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Brexanolone injection for postpartum depression

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Postpartum depression (PPD) is one of the most prevalent complications associated with pregnancy and childbirth in the United States, affecting more than 400,000 women annually.1 Postpartum depression is most commonly treated with psychotherapy and antidepressants approved for the treatment of major depressive disorder. Until recently, there was no pharmacologic therapy approved by the FDA specifically for the treatment of PPD. Considering the adverse outcomes associated with untreated or inadequately treated PPD, and the limitations of existing therapies, there is a significant unmet need for pharmacologic treatment options for PPD.2 To help address this need, the FDA recently approved brexanolone injection (brand name: ZULRESSO) (Table 13) as a first-in-class therapy for the treatment of adults with PPD.3

Fast facts about brexanolone injection

Clinical implications

Postpartum depression can result in adverse outcomes for the patient, baby, and family when under- or untreated, and the need for rapid resolution of symptoms cannot be overstated.2 Suicide is strongly associated with depression and is a leading cause of pregnancy-related deaths.4 Additionally, PPD can impact the health, safety, and well-being of the child, with both short- and long-term consequences, including greater rates of psychological or behavioral difficulties among children of patients with PPD.5 Postpartum depression can also have negative effects on the patient’s partner, with 24% to 50% of partners experiencing depression.6 Current PPD management strategies include the use of psychotherapy and pharmacologic interventions for major depressive disorder that may take up to 4 to 6 weeks for some patients, and may not achieve remission for all patients.7-9

Brexanolone injection is a first-in-class medication with a novel mechanism of action. In clinical studies, it achieved rapid (by Hour 60) and sustained (through Day 30) reductions in depressive symptoms and could provide a meaningful new treatment option for adult women with PPD.10,11

How it works

Animal and human studies have established the relevance of GABAergic signaling in the etiology and symptoms of depression, and supported the investigation of gamma-aminobutyric acid A receptor (GABAAR) positive allosteric modulators (PAMs)—and particularly neuroactive steroids, such as brexanolone—as potential therapeutics in PPD (Table 212-14). Through pregnancy, the levels of allopregnanolone, a neuroactive steroid metabolite of progesterone, rise in concert with progesterone, before a precipitous decrease at childbirth. This fluctuation, as well as other perturbations of GABAergic signaling in the peripartum period, may contribute to the development of PPD.12-15

Key facts: Neuroactive steroids and GABA

Brexanolone is a neuroactive steroid that is chemically identical to endogenous allopregnanolone produced in the CNS. Brexanolone potentiates GABA-mediated currents from recombinant human GABAARs in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits.3 Positive allosteric modulation of both synaptic and extrasynaptic GABAARs differentiates brexanolone from other GABAAR modulators, such as benzodiazepines.10,11

Brexanolone’s mechanism of action in the treatment of PPD is not fully understood, but it is thought to be related to GABAAR PAM activity.3

Supporting evidence

The FDA approval of brexanolone injection was based on the efficacy demonstrated in 2 Phase III multicenter, randomized, double-blind, placebo-controlled studies in adult women (age 18 to 45) with PPD (defined by DSM-IV criteria for a major depressive episode, with onset of symptoms in the third trimester or within 4 weeks of delivery). Exclusion criteria included the presence of bipolar disorder or psychosis. In these studies, 60-hour continuous IV infusions of brexanolone or placebo were given, followed by 4 weeks of observation. Study 1 (202B) enrolled patients with severe PPD (Hamilton Rating Scale for Depression [HAM-D] total score ≥26), and Study 2 (202C) enrolled patients with moderate PPD (HAM-D score 20 to 25). A titration to the recommended target dosage of 90 μg/kg/hour was evaluated in both studies. BRX90 patients received 30 μg/kg/hour for 4 hours, 60 μg/kg/hour for 20 hours, 90 μg/kg/hour for 28 hours, followed by a taper to 60 μg/kg/hour for 4 hours and then 30 μg/kg/hour for 4 hours. The primary endpoint in both studies was the mean change from baseline in depressive symptoms as measured by HAM-D total score at the end of the 60-hour infusion. A pre-specified secondary efficacy endpoint was the mean change from baseline in HAM-D total score at Day 30.

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