Wijkstra J, Burger H, van den Broek WW, Birkenhäger TK, Janzing JGE, Boks MPM, Bruijn JA, van der Loos MLM, Breteler LMT, Ramaekers GMGI, Verkes RJ, Nolen WA. Treatment of unipolar psychotic depression: a randomized, double‐blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Objective:  It remains unclear whether unipolar psychotic depression should be treated with an antidepressant and an antipsychotic or with an antidepressant alone. Method:  In a multi‐center RCT, 122 patients (18–65 years) with DSM‐IV‐TR psychotic major depression and HAM‐D‐17 ≥ 18 were randomized to 7 weeks imipramine (plasma‐levels 200–300 μg/l), venlafaxine (375 mg/day) or venlafaxine–quetiapine (375 mg/day, 600 mg/day). Primary outcome was response on HAM‐D‐17. Secondary outcomes were response on CGI and remission (HAM‐D‐17). Results:  Venlafaxine–quetiapine was more effective than venlafaxine with no significant differences between venlafaxine–quetiapine and imipramine, or between imipramine and venlafaxine. Secondary outcomes followed the same pattern. Conclusion:  That unipolar psychotic depression should be treated with a combination of an antidepressant and an antipsychotic and not with an antidepressant alone, can be considered evidence based with regard to venlafaxine–quetiapine vs. venlafaxine monotherapy. Whether this is also the case for imipramine monotherapy is likely, but cannot be concluded from the data.