Emerging treatments
Zuranolone
Zuranolone is an oral, next-generation positive allosteric modulator of gamma-aminobutyric acid (GABA) type A receptors. Zuranolone is approved by the US Food and Drug Administration (FDA) for the treatment of postpartum depression and is given for 14 days. Approval was based two positive phase 3 clinical trials.[172][173] The first study randomly assigned women up to 6 months after delivery to receive zuranolone or a placebo pill once daily for 2 weeks. The second study included women up to 12 months after delivery who were either given the drug (at a higher dose than in the first study) or placebo for 2 weeks.[173] In both studies, approximately 15% of the women continued taking another antidepressant throughout the entire study period. Both studies met their primary endpoint, which was a significant reduction on average from baseline in the Hamilton Rating Scale for Depression (HAM-D) scoring. Notably, in the second study, where a higher dose of zuranolone was utilized, a significant reduction in depressive symptoms was observed early in the course of treatment (by day 3), and this improvement was maintained until the study concluded on day 45.[173] The long-term efficacy of zuranolone is currently unknown. The prescribing information for zuranolone features a warning highlighting the risk of impairment of a person’s ability to drive and perform other activities that may pose a safety hazard. People should not drive or operate heavy machinery within 12 hours of taking zuranolone. Adverse effects associated with central nervous system depression have been observed, such as drowsiness, cognitive confusion, and dizziness. The most frequently encountered adverse effects include cold symptoms, diarrhea, fatigue, and urinary tract infections. Safety in breast-feeding is currently unknown, as neither trial allowed participants to breast-feed for the trial period and for 1 week afterward. Women taking zuranolone are advised to use effective contraception while taking zuranolone and for one week following treatment.[174] The American College of Obstetricians and Gynecologists (ACOG) recommends consideration of zuranolone in the postpartum period for depression that has onset in the third trimester of within 4 weeks postpartum, although this approach is not universally accepted outside the US and the placement of zuranolone within established treatment algorithms for postpartum depression is still under consideration.[175] Zuranolone is not available in Europe.
Brexanolone
Brexanolone (also known as allopregnanolone) is a positive allosteric modulator of GABA type A receptors that is given by intravenous infusion over 60 hours (2.5 days). One small (n=21) phase 2 trial and two larger (n=375) phase 3 double-blind, randomized, placebo-controlled trials in the US suggest that brexanolone is a novel and safe treatment for postpartum depression. Women who had a major depressive episode, with onset no earlier than the third trimester and no later than 4 weeks after delivery, and who were ≤6 months postpartum at screening, received a single continuous infusion of brexanolone or placebo for 60 hours. The phase 2 and 3 trials found statistically significant differences in the reductions of the HAM-D total scores from baseline in brexanolone groups compared with placebo groups. In the phase 2 trial, remission from depression (HAM-D total score ≤7) was observed in 7 in 10 patients in the brexanolone group and 1 in 11 patients in the placebo group at 60 hours. The effect was still observable after 30 days.[176] The phase 3 trials also found statistically higher remission rates in women treated with brexanolone than controls at 60 hours, but not after 30 days. The proportion of patients who required rescue medication was similar in the brexanolone and placebo groups, around 12% to 13%.[177] Overall, the level of evidence on efficacy of brexanolone is moderate; of note in the quoted trials, many participants were also taking concurrent medications that may have affected the overall results. The most common treatment-emergent adverse effects in the brexanolone groups were headache, dizziness, and somnolence. Four serious adverse effects were reported in total: suicidal ideation, intentional overdose attempt, altered state of consciousness, and syncope (the last two, in particular, were considered to be treatment related). Brexanolone is approved by the FDA for the treatment of postpartum depression in adult women. ACOG recommends consideration of brexanolone in the postpartum period for selected patients with moderate-to-severe perinatal depression, although this approach is not universally accepted outside the US, and the placement of brexanolone within established treatment algorithms for postpartum depression is still under consideration.[82] Because of concerns about potential serious risks during infusion, including excessive sedation or sudden loss of consciousness, brexanolone is available only through a Risk Evaluation and Mitigation Strategy (REMS) at certified medical facilities. Women having the infusion must be monitored continuously during the 60-hour infusion, and be accompanied during any interactions with their children. Brexanolone is not available in Europe.
Other steroid hormones
One Cochrane review on estrogens and progestins for preventing and treating postpartum depression suggests that synthetic progestins may be used with significant caution in the postpartum period and that estrogen therapy may be of modest value.[178] However, estrogens have not been evaluated rigorously, and given the increased risk of thromboembolism associated with their use, further research is warranted.
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