Negative association between cognitive functioning and antipsychotic D₂ receptor occupancy, affinity, and dose after first episode psychosis

Background. Evidence regarding the effects of antipsychotic medication on cognitive functioning after a first-episode psychosis (FEP) remains inconclusive. This study examined whether dopamine D₂ 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. D₂ receptor occupancy was estimated based on antipsychotic type and dose. Antipsychotics were categorized into partial agonists, or antagonists with high or low D₂ receptor affinity. Linear regression analyses were performed with inverse probability of treatment weighting to control for differences in characteristics between groups. Results. D₂ 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 D₂ 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 D₂ receptor occupancy and affinity for cognitive functioning and suggest better cognitive functioning in users of partial agonists and low D₂ receptor affinity antipsychotics. This can be important when selecting antipsychotics for individuals with FEP.