Antipsychotic Drugs May Improve Neurocognition in Patients With Chronic Schizophrenia

After 2 months of treatment with various antipsychotic drugs, patients with chronic schizophrenia had small but significant improvements in neurocognition, according to the results of a randomized, double-blind study reported in the May issue of the Archives of General Psychiatry.

"Neurocognitive impairment in schizophrenia is severe and is an important predictor of functional outcome," write Richard S.E. Keefe, PhD, and colleagues from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators and the Neurocognitive Working Group. "The relative effect of the second-generation (atypical) antipsychotic drugs and older agents on neurocognition has not been comprehensively determined."

The objective of this study was to compare the neurocognitive effects of several second-generation antipsychotics (olanzapine, quetiapine fumarate, or risperidone) and a first-generation antipsychotic, perphenazine, used for up to 18 months. After its approval by the US Food and Drug Administration, the second-generation antipsychotic, ziprasidone hydrochloride, was also included.

Of 1493 patients randomized to treatment at 57 academic sites and treatment mental health facilities, 817 completed neurocognitive testing immediately before randomization and then after 2 months of treatment. The main endpoint was change in a neurocognitive composite score after 2 months of treatment, and secondary outcome measures included neurocognitive composite score change at 6 and 18 months after continued treatment, and changes in neurocognitive domains.

At 2 months, treatment resulted in small neurocognitive improvements: z = 0.13 for olanzapine (P < .002), z = 0.25 for perphenazine (P < .001), z = 0.18 for quetiapine (P < .001), z = 0.26 for risperidone (P < .001), and z = 0.12 for ziprasidone (P < .06). There were no significant differences between groups, and results were similar at 6 months.

Neurocognitive improvement after 18 months of treatment was greater in the perphenazine group than in the olanzapine and risperidone groups. In patients treated with quetiapine or ziprasidone, neurocognitive improvement predicted longer time to treatment discontinuation, independent of symptom improvement.

"After 2 months of antipsychotic treatment, all groups had a small but significant improvement in neurocognition," the authors write. "There were no differences between any pair of agents, including the typical drug perphenazine. These results differ from the majority of previous studies."

The authors further note that the lack of a neurocognitive advantage for second-generation antipsychotics in this study suggests that the positive findings from earlier studies may not generalize well to the type of everyday clinical practice studied in the CATIE trial. Differing results may be explained in part by methodologic differences between the studies.

Study limitations include exclusion of patients with schizoaffective disorder, those with only 1 schizophrenic episode, or those who had adverse reactions to any of the treatments or were treatment resistant, limiting generalizability; randomization precluding assignment of a medication known to be more effective for certain subgroups of patients; randomization scheme preventing patients with tardive dyskinesia from receiving treatment with perphenazine; only 56% of the 1460 patients in the trial generated neurocognitive data at baseline and only 303 patients (21%) generated neurocognitive data after having been treated with the same antipsychotic for 18 months; and the possibility that neurocognitive improvement was related solely to practice effects or expectation bias.

"The small but statistically significant associations between symptomatic and cognitive improvement in the CATIE trial are consistent with the idea that decreases in distress and psychopathologic features lead to enhanced performance," R. Walter Heinrichs, PhD, from York University in Toronto, Ontario, Canada, writes in an accompanying commentary. "Therefore, many avenues of influence may exist, some related to the psychological and biological conditions that optimize or reduce performance and others involving the neural operations underlying performance itself. The unselective and modest cognitive effects of existing medications are a spur to the exploration of these avenues and hence to the discovery of more powerful and focused treatments for schizophrenia."