ObjectiveThis study aimed to evaluate the longitudinal treatment effect on depression measured by Hamilton Depression Rating Scale (HAM-D) score in a randomized clinical trial for the treatment of opioid use disorder (OUD). MethodsWe conducted a secondary data analysis of data from the National Institute on Drug Abuse's Clinical Trials Network Protocol-0051. Patients with OUD (N = 570) were randomized to receive buprenorphine/naloxone (BUP-NX, n = 287) or extended-release naltrexone injection (XR-NTX, n = 283). The HAM-D score was completed at baseline and follow-up visit up to 36 weeks. A linear mixed model analysis was performed for log transformed HAM-D score and a generalized linear mixed model analysis was conducted for depression status. ResultsCompared with BUP-NX, subjects randomized to XR-NTX had higher HAM-D scores at weeks 1 and 3 (p<0.05). There were significant interactions between treatment and visit on HAM-D score and depression status during the first four weeks of treatments in individuals without lifetime major depressive disorder (MDD). Past year cocaine use was associated with HAM-D score and depression status just in individuals without MDD, whereas past year cannabis use was associated with HAM-D score and depression status just in individuals with MDD. Past year amphetamine use was associated with HAM-D score just in individuals without MDD, however, lifetime anxiety was associated with HAM-D scores regardless of MDD. ConclusionWhen prescribing XR-NTX, particularly in the first month of treatment, it is essential to monitor for depressive symptoms. Screening for depression and multiple substance abuse may help clinicians identify appropriate treatment.