Zuranolone: A Novel Approach to Treating Postpartum Depression

Introduction Postpartum depression (PPD) is a mood disorder that affects mothers within 1 year after childbirth. Worldwide, 17% of pregnancies are affected by PPD.[1] It is characterized by persistent sadness, loss of interest, lack of appetite, low self-esteem, sleep disturbances, and maternal anxiety often accompanied by a hostile feeling directed toward the infant.[2] The pathophysiology of PPD is believed to be multifactorial.[3] Studies indicate that disrupted gamma-aminobutyric acid (GABA) signaling in PPD is caused by fluctuating plasma levels of the endogenous neuroactive steroid “allopregnanolone” during the perinatal period.[4] Traditionally, pharmacological treatment of PPD has been focused on using antidepressants approved for major depressive disorder, such as selective serotonin reuptake inhibitors, which neither provide rapid symptomatic relief nor are they specific to PPD.[5] Therefore, there is an urgent need to explore novel treatment options that address PPD. Neuroactive steroids represent a promising class of drugs with the ability to modulate GABA type A (GABAA) receptor activity.[6] In August 2023, the US Food and Drug Administration approved zuranolone (a synthetic neurosteroid) as the first oral-specific treatment option for PPD.[6,7] Indication Treatment of PPD in adults. Mechanism of Action Zuranolone is a neuroactive steroid that works by acting as a positive allosteric modulator of the GABAA receptor. It acts on both synaptic and extrasynaptic GABAA receptors [Figure 1].[8] GABA is an inhibitory neurotransmitter, by enhancing its activity it results in neuronal hyperpolarization and reduced neuronal excitability. This is the reason for the antidepressant action of zuranolone. Clinical studies,[4,8] have demonstrated that unlike traditional antidepressants, it has a rapid onset of action noted as early as day 3.Figure 1: Mechanism of action of zuranolonePharmacokinetics Following oral administration, zuranolone reaches its peak plasma concentration (Cmax) at 5–6 h. Oral absorption is increased when the drug is administered with a fatty meal. It is a high plasma protein-bound drug (99.5%) and is primarily metabolized in the liver by cytochrome P450 3A4 (CYP3A4) enzymes. Co-administration with CYP3A4 inhibitors or inducers can significantly alter zuranolone’s metabolism and efficacy. The drug has a half-life of 16–22 h, allowing for once-daily dosing. It is excreted through both urine and feces. Dosage Forms and Strength Zuranolone is available in capsules with strengths of 20, 25, and 30 mg. Dosage and Administration The recommended dose of zuranolone is 50 mg, administered orally once daily in the evening for 14 days. The drug should be taken with a fatty meal to enhance absorption. It is important to note that the safety and effectiveness of zuranolone have not been established for use beyond 14 days in a single treatment cycle. Dosage adjustments are required in patients with severe hepatic impairment and moderate-to-severe renal impairment. In these individuals, the dosage should be reduced to 30 mg taken once daily in the evening for 14 days. Clinical Studies A phase 3, double-blind, randomized, placebo-controlled clinical trial was conducted to evaluate the efficacy and safety of a 50 mg dose of zuranolone in women with severe PPD. The primary efficacy endpoint was to assess the change in depressive symptoms by day 15, which was measured by the Hamilton Depression Rating Scale (HAM-D score). The zuranolone group demonstrated a statistically significant (P = 0.0007) reduction in depressive symptoms compared with the placebo by day 15 and its antidepressant effect was noted as early as day 3. It was generally well-tolerated during the study period; the most frequent side effects that were reported were somnolence, dizziness, and sedation which was consistent with previous trials.[8] Adverse Drug Reactions Zuranolone is generally a well-tolerated drug. The most frequently reported side effects were sedation, somnolence, headache, dizziness, diarrhea, and urinary tract infection. Somnolence and sedation were expected with this drug, due to its positive allosteric action on GABAA receptors. Due to its central nervous system depressant effects, caution is advised when performing activities that require mental alertness, such as driving or operating heavy machinery. It is recommended to avoid engaging in such tasks for at least 12 h after administration. Contraindications Contraindicated in pregnancy due to potential fetal risks. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.