PMDD Treatment with Serotonin Reuptake Inhibitors: Neuroactive Steroids and GABA May Play a Role

Premenstrual dysphoric disorder (PMDD) affects about 5% of menstruating individuals and is associated with significant negative mood symptoms during the luteal phase of the menstrual cycle. For decades, the treatment of PMDD has primarily consisted of two distinct approaches. Treatments that suppress ovulation, including oral contraceptives and GnRH antagonists (Lupron), can improve premenstrual symptoms, but many women cannot tolerate these hormonal interventions. More commonly, women with PMDD are treated with serotonergic reuptake inhibitor (SRI) antidepressants, such as fluoxetine (Prozac) and sertraline (Zoloft).

Recently other options have emerged. The advent of a novel class of antidepressants — neuroactive steroids that modulate the effects of the inhibitory neurotransmitter GABA at GABA-A receptors — have led to the development of two new treatments for postpartum depression, brexanolone and zuranolone. This has led researchers to speculate that these neuroactive steroids may also be effective for the treatment of other hormone-mediated mood disorders, including PMDD

While SRIs continue to be the first line treatment for PMDD, exactly how they work to relieve PMDD symptoms is not well understood. A new study from Miller and colleagues asks whether SRI treatment affects the levels of neuroactive steroids that act at GABA-A receptors and if so, whether increases in levels of neurosteroids are associated with improvement in PMDD symptoms.

This study included 32 individuals with PMDD confirmed with prospective ratings of PMDD symptoms using the Daily Record of Severity of Problems (DRSP) and 38 unaffected controls. At baseline, serum levels of nine neuroactive steroids were measured (3?,5?-THP; 3?5?-THP; pregnenolone; 3?,5?-androsterone; 3?,5?-androsterone; 3?,5?-A-diol; 3?5?-A-diol; 3?,5?-THDOC; 3?5?-THDOC) during the follicular (before ovulation) and luteal (after ovulation) phases of the participants’ menstrual cycles. 

In the subsequent menstrual cycle, participants in the PMDD group were treated with 50 mg sertraline during the luteal phase (from ovulation to the onset of menses), and levels of neuroactive steroids were again measured.

Treatment with SSRI Alters Luteal Levels of Neuroactive Steroids

At baseline, there were no significant differences in levels of neuroactive steroid levels between participants with PMDD and controls during the luteal phase of the cycle (p > 0.05). After treatment with sertraline, however, participants in the PMDD group had significantly increased levels of pregnenolone, increases in the pregnenolone:progesterone ratio, and decreased levels of 3?,5?-androsterone.

A total of 27 participants in the PMDD group were treated with sertraline. Within the PMDD group, 12 participants (44.4%) were considered sertraline treatment responders, while 15 were non-responders. The researchers observed no significant association between changes in neuroactive steroid levels and changes in luteal phase PMDD symptoms among individuals treated with sertraline (p > .05). Among non-responders, 3?,5?-androsterone levels decreased with SSRI treatment; in contrast the responders showed an increase in 3?,5?-androsterone levels with SSRI treatment. 

What is the Role of Neuroactive Steroids in the Pathophysiology of PMDD?

This is a small but thought-provoking study, the first to examine the impact of SSRI treatment on luteal phase levels of neuroactive steroids in individuals with confirmed PMDD. Treatment with sertraline during the luteal phase was associated with increased pregnenolone levels, as well as increases in the pregnenolone:progesterone ratio.

The findings of this study suggest that pregnenolone may play a role in the pathophysiology of PMDD. Progesterone is converted to the metabolite allopregnenolone, as well as pregnenolone (first to 5?-DHP by 5?-reductase and then to pregnenolone by 3?-HSD). Thus, elevated pregnenolone levels, and particularly an increase in the ratio of pregnenolone relative to progesterone, suggests that the enzymes 5?-reductase or 3?-HSD are more efficiently converting progesterone to pregnenolone as a result of SSRI treatment. This is consistent with previous studies finding that SSRIs increase the efficiency of the enzyme 3?-HSD, resulting in increased conversion of progesterone to pregnenolone. 

The findings suggest a possible mechanism of action for serotonergic reuptake inhibitors in the treatment of PMDD. Clinically we see that women with PMDD often experience rapid relief after initiating treatment with SRIs–in days as opposed to weeks, as is the case when SRIs are used to treat depressive symptoms. This more rapid onset of action suggests that SRIs may work differently for the treatment of PMDD than for major depressive disorder. The authors hypothesize that in individuals with PMDD, SRIs may ameliorate premenstrual symptoms by increasing levels of neuroactive steroids with GABA-ergic effects. The rapid action of SRIs in this setting may reflect more rapid changes in neuroactive steroid levels, similar to those observed when brexanolone or zuranolone are used to treat postpartum depression.

Several studies have looked at the efficacy of neuroactive steroids for the treatment of PMDD. One example is sepranolone (or isoallopregnanolone), a metabolite of allopregnanolone that acts as an antagonist at the GABA-A receptor. In a double-blind randomized controlled trial from Bäckström and colleagues, sepranolone was shown to be effective for the treatment of PMDD symptoms and well-tolerated. 

Stay tuned…

Ruta Nonacs, MD PhD

References

Miller KN, Standeven L, Morrow AL, Payne JL, Epperson CN, Hantsoo L. GABAergic neuroactive steroid response to sertraline in premenstrual dysphoric disorder. Psychoneuroendocrinology. 2024 Feb; 160:106684.

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