As postpartum depression shadows the joy of many new mothers, Zuranolone emerges as a promising oral alternative, addressing the constraints of the current intravenous treatment.
Postpartum depression (PPD) occurs in about 6.5% to 20% of women[1]. While the birth of a child is traditionally associated with happiness and celebration, some find themselves grappling with a profound sense of sadness, anxiety, and emotional turmoil in the weeks or months following childbirth. Risk factors include depression prior to or during pregnancy, experiencing stressful events during pregnancy, low levels of social and familial support, obstetric complications etc. Not only does untreated PPD affect the mother, it can adversely impact the infant as well as their partners. Women with PPD are at a higher risk of alcohol and/or substance abuse, while negative maternal-infant interactions have been known to affect cognitive functioning and emotional development in children [2].
Current treatment options for PPD include psychotherapy and antidepressants. Antidepressants are used on an off-label basis in PPD and often have slow onset of response and/or failure to achieve remission. Recently in 2019, intravenous Brexanolone was approved for severe PPD who have failed initial pharmacotherapy, psychotherapy and electroconvulsive therapy. However, it is a 60 hour infusion which requires inpatient admission and continuous monitoring by clinicians [3].
Come Zuranolone (Zurzuvae), the first oral medication approved by the FDA for treatment of PPD. Developed through a collaboration between Sage Therapeutics and Biogen, Zuranolone aims to address the logistical barriers posed by intravenous Brexanolone. It has a half-life of 16 to 23 hours compared to 9 hours for Brexanolone. The pathophysiology of PPD is likely multifactorial, with evidence supporting a role for disruption of perinatal γ-aminobutyric acid (GABA) signalling, the major inhibitory signalling pathway of the central nervous system [3]. Zuranolone is an investigational oral GABAAR positive allosteric modulator and neuroactive steroid, similar to Brexanolone. By upregulating GABAAR expression and increasing phasic and tonic inhibitory GABAergic signalling, Zuranolone may rapidly restore and maintain excitatory-inhibitory balance in brain networks, thus allowing the brain to potentially respond appropriately to internal and external stimuli [4].
FDA has approved Zuranolone based on the results from SKYLARK and ROBIN trial. In SKYLARK, 200 women diagnosed with severe PPD (baseline HAMD-17 total score >= 26) were recruited. Treatment group was given 14 days of Zuranolone 50mg and there was a 4 week follow up period after participants completed the study treatment. Patients could still be on antidepressants as long as doses were stable for at least a month and patients agreed to keep on the same dose throughout the study duration.
Figure 1: SKYLARK study regimen
At Day 15, the treatment group showed greater improvement in HAMD (Hamilton Depression Rating Scale)-17 score compared to the placebo group, and this improvement was sustained at Day 45. There was also significant reduction in Clinical Global Impression – Severity (CGI-s) score by the end of treatment duration. In the ROBIN trial, which assessed the efficacy and safety of Zuranolone 30mg in 150 patients with diagnosis of PPD, also showed greater improvement in HAMD-17 score for the Zuranolone group and this was seen as early as Day 3 of treatment.
Figure 2: SKYLARK trial – Change from baseline in HAMD-17 total score at Day 15
Figure 3: ROBIN trial – Change from baseline in HAMD-17 score throughout Day 45
Figure 4: Change from baseline in CGI-S at Day 15
Common treatment adverse event include somnolence, dizziness, sedation, headache, diarrhea, nausea and urinary tract infection. The incidence of treatment adverse events were 66.3% In the treatment group and 53.1% in the placebo group. There was no evidence of increased suicidal ideation and behavior compared to baseline and no occurrence of withdrawal symptoms after treatment discontinuation. Discontinuation rates in the treatment group were low at 4.1% compared to 2% in the placebo group.
The FDA approved dose for Zuranolone in PPD is 50mg once every evening for 2 weeks, taken with a fatty meal. However, one limitation from the trials is that the long term safety and efficacy of Zuranolone remains unknown since the trials only followed up with its participants up to 45 days. Patients were also not allowed to breastfeed during the treatment period and 1 week after treatment ended, thus it is not known if Zuranolone can be administered while breastfeeding. This will only be known after clinicians obtain sufficient real world experience with
Zuranolone and with post-marketing follow up. Nevertheless, the approval of Zuranolone provides patients with PPD a convenient oral treatment option, helping these women cope with their condition and reducing the risk negative maternal-infant outcomes.
References:
1) Reference 2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039003/
2) https://www.ncbi.nlm.nih.gov/books/NBK519070/
3) ROBIN https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246337/
4) https://investor.sagerx.com/static-files/59444b6d-1349-459e-8ee0-2390ebe7dc6b
5) MOA: ttps://www.cambridge.org/core/journals/cns-spectrums/article/zuranolone-a-positive-allosteric-modulator-of-the-gabaa-receptor-hypothesized-mechanism-of-action-in-major-depressive-disorder/5B9708B1780570EBA9FCE6CFED255BBA
6) Pathophysio of PPD: jamapsychiatry_deligiannidis_2021_oi_210036_1669133790.10656.pdf
