Dopamine D2 Receptor Occupancy and Cognition in Schizophrenia: Analysis of the CATIE Data

Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D-2 receptors in the treatment of schizophrenia. However, effects of D-2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D-2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D-2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D-2 occupancy levels, on neurocognitive functions. Results: D-2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D-2 receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that 1)2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.