Brexanolone

Continuous monitoring is necessary as brexanolone can cause excessive sedation and sudden loss of consciousness. Because of this, brexanolone is only available through the restricted distribution program. During infusion, patients need continuous monitoring with pulse oximetry and must be accompanied at all times by staff or family members while interacting with their children. 

If patients experience hypoxia, infusion needs to be stopped immediately and should not be resumed. FDA has cautioned providers to monitor patients every 2 hours for sedative effects during non-sleep periods. In the case of excessive sedation or sudden loss of consciousness, dose interruption is recommended. Patients regain consciousness within 15 to 60 minutes of dose interruption.[10] After recovery, infusion may be resumed at the same or lower dose as determined by the health care provider.

Patients are prohibited from driving or operating machinery until the sedative effects of the drug have entirely resolved.

Patients require close monitoring for worsening depression and suicidal thoughts or behaviors. In such cases, it is recommended to change the dosing regimen or discontinue brexanolone altogether. Concomitant use with central nervous system(CNS) depressants such benzodiazepines, alcohol, opioids, and antidepressants also requires close monitoring and/or avoidance of these agents.

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 which limits data on toxicity on a long term basis. Long term efficacy of brexanolone, when compared with other antidepressants, is unknown and needs further research.[10]

Limited clinical trial data is available concerning overdose. The manufacturer's labeling describes two cases of accidental overdose. These were due to 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 their 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 longterm consequence of this disruptive parenting results in multiple adverse child outcomes, including increased risk for behavioral problems, lower mathematics grades, and development of depression.[16] Therefore screening and early treatment for the postpartum depression is 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 was needed.

Several studies have demonstrated the peripartum fluctuations in reproductive hormones, most importantly, allopregnanolone (the primary progesterone metabolite) play 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 prevent the GABA type A receptors from adaptation resulting in triggering of the postpartum depression.[20]

Since allopregnanolone has poor aqueous solubility, oral bioavailability and rapidly metabolized, an aqueous intravenous formulation, brexanolone, a proprietary of allopregnanolone, has been in development for the treatment of postpartum depression. To this 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 60th hour when 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]

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 were higher in the brexanolone treatment group, the events were typically mild and did not require discontinuation of treatment.[9][10] Currently, an ongoing phase 3 randomized, double-blind placebo-controlled trial is evaluating the efficacy and safety of brexanolone in the adolescent females (15 to 17 years of age) with postpartum depression. 

Although these trials showed promising results, there are few limitations. Generalizability of brexanolone to the wider 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] Need for a 60-hour intravenous infusion may be problematic for some patients because of logistic reasons.  It would be interesting to see if an oral formulation of brexanolone with a similar efficacy is formulated or 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.

Administration of brexanolone requires the effort of an interprofessional team consisting of physicians, specialists, specialty-trained nurses, and pharmacists, communicating and collaborating to bring about the optimal therapeutic results in these cases. Pharmacy needs to verify the dosing and administraiton schedule, as well as check for potential drug-drug interactions, and let nursing know if any red flags are present. Nursing will adminsiter the medicaiton, and must watch for signs of intolerance or adverse reactions as the dose titrates upward, and inform the order clinician if they notice any issues, so therapy can be discontinued or modified. Only through this type of interprofessinoal teamwork can brexanolone be effective in treating post-partum depression. [Level V]