Antidepressants are frequently prescribed in first episode schizophrenia (FES) patients for negative symptoms or for subsyndromal depressive symptoms, but therapeutic benefit has not been established, despite evidence of efficacy in later-stage schizophrenia. We conducted a 52 week, placebo-controlled add-on trial of citalopram in patients with FES who did not meet criteria for major depression to determine whether maintenance therapy with citalopram would improve outcomes by preventing or improving negative and depressive symptoms. Primary outcomes were negative symptoms measured by the Scale for Assessment of Negative Symptoms and depressive symptoms measured by the Calgary Depression Scale for Schizophrenia; both were analyzed by an intent-to-treat, mixed effects, area-under-the-curve analysis to assess the cumulative effects of symptom improvement and symptom prevention over a one-year period. Ninety-five patients were randomized and 52 (54%) completed the trial. Negative symptoms were reduced with citalopram compared to placebo (p = .04); the effect size of citalopram versus placebo was 0.32 for participants with a duration of untreated psychosis (DUP) of <18 weeks (median split) and 0.52 with a DUP >18 weeks. Rates of new-onset depression did not differ between groups; improvement in depressive symptoms was greater with placebo than citalopram (p = .02). Sexual side effects were more common with citalopram, but overall treatment-emergent side effects were not increased compared to placebo. In conclusion, citalopram may reduce levels of negative symptoms, particularly in patients with longer DUP, but we found no evidence of benefit for subsyndromal depressive symptoms.
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