Five hundred and twenty chronic, withdrawn and apathetic schizophrenic men were selected for 20 weeks of treatment with combined drug therapy. All had been on maintenance doses of chlorpromazine (200-600 mg.) for 2 or more months. Activator drugs were added to chlorpromazine adlibidum in the following maximum daily dosage (or less): dextro-amphetamine, 60 mg.; isocarboxazid and trifluoperazine, 30 mg.; imipramine, 225 mg.; and placebo.Prior to the study and after 4 and 20 weeks of treatment, 462 patients were rated on 17 measures from an interview scale (IMPS) and a ward scale (PRP). Changes after 4 weeks of combined drugs were not impressive. At the end of 20 weeks, every treatment group except dextro-amphetamine improved, including the chlorpromazine-placebo group. None of the drug combinations was superior to chlorpromazine and placebo. Adding dextro-amphetamine increased hostile and paranoid belligerency and thinking disturbance.Only 5% of the patients were dropped from the study because of side effects or complications. Abnormal laboratory tests were also infrequent and evenly distributed among the treatment groups. Trifluoperazine added to chlorpromazine increased the prevalence of extra-pyramidal syndromes, while dextro-amphetamine produced appetite and weight loss. All other treatment groups gained weight, significantly more from adding imipramine and isocarboxazid than from adding trifluoperazine or placebo.Although the present study did not demonstrate substantial benefit from combined drug therapy, the chronicity of the patients and the method of drug administration limit generalization.Abstract Teaser