Postpartum depression (PPD) is an often-debilitating major depressive episode occurring in the postnatal period and affects a significant portion of women (~20% of new mothers). Unfortunately, standard antidepressant treatments are often ineffective for PPD and may leave the mother at risk of causing harm to herself or to her infant. It is therefore exciting news that the FDA has approved the first treatment specifically for PPD: brexanolone (Zulresso™). As a positive allosteric modulator of GABA-A receptors, brexanolone has a mechanism of action unique from that of existing antidepressant therapies (including SSRIs and SNRIs) (Figure). Clinical testing of brexanolone showed that it dramatically reduced symptoms of PPD within just a few hours for many patients and the antidepressant effects were still apparent at the 30 day evaluation point. This new treatment must be administered intravenously over a period of 60 hours under supervision of a medical professional in a certified health care facility and patients must be registered with the Zulresso Risk Evaluation and Mitigation Strategy (REMS) program; high cost of the drug at this point may also be prohibitive for some patients. However, despite these limitations, the FDA approval of a treatment for PPD is groundbreaking and will hopefully save many patients and their families from the potential devastation of PPD.
The hypothalamic-pituitary-adrenal (HPA) axis, a circuit of hormones and neurosteroids that regulates response to stress, may be over-reactive in women with postpartum depression (PPD). One mechanism by which the HPA axis response is dampened is via the binding of allopregnanolone, a metabolite of progesterone, to GABA-A receptors located in the hypothalamus. Binding of allopregnanolone to GABA-A receptors has a positive allosteric effect, increasing the binding of GABA to GABA-A receptors and shutting down overactivation of the HPA axis. After childbirth, progesterone levels (and thus allopregnanolone levels) drop dramatically and it is hypothesized that this de-regulation of the HPA axis via GABA-A receptors may be associated with PPD. Brexanolone is an allopregnanolone agonist and acts in the same positive allosteric way on GABA-A receptors as does allopregnanolone itself. Intravenous administration of brexanolone to women with PPD has been shown to significantly improve symptoms of depression in a matter of hours.
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