By: Shivani Kaneria, Pharm D. Candidate c/o 2020

Postpartum depression is a mood disorder that affects 10 – 20 percent of new mothers post childbirth per year, and is caused by a combination of both physical and emotional factors.⁵ Mothers who experience this form of depression undergo common symptoms of feeling sad, crying often with no apparent reason, excessively worrying, irritability, trouble sleeping, trouble concentrating, losing interest in otherwise enjoyable activities (anhedonia), and withdrawing from social interactions. In some cases, they may be unable to establish a bond with their newborn which further adds to their emotional stress. From a chemical perspective, there is a decrease in estrogen and progesterone levels which lead to chemical changes in the brain and may trigger mood swings. In addition, constant sleep deprivation, physical exhaustion, and inability to get enough rest to recover may also be contributing risk factors.¹

Treatment for postpartum depression includes counseling with a mental health professional who may use techniques such Cognitive Behavioral Therapy (CBT) and Interpersonal Therapy. CBT helps patient recognize and change negative thoughts. Interpersonal therapy helps the patient understand and work through problematic personal relationships. Antidepressant medications are also used off-label. Older agents used include Tricyclic antidepressants like amitriptyline (Elavil^®), trimipramine (Surmontil^®), desipramine (Norpramin^®). Newer agents of the Selective Serotonin Reuptake Inhibitor class such as escitalopram (Lexapro^®), fluoxetine (Prozac^®), sertraline (Zoloft^®) and paroxetine (Paxil^®) are also used in the off-label treatment of postpartum depression².

Brexanolone (Zulresso™) is the first Food and Drug Administration (FDA) approved drug for the treatment of postpartum depression in adults. It is administered intravenously by a healthcare professional as a continuous infusion over 60 hours. The infusion usually begins as 30 mcg/kg/hour over the first 4 hours, increased to 60 mcg/kg/hour for hours 4-24, and finally increased to 90 mcg/kg/hour for hours 24-52.  The infusion rate is then tapered down to 60 mcg/kg/hour for hours 52-56, and finally to 30 mcg/kg/hour for hours 56 to 60.⁷ This drug is part of the FDA-approved Risk Evaluation and Mitigation Strategy (REMS) program which is put forth to minimize the risk of serious harm that may result due to the excessive sedative power of brexanolone. There are no prescriber requirements, however, it is required that pharmacies are specifically certified in the Zulresso REMS program.⁶ Patients who are to receive brexanolone must review the patient information guide and be enrolled in the REMS program through completing the patient enrollment form and must receive counseling from a healthcare provider regarding the black box warnings (BBW) of the drug. The BBW associated with brexanolone include excessive sedation and loss of consciousness. Because of this risk, patients must be monitored every 2 hours during the IV administration and their oxygen saturation monitored using pulse oximetry.⁶

From a mechanistic perspective, brexanolone is a GABA-A receptor positive modulator and is an injectable form of allopregnanolone. Allopregnanolone is the predominant metabolite of progesterone that decreases in levels post childbirth, possibly leading to postpartum depression.⁴ The main reason for FDA approval was because of its rapid onset of action. The disadvantage of this drug is that it needs to be administered in a hospital-like facility with careful monitoring.⁶

The approval was based on the findings of two placebo-controlled trials: one in patients with moderate depression and the other in patients with severe depression. Brexanolone showed better clinical outcomes in comparison to placebo in both trials. The primary clinical endpoint was improvement in depressive symptoms post infusion and 30 days post-infusion. The efficacy of brexanolone IV over 60 minutes was tested in 246 women with postpartum depression. The Hamilton Depression Rating Scale (HAM-D) score in the patient population was >20 (19-22 indicated severe depression and >23 indicates very severe depression); onset of depression was during the third trimester of pregnancy or within 6 months postpartum. In trial 1, brexanolone doses of 60 µg/kg/hour and 90 µg/kg/hour were compared with the placebo. In trial 2, the 90-µg/kg/hour dose was evaluated relative to placebo. After the 60-hour infusion in both studies, the HAM-D scores differed greatly from placebo for both doses and the effect was maintained for 30 days (differences were −5.2 [60-µg] and −2.5 to −3.7 [90-µg]). At 60 hours, higher proportions of patients achieved remission (HAM-D ≤7) with brexanolone compared to placebo (51% vs. 16% [60-µg] and 61% vs. 38% [90-µg]), indicative of a significant difference.³

Furthermore, in a combined analysis of both studies plus a third previous study, 94% of patients who responded to the 90-µg dose maintained a response at 30 days. Efficacy was similar regardless of whether other antidepressants were used. The most common side effects experienced by patients were headache, dizziness, and somnolence however, two patients experienced serious side effects of syncope which were resolved with infusion cessation.

In conclusion, although more studies with larger patient populations may need to be carried out to further solidify the efficacy of brexanolone, this novel drug seems to portray promising results and efficacy in decreasing the rates of postpartum depression. Since this is a relatively new drug, it is important to note the BBW and monitoring parameters during patient administration to avoid any possible adverse events. With further trials, brexanolone may become a novel drug in the treatment of the otherwise undervalued disorder of postpartum depression.

Sources:

1. National Institutes of Health N. Postpartum Depression Facts. National Institute of mental health. https://www.nimh.nih.gov/health/publications/postpartum-depression-facts/index.shtml. Published 06/06/2019.
2. Fitelson, E., Kim, S., Baker, A. S., & Leight, K. (2010, December 30). Treatment of postpartum depression: clinical, psychological and pharmacological options. Retrieved March 25, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039003/
3. Kanes S, Colquhoun H, Doherty J. Open‐label, proof‐of‐concept study of Brexanolone in the treatment of severe postpartum depression. US National Library of Medicine National Institutes of Health. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396368/. Published 03/30/2017.
4. Carberg, J. (2019, May 3). Statistics on Postpartum Depression – Postpartum Depression Resources. Retrieved June 25, 2019, from https://www.postpartumdepression.org/resources/statistics/
5. Brexalonone. Lexicomp. http://online.lexi.com:Brexalonone
6. Azhar, Y. (2019, December 21). Brexanolone. Retrieved April 10, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK541054/

Published by Rho Chi Post