AbstractBackgroundAlcohol use disorder (AUD) and depression are highly prevalent and tied to significant psychological, physiological, social and economic consequences. Their co‐occurrence presents a complex clinical challenge, as the impact of antidepressant medication on AUD outcomes remains equivocal. In this multicenter, longitudinal study we investigated the relationship between antidepressant medication and changes in depression symptoms and alcohol use in AUD patients.MethodsWe analyzed data from 153 detoxified AUD patients who attended a 12‐week residential treatment program between 2015 and 2019. Within a mediation analysis, adopting a bootstrapping approach and a quasi‐Bayesian framework, we estimated the total, direct, and mediated effects of antidepressants on the percentage of days abstinent to assess the role of changes in depression symptoms as a mediating factor.ResultsThe mediation analysis revealed a dual impact pathway model with a negative direct effect of antidepressants on abstinence (p = 0.004) and a positive indirect effect, mediated through the reduction of depression symptoms (p = 0.002).ConclusionsThe findings of the mediation analysis show that patients treated with antidepressants and whose depression symptoms do not improve over time show more relapses, while patients treated with antidepressants who achieve a reduction in depression symptoms show fewer relapses over time. Thus, to optimize treatment outcome, depression symptoms should be vigilantly monitored when antidepressants are prescribed during AUD treatment.