Mediators of treatment response in a clinical trial of naltrexone and bupropion for methamphetamine use disorder: A longitudinal mediation analysis

BACKGROUND: The mechanisms underlying pharmacological treatments for stimulant use disorders are poorly understood. This study examined whether changes in craving, depressive symptoms, and/or impulsivity mediate treatment effect in pharmacotherapy with combined naltrexone and bupropion for methamphetamine use disorder (MUD). METHODS: The study was based on secondary analysis of data from the Accelerated Development of Additive Pharmacotherapy Treatment for methamphetamine disorder (ADAPT-2) trial which randomized adults with MUD to combined treatment with injectable naltrexone (380 mg every 3 weeks) plus oral bupropion (450 mg daily) versus placebo. A total of 403 adults with MUD participated in the first stage; 225 of first stage participants in the placebo arm who did not respond to treatment were re-randomized in the second stage. Mediation effects were examined using longitudinal multi-level structural equation modeling. RESULTS: Naltrexone-bupropion treatment was associated with decreases in drug use, craving, depressive symptoms, and impulsivity. The indirect effect of treatment through change in craving was significant (self-reported use = -0.21, 95% credible interval (CrI) = -0.35, -0.09; drug screen-ascertained use = -0.36, 95% CrI = -0.63, -0.16). Change in craving mediated 56% of the treatment effect on self-reported drug use and 45% of the effect on drug screen-ascertained use. Estimates for mediated effects for depressive symptoms and impulsivity were smaller in magnitude and nonsignificant. CONCLUSION: Reduction in craving mediates the effect of naltrexone-bupropion pharmacotherapy in MUD. Craving may serve as a surrogate measure of treatment efficacy in short-term trials and help identify promising candidate medications to be tested in larger and longer-term trials. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT03078075.