Many published guidelines (including the American Psychiatric Association Clinical Practice Guidelines for schizophrenia), recommend second-generation antipsychotics for the treatment of depression in schizophrenia. This study compared a first-generation antipsychotic (perphenazine) with 4 second-generation antipsychotics (olanzapine, quetiapine, risperidone, and ziprasidone) and the impact these drugs had on the symptoms of depression.  The authors used data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) randomised controlled trial, which was conducted between January 2001 and December 2004.

Patients with DSM-IV-defined schizophrenia (N = 1,460) were given perphenazine or one of the 4 second-generation drugs (olanzapine, quetiapine, risperidone, or ziprasidone) and followed for up to 18 months (phase 1). Patients with tardive dyskinesia were excluded from the randomization that included perphenazine. The Calgary Depression Scale for Schizophrenia (CDSS) was used to assess depression severity. Group differences during treatment with the first drug patients received were measured using mixed models. An interaction analysis evaluated differences in drug response by whether patients had a baseline score on the CDSS of ≥ 6, indicative of a current major depressive episode.

Patients taking all drugs saw significant improvement in depression, but the study found no significant differences between the first and second generation antipsychotics on phase 1 analysis. A significant interaction was found between treatment and experiencing a major depressive episode at baseline (P = .05), and further paired comparisons suggested that quetiapine was superior to risperidone among patients who were in a major depressive episode at baseline (P = .0056).

The research team concluded:

We found no differences between any second-generation antipsychotic and the first-generation antipsychotic perphenazine and no support for the clinical practice recommendation, but we did detect a signal indicating a small potential difference favoring quetiapine over risperidone only in patients with a major depressive episode at baseline.

Addington DE, Mohamed S, Rosenheck RA, Davis SM, Stroup TS, McEvoy JP, Swartz MS, Lieberman JA. Impact of second-generation antipsychotics and perphenazine on depressive symptoms in a randomized trial of treatment for chronic schizophrenia. J Clin Psychiatry. 2011 Jan;72(1):75-80. Epub 2010 Sep 21. [PubMed abstract]