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

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.

Figure 1.. Improvement in Depression Severity With Naltrexone-Bupropion Combination Vs Placebo in the ADAPT-2 Trial Among Participants With Mild or Higher Severity of Self-Reported Depressive Symptoms

Abbreviations: ADAPT = Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder, LS means = least square means, NNT = number needed to treat, PHQ-9 = 9-Item Patient Health Questionnaire.

Figure 2.. Mediation of the Effect of Naltrexone-Bupropion Combination on Methamphetamine Treatment Response by Reduction in Depression Severity

Abbreviations: PHQ-9 = 9-Item Patient Health Questionnaire.

Figure 3.. Cross Lagged Panel Model to Evaluate the Effect of Post-Baseline Urine Drug Test on Subsequent Depression Improvement and Vice Versa^a

^aPHQ-9 response indicates improvement in PHQ-9 by ≥50% as compared to baseline. UDS positive indicated urine drug screen positive for methamphetamine at that visit. Abbreviation: PHQ-9 = 9-Item Patient Health Questionnaire.