Background: This study aimed at the impact of medical comorbidity (MC) on response to antidepressant treatment over 6 weeks in diagnostic subtypes of patients with major depressive episode (MDE). Methods: In a clinical sample of 241 admitted patients with MDE, MC was assessed by medical specialists and weekly response to antidepressant treatment was assessed with the Hamilton Depression Scale (HAM-D 21). Results: Over 6 weeks of treatment, patients with melancholic depression and MC had poorer treatment response on the HAM-D scale and a worse functional outcome (GAF) as opposed to their counterparts without MC, which was first detected after 4 weeks of treatment (p = 0.02). More specifically, subjects with melancholic depression and cardiovascular or endocrinological MC showed significantly poorer treatment response over 6 weeks. Interestingly, these effects were not related to various antidepressant treatment regimens. Conclusions: MC has a negative impact on treatment response in patients with melancholic depression.

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