 and 2. This positive effect on hot flashes could in turn affect mood positively. Further research is, however, needed to evaluate the long-term safety and efficacy of these molecules.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.