What is the recommended dosing regimen, contraindications, monitoring, and management of side effects for Zuranolone in adult patients with major depressive disorder (MDD) or postpartum depression (PPD)?

Zuranolone for Major Depressive Disorder and Postpartum Depression

Recommended Dosing Regimen

Zuranolone is administered as 50 mg orally once daily in the evening for exactly 14 days, taken with fat-containing food (400-1,000 calories, 25-50% fat content). 1

Standard Dosing

• Primary dose: 50 mg once daily in the evening for 14 days 1
• Must be taken with fat-containing food to ensure adequate absorption 1
• Can be used as monotherapy or adjunctively with oral antidepressants 1
• If CNS depressant effects occur during the 14-day period, reduce to 40 mg once daily 1

Dosage Adjustments for Drug Interactions

• With strong CYP3A4 inhibitors: Reduce to 30 mg once daily for 14 days 1
• With CYP3A4 inducers: Avoid concomitant use entirely 1
• With moderate CYP3A4 inhibitors: No dosage adjustment needed 1

Dosage Adjustments for Organ Impairment

• Severe hepatic impairment (Child-Pugh C): 30 mg once daily for 14 days 1
• Mild-to-moderate hepatic impairment (Child-Pugh A-B): Standard 50 mg dose 1
• Moderate-to-severe renal impairment (eGFR <60 mL/min/1.73 m²): 30 mg once daily for 14 days 1
• Mild renal impairment (eGFR 60-89 mL/min/1.73 m²): Standard 50 mg dose 1

Missed Dose Management

• If an evening dose is missed, take the next dose at the regular time the following evening 1
• Do not double up doses on the same day 1
• Continue once-daily dosing until the 14-day course is completed 1

Contraindications

Zuranolone has no absolute contraindications listed in the FDA label. 1

Critical Safety Warnings and Monitoring

Driving and Hazardous Activities (Black Box Warning)

Patients must not drive or engage in potentially hazardous activities until at least 12 hours after each zuranolone dose for the entire 14-day treatment course. 1

• Zuranolone causes dose-dependent driving impairment due to CNS depressant effects 1
• Patients cannot reliably assess their own driving competence or degree of impairment 1
• This restriction applies throughout the entire 14-day treatment period 1

CNS Depressant Effects

• Monitor for excessive sedation, somnolence, and cognitive impairment 1
• Avoid concomitant use with other CNS depressants (alcohol, benzodiazepines, opioids) 1
• Consider dosage reduction to 40 mg if CNS effects are problematic 1

Suicidality Monitoring

• Monitor for emergence of agitation, irritability, unusual behavioral changes, or suicidal ideation within 1-2 weeks of therapy initiation 2
• This is particularly important in younger adults and those with prior suicide attempts 1

Treatment Response Assessment

• Assess treatment response at 6-8 weeks when used adjunctively with antidepressants 2
• For zuranolone monotherapy, rapid improvement typically occurs by day 3, with peak effect at day 15 3

Common Adverse Effects and Management

Most Common Adverse Effects (≥5% and greater than placebo)

The following adverse effects occurred in clinical trials at the 50 mg dose 1:

• Somnolence (36% vs 6% placebo): Most common adverse effect; consider dose reduction to 40 mg if severe 1
• Dizziness (13% vs 9% placebo): Usually mild-to-moderate; advise caution with position changes 1
• Diarrhea (6% vs 2% placebo): Generally self-limited 1
• Fatigue (5% vs 2% placebo): May improve with continued treatment 1
• Urinary tract infection (5% vs 4% placebo): Monitor for symptoms 1

Adverse Effects Leading to Discontinuation

• Overall discontinuation rate due to adverse events: 2% (vs 1% placebo) 1
• Most common reason for discontinuation: somnolence 1
• Dosage reduction due to adverse events occurred in 14% of patients, primarily for somnolence (10%) and dizziness (6%) 1

Serious Adverse Events

• Confusional state occurred in 1% of patients across all doses studied 1
• Most patients who experienced adverse events (90.9%) reported mild-to-moderate severity 4

Clinical Efficacy and Treatment Duration

Efficacy Timeline

• Rapid onset: Significant improvement by day 3 compared to placebo 3
• Peak effect: Day 15 (end of 14-day treatment course) 3
• Sustained benefit: Effects maintained through day 42 (4 weeks post-treatment) 5, 3

Repeat Treatment Courses

• The majority of initial responders (68.5-79.5%) required ≤2 total treatment courses over one year 4
• 42.9-54.8% of patients received only one treatment course during their time on study 4
• Repeat courses showed similar efficacy to initial treatment 4
• Safety and effectiveness beyond 14 days in a single treatment course have not been established 1

Continuation Treatment Recommendations

When used adjunctively with antidepressants:

• Continue antidepressant therapy for 4-9 months after satisfactory response in first-episode MDD 2
• Continue for years to lifelong in patients with two or more depressive episodes 2

Special Populations

Postpartum Depression

• FDA-approved indication for PPD in adults 1
• Same dosing regimen as MDD (50 mg for 14 days) 1
• Clinical trials included women aged 18-44 years with PPD 1

Major Depressive Disorder

• Under investigation for MDD; not yet FDA-approved for this indication 4, 6
• Can be co-initiated with standard antidepressants for potentially more rapid symptom improvement 6

Key Clinical Pearls

• Zuranolone provides rapid antidepressant effects (by day 3) with a fixed 14-day treatment course, unlike traditional antidepressants that require weeks to months 3
• The driving restriction is absolute and non-negotiable for the entire 14-day period—patients must plan accordingly 1
• Fat-containing food is required for adequate absorption; without it, efficacy may be compromised 1
• Most patients who respond initially do not require frequent repeat courses—the majority need ≤2 courses over one year 4
• When co-initiated with traditional antidepressants, zuranolone may provide a "bridge" to faster symptom relief while the antidepressant takes effect 6