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.

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.

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.

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.

Evidence on psychological side effects (PSEs) of antipsychotic medication after remission from first-episode psychosis (FEP), and their momentary impact on daily life, is limited. This study examined how Dopamine-2 (D2) affinity and antipsychotic dosage relate to momentary PSEs.

This ecological momentary assessment (EMA) study included baseline data from 56 participants in the ongoing Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment (HAMLETT) trial. Momentary mental states indicative of reduced affect intensity, stability, and variability, as well as avolition and mental fatigue, were assessed 10×/day for eight days (N = 3,005 data points). Since these PSEs may result from D2-receptor actions, antipsychotics were classified by receptor affinity and mechanism of action. Multilevel mixed-effects regression models examined serial cross-sectional associations between D2 affinity or dosage and concurrent PSEs, both overall and separately for mornings, daytimes, and evenings.

Higher antipsychotic dosages were associated with reduced affect variability (Beta [B] = −1.40 [95% confidence interval [CI]: −2.52; −0.29]) and decreased positive affect stability (B = 0.23 [95% CI: 0.04; 0.42]) and intensity (B = −1.11 [95% CI: −1.97; −0.24]). The latter was also associated with the use of high-affinity D2 antagonists versus partial D2 agonists (B = 12.98 [95% CI: 2.43; 23.53]) and versus low-affinity D2 antagonists (B = 10.04 [95% CI: 0.59; 19.49]). Other PSEs were not associated with D2 affinity/dosage. Results were relatively consistent across daytimes.

Higher antipsychotic dosage and high-affinity D2 antagonists were associated with decreased positive affect after remission from FEP, which may partly drive the frequently reported blunting of emotional experience.

Cognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes.

204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up.

Three distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present.

Current results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.