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Brexanolone has a rapid onset of action within 60 hours of infusion and has a sustained response for up to 30 days after infusion. Patients in clinical trials were not followed after a 30-day follow-up period, limiting data on toxicity from long-term use. Long-term efficacy of brexanolone, when compared with other antidepressants, is unknown and needs further research.[10] Limited clinical trial data are available concerning overdose. The manufacturer's labeling describes two cases of accidental overdose. These were due to an infusion pump malfunction resulting in the sudden loss of consciousness. Patients recovered after 15 minutes of discontinuation without the need for supportive measures. The infusion was resumed, and patients completed treatment. It is recommended to stop the infusion immediately in case of overdose and initiate supportive measures as needed. Clinical studies on exogenous allopregnanolone administration have reported sedation, intoxication, flushing, and headaches; however, there are no reports of severe adverse events.[11][12][13]

Postpartum depression presents as one of the most common complications after childbirth and can be a significant cause of suffering for the mother, infant, siblings, and family.[3] In the USA, the estimated prevalence of postpartum depression varies in states ranging from 8 to 20%, with an overall mean prevalence of 11.5%. Postpartum depression affects at a multifactorial level, resulting in maternal suicide, inability to work, child morbidity associated with impaired mother-infant bonding, and malnutrition within the first year of life.[4][14][15] The long-term consequence of this disruptive parenting results in multiple adverse child outcomes, including increased risk for behavioral problems, lower mathematics grades, and the development of depression.[16] Therefore, screening and early treatment for postpartum depression are essential. Many women treated with selective serotonin reuptake inhibitors (SSRIs) for postpartum depression do not achieve adequate response or full remission of depressive symptoms.[17][18] Therefore, an urgent need for therapy specifically designed for postpartum depression. Several studies have demonstrated the peripartum fluctuations in reproductive hormones; most importantly, allopregnanolone (the primary progesterone metabolite) plays a pivotal role in the etiology of postpartum depression.[19] Allopregnanolone is a potent positive allosteric modulator at the synaptic and extrasynaptic GABA type A receptors. Postulates are that the sudden decrease in the allopregnanolone levels after childbirth prevents the GABA type A receptors from adaptation, resulting in postpartum depression.[20]

Several studies have demonstrated the peripartum fluctuations in reproductive hormones; most importantly, allopregnanolone (the primary progesterone metabolite) plays a pivotal role in the etiology of postpartum depression.[19] Allopregnanolone is a potent positive allosteric modulator at the synaptic and extrasynaptic GABA type A receptors. Postulates are that the sudden decrease in the allopregnanolone levels after childbirth prevents the GABA type A receptors from adaptation, resulting in postpartum depression.[20] Since allopregnanolone has poor aqueous solubility, oral bioavailability, and is rapidly metabolized, an aqueous intravenous formulation, brexanolone, a proprietary form of allopregnanolone, has been in development for the treatment of postpartum depression. To date, one phase 2 and two phase 3 randomized, double-blind, placebo-controlled trials have been conducted, showing promising results of brexanolone in the treatment of postpartum depression. All clinical trials showed a substantial reduction in the Hamilton Rating Scale for Depression [HAM-D] at 60 hours compared with the placebo; there was a rapid onset of action and sustained response during the treatment period with brexanolone.[9][10] Rapid onset of action is essential, as when postpartum patients receive treatment with SSRIs, it takes 4 to 6 weeks to achieve an adequate antidepressant response.[21] Furthermore, the prompt onset of action determines the likelihood of near-term recovery and full remission of symptoms.[22] The most common adverse effects in phase 3 trials were headache, dizziness, and somnolence; therefore, close monitoring is required during infusion treatment with brexanolone. Although the incidence of dizziness and somnolence was higher in the brexanolone treatment group, the events were typically mild and did not require discontinuation of treatment.[9][10] As of this writing, an ongoing phase 3 randomized, double-blind, placebo-controlled trial is evaluating the efficacy and safety of brexanolone in adolescent females (15 to 17 years of age) with postpartum depression.

The most common adverse effects in phase 3 trials were headache, dizziness, and somnolence; therefore, close monitoring is required during infusion treatment with brexanolone. Although the incidence of dizziness and somnolence was higher in the brexanolone treatment group, the events were typically mild and did not require discontinuation of treatment.[9][10] As of this writing, an ongoing phase 3 randomized, double-blind, placebo-controlled trial is evaluating the efficacy and safety of brexanolone in adolescent females (15 to 17 years of age) with postpartum depression. Although these trials showed promising results, several limitations exist. The generalizability of brexanolone to the broader population is yet to be determined, as the trials have focused on women with moderate to severe postpartum depression. No data exists on the effects of brexanolone after the completion of a 30-day follow-up period.[10] The need for a 60-hour intravenous infusion may be problematic for some patients due to logistical constraints. It would be interesting to see if an oral formulation of brexanolone with similar efficacy is developed in the future.[23] Despite these limitations, brexanolone is the first therapeutic drug to be approved by the FDA, specifically for the treatment of postpartum depression. More large-scale clinical trials are needed to determine the long-term safety and efficacy of brexanolone in the treatment of postpartum depression. The administration of brexanolone requires the effort of an interprofessional team consisting of physicians, specialists, specialty-trained nurses, and pharmacists, who communicate and collaborate to achieve optimal therapeutic outcomes in these cases. The pharmacy needs to verify the dosing and administration schedule, check for potential drug-drug interactions, and notify nursing if any red flags are present. Nursing will administer the medication and must monitor for signs of intolerance or adverse reactions as the dose is titrated upward, and inform the ordering clinician if any issues are noticed, so that therapy can be discontinued or modified. Only through this type of interprofessional teamwork can brexanolone be effective in treating postpartum depression. As of the time of this topic's update, brexanolone has been removed from the market. (Discontinued by manufacturer)