Based on randomized controlled trial evidence, it is unclear whether the very modest benefits of antidepressants outweigh their adverse effects in depressed patients with opioid dependence.

Low‐quality evidence suggests that antidepressants were no more effective than placebo in reducing depression severity at the end of treatment.

At the same time, moderate‐quality evidence shows a greater rate of dropouts due to medical reasons among patients receiving antidepressants, suggesting higher risk of adverse events. Rates of specific adverse events did not differ, however, between antidepressant and placebo groups, but since sample sizes in trials reporting on them ranged from 76 to 131, the studies were likely underpowered to detect small but significant differences.

Antidepressants may reduce frequency of drug use, but this finding derives from a single trial with 137 patients, albeit one that was deemed to be at low risk of bias.