Depressive signs and symptoms during the course of schizophrenia are common and have been associated with impaired recovery and a higher risk of self-harm. Novel antipsychotic agents introduce new pharmacological avenues that may differentially affect schizophrenic signs and symptoms, including depression. This was a 17-country investigation of 1996 patients with schizophrenia or a related diagnosis randomly assigned to a blinded, comparative trial of the novel antipsychotic agent olanzapine (5-20 mg/d) or the conventional D2 antagonist haloperidol (5-20 mg/d). Patients were evaluated with the Positive and Negative Syndrome Scale, the Montgomery-Asberg Depression Rating Scale, and the Simpson-Angus Rating Scale. The trial consisted of a 6-week and a 46-week masked responder maintenance period. At least moderate depressive signs and symptoms (Montgomery-Asberg Depression Rating Scale score, > or =16) were seen in slightly more than half of this sample. Although both treatments were associated with short-term baseline-to-end point improvement on the Montgomery-Asberg Depression Rating Scale, olanzapine-associated improvements were significantly superior to those observed with haloperidol (P=.001). Furthermore, the response rate for the group receiving olanzapine (> or =50% improvement on the Montgomery-Asberg Depression Rating Scale after at least 3 weeks of treatment) was also significantly higher (P=.008). Analysis demonstrated that improvement in positive, negative, and/or extrapyramidal symptoms was associated with mood improvement (indirect effect); however, most of the olanzapine treatment effect on mood was a primary direct effect (57%) that alone was significantly greater than that seen with haloperidol treatment (P<.001). Depressive signs and symptoms in schizophrenia are responsive to treatment. The pleotrophic pharmacological features of olanzapine, through 1 or more non-D2-mediated pathways, likely contribute to its superior treatment effect. Better control of the mood disorders accompanying schizophrenia holds the possibility for improved patient outcomes.