What is Zuranolone?

What is Zuranolone?

Zuranolone (brand name ZURZUVAE) is an oral neuroactive steroid and positive allosteric modulator of GABA-A receptors, FDA-approved as a 14-day treatment course for postpartum depression in adults, and currently under investigation for major depressive disorder. 1

Mechanism of Action

• Zuranolone functions as a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors, though the complete mechanism in treating depression is not fully understood 1, 2
• The drug is a synthetic neuroactive steroid structurally related to progesterone metabolites, with the chemical formula C25H35N3O2 and molecular weight of 409.57 1

Clinical Indications and Dosing

• FDA-approved indication: Postpartum depression in adults, administered as a 14-day treatment course 1, 3
• Under investigation: Major depressive disorder, with clinical trials evaluating both monotherapy and combination with standard antidepressants 2, 4, 5
• Available in 20 mg, 25 mg, and 30 mg oral capsules 1
• Standard dosing in clinical trials has been 30 mg or 50 mg once daily for 14 days 2, 4

Pharmacokinetics

• Peak plasma concentrations occur at 5-6 hours after oral administration 1
• Terminal half-life is approximately 19.7 to 24.6 hours 1
• Food significantly increases absorption: High-fat meals increase Cmax by 4.3-fold and AUC by 2-fold compared to fasted conditions 1
• Extensively metabolized by CYP3A4 enzyme 1
• Plasma protein binding exceeds 99.5% 1
• Steady state achieved in 3-5 days with once-daily dosing 1

Clinical Efficacy

• In the CORAL study, zuranolone co-initiated with standard antidepressants showed significant improvement in depressive symptoms by Day 3 compared to placebo plus antidepressant (p=0.0004) 5
• Meta-analysis of 1,357 patients demonstrated statistically significant improvements in HAM-D scores (p=0.0009), MADRS scores (p=0.02), and HAM-A anxiety scores (p=0.03) at day 15 6
• The MOUNTAIN study showed rapid improvements at days 3,8, and 12 with the 30 mg dose, though the primary endpoint at day 15 was not met (p=0.116) 4
• In the SHORELINE long-term study, 68% of patients responded to initial treatment, with mean HAM-D score improvements of -15.2 to -16.0 points from baseline 2
• Approximately 43-55% of responders required only one treatment course during follow-up, while the majority who needed retreatment received ≤2 total courses 2

Safety Profile and Adverse Events

• Most treatment-emergent adverse events (TEAEs) are mild to moderate in severity (86-91% of those experiencing TEAEs) 2
• Most common adverse events (≥5%): Somnolence, dizziness, headache, fatigue, sedation, nausea, and diarrhea 4, 5
• Zuranolone significantly increases risk of experiencing one or more TEAEs compared to placebo (RR 1.14, p=0.006), but does not significantly increase serious adverse events or discontinuations 6

Critical Safety Warnings

CNS Depression and Impaired Driving

• Co-administration with alcohol or alprazolam causes significant psychomotor impairment 1
• Patients should not drive or operate heavy machinery for at least 12 hours after taking zuranolone 1

Abuse Potential and Dependence

• Zuranolone demonstrates dose-dependent abuse potential comparable to alprazolam and greater than placebo on measures of "drug liking," "take drug again," and "high" 1
• Physical dependence can develop, with withdrawal symptoms reported after abrupt discontinuation including insomnia, palpitations, decreased appetite, nightmares, nausea, hyperhidrosis, and paranoia 1
• In animal studies, convulsions occurred upon abrupt discontinuation after 14 days of high-dose exposure 1

Overdose

• One case of intentional overdose with 330 mg (6.5 times maximum recommended dose) resulted in altered consciousness that resolved within 24 hours with supportive care 1
• No specific antidote exists for zuranolone overdose 1

Distinguishing Features from Other Treatments

• Unlike brexanolone (another neurosteroid for postpartum depression requiring 60-hour IV infusion), zuranolone offers oral administration over 14 days 3
• Provides more rapid onset of action (3 days) compared to traditional SSRIs which typically require 2-4 weeks 6
• Demonstrates anti-anxiolytic effects in addition to antidepressant properties 6
• Short treatment course (14 days) distinguishes it from chronic antidepressant therapy 2, 3

Clinical Context

The development of zuranolone represents a novel approach to treating depression through GABA-A receptor modulation rather than monoamine reuptake inhibition, offering potential advantages in speed of onset but requiring careful monitoring for CNS depression and abuse potential 1, 3. The drug's approval for postpartum depression and ongoing investigation for major depressive disorder reflects growing recognition of neurosteroid dysregulation in mood disorders 3.