Early Change in Depressive Symptom Severity With Naltrexone-Bupropion Combination and Its Association With Reduction in Methamphetamine Use in ADAPT-2 Trial

Manish K. Jha, MBBS; Udi E. Ghitza, PhD; Steve Shoptaw, PhD; Abu Minhajuddin, PhD; Snoben Kuruvila, MPAS; Sidarth Wakhlu, MD; Edward V. Nunes, MD; Joy Schmitz, PhD; Phillip O. Coffin, MD; Gavin Bart, MD, PhD; Thomas Carmody, PhD; Madhukar H. Trivedi, MD

J Clin Psychiatry 2025;86(3):25m15825.

Abstract

Objective: This study evaluated whether depressive symptom severity improved early with extended-release naltrexone and bupropion combination (naltrexone bupropion) compared to a placebo in individuals with moderate/severe methamphetamine use disorder and predicted subsequent use of methamphetamine.

Methods: This secondary analysis from the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial, which was conducted from May 23, 2017–July 25, 2019, included 326 individuals with a 9-item Patient Health Questionnaire (PHQ-9) score ≥5 at baseline. Repeated-measures mixed model analyses evaluated early (baseline-to-week-4) changes in depressive symptom severity with naltrexone-bupropion versus placebo and provided slope estimates for PHQ-9 change. Additional depression outcomes included response (≥50% reduction in PHQ-9 from baseline) and remission (PHQ-9 ≤4). Methamphetamine treatment response was ascribed if 3 out of 4 urine drug screens were negative during weeks 5 and 6. Logistic regression analyses evaluated whether changes in depression predicted methamphetamine treatment response. Covariates included age, sex, race, ethnicity, and baseline PHQ-9.

Results: There was a greater reduction in PHQ-9 scores at week 4 with naltrexone-bupropion versus placebo (estimate = −2.52; standard error = 0.81). At week 4, depression response (odds ratio [OR] = 2.54; 95% confidence limit [CL], 1.42–4.55) and remission (OR = 3.04; 95% CL, 1.57–5.87) were more likely with naltrexone-bupropion versus placebo. Greater baseline-to-week 4 reduction in PHQ-9 was associated with a higher likelihood of methamphetamine treatment response (OR = 3.74, 95% CL, 1.28–10.93) and explained 24.8% (95% CI, 6.7%–60.3%) of the effect of naltrexone-bupropion on methamphetamine treatment response.

Conclusion: Use of naltrexone bupropion was associated with early reduction in depressive symptom severity compared to a placebo, which was associated with a higher likelihood of reduction in subsequent methamphetamine use.

Trial Registration: ClinicalTrials.gov identifier: NCT03078075

J Clin Psychiatry 2025;86(3):25m15825

Author affiliations are listed at the end of this article.

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