Negative association between cognitive functioning and antipsychotic D 2 receptor occupancy, affinity, and dose after first episode psychosis

Abstract Background Evidence regarding the effects of antipsychotic medication on cognitive functioning after a first-episode psychosis (FEP) remains inconclusive. This study examined whether dopamine D 2 receptor occupancy, affinity, and antipsychotic dose are related to cognitive functioning in people in remission from FEP. Methods 278 remitted FEP participants from the HAMLETT-trial were included. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia, 3–6 months after remission. D 2 receptor occupancy was estimated based on antipsychotic type and dose. Antipsychotics were categorized into partial agonists, or antagonists with high or low D 2 receptor affinity. Linear regression analyses were performed with inverse probability of treatment weighting to control for differences in characteristics between groups. Results D 2 receptor occupancy was negatively related to global cognition ( β = −0.18), verbal fluency ( β = −0.22), and attention and processing speed ( β = −0.17, all p < 0.003). The interaction between daily dose and D 2 receptor affinity category was significant for global cognition ( p = 0.0046) and working memory ( p = 0.0019), but not for verbal fluency after correction for multiple testing ( p = 0.029). Interactions showed that higher daily dose was related to lower cognitive functioning, with significantly stronger negative effects in high-affinity antagonists compared to other antipsychotics. Conclusions The current findings underscore the importance of antipsychotic D 2 receptor occupancy and affinity for cognitive functioning and suggest better cognitive functioning in users of partial agonists and low D 2 receptor affinity antipsychotics. This can be important when selecting antipsychotics for individuals with FEP.