What antidepressant is first‑line for an adult with co‑occurring depression and alcohol‑use disorder to reduce alcohol cravings?

Sertraline Combined with Naltrexone for Co-Occurring Depression and Alcohol Use Disorder

For an adult with co-occurring depression and alcohol use disorder, sertraline (200 mg/day) combined with naltrexone (100 mg/day) is the first-line pharmacologic approach to reduce both alcohol cravings and depressive symptoms. 1

Evidence for Combination Therapy

The strongest and most recent evidence demonstrates that sertraline monotherapy has minimal impact on reducing alcohol consumption or cravings, despite effectively treating depressive symptoms in patients with co-occurring disorders. 2, 3, 4, 5 Multiple well-controlled trials show that antidepressants alone reduce depression but do not significantly decrease heavy drinking in this population. 4, 5

However, combining sertraline with naltrexone produces superior outcomes for both conditions:

• The combination achieved a 53.7% alcohol abstinence rate compared to 21-27% with either medication alone or placebo 1
• Median time to relapse to heavy drinking was 98 days with combination therapy versus 23-29 days with monotherapy 1
• 83.3% of patients were no longer depressed by end of treatment with the combination 1
• The combination had fewer serious adverse events (11.9%) compared to other treatment groups (25.9% overall) 1

Practical Implementation

Start both medications simultaneously while providing weekly cognitive-behavioral therapy focused on both alcohol relapse prevention and depression management:

• Sertraline: Begin at 50 mg daily, titrate to 200 mg/day over 2-4 weeks 6, 1
• Naltrexone: Start at 50 mg daily, increase to 100 mg/day 7, 1
• Treatment duration: Minimum 14 weeks for the acute phase, then continue for 4-9 months after achieving remission 6, 1

Critical Safety Monitoring

• Suicidality surveillance: Assess weekly during the first month, especially in patients under age 24, as SSRIs carry FDA black box warnings for treatment-emergent suicidal ideation 6, 8
• Hepatotoxicity monitoring: Check baseline liver function tests before starting naltrexone; naltrexone is contraindicated in acute hepatitis or liver failure 7
• Adherence assessment: Monitor medication adherence at weeks 4 and 8, as poor adherence predicts treatment failure 6, 8

Why Not Sertraline Alone?

Low-quality evidence from multiple trials demonstrates that sertraline monotherapy does not reduce alcohol consumption in patients with co-occurring disorders, even when it successfully treats depression. 2, 3, 5 A large multicenter trial of 328 patients found no reliable differences between sertraline and placebo on drinking behavior, despite substantial decreases in depressive symptoms. 2 Another trial showed only modest benefits—fewer drinks per drinking day but no difference in other drinking outcomes. 3

The mechanism is clear: antidepressants treat depression but have little direct impact on alcohol dependence pathophysiology. 4 Naltrexone is required to address the opioid-mediated reward pathways that drive alcohol cravings and consumption. 7, 1

Alternative Approaches if Combination Therapy Fails

If the patient cannot tolerate naltrexone or has contraindications (acute hepatitis, current opioid use):

• Acamprosate (666 mg three times daily) can be substituted for naltrexone to reduce relapse in alcohol-dependent patients 7
• Disulfiram (250 mg daily) is effective but requires high motivation and specialist support 7
• Continue sertraline for depression management while intensifying psychosocial interventions for alcohol use 6, 3

Common Pitfalls to Avoid

• Don't prescribe sertraline alone expecting it to reduce alcohol cravings—the evidence consistently shows antidepressants do not impact drinking behavior without concurrent anti-craving medication 2, 3, 4, 5
• Don't delay naltrexone initiation—waiting to "stabilize depression first" misses the critical window for preventing early relapse to heavy drinking 1
• Don't use tricyclic antidepressants in this population due to high lethality in overdose and increased risk in patients with substance use disorders 6
• Don't assume depression is substance-induced—treat both conditions simultaneously rather than waiting for prolonged abstinence to clarify diagnosis 1, 3