Effects of antipsychotics on human cognitive function: causal evidence from healthy volunteers following sustained D2/D3 antagonism, D2/D3 partial agonism and placebo

Dopamine D2/D3 receptor modulation with antipsychotics is thought to affect cognitive function, but causal evidence in humans is scant, and largely limited to single administrations. Clarifying this is of importance given the widespread use of antipsychotics, and to understand the role of D2/D3 signalling in human cognition. We therefore conducted a double-blind, placebo-controlled crossover study following sustained administration of either a dopamine D2/D3 receptor antagonist (amisulpride at 400 mg daily) or a D2/D3 partial agonist (aripiprazole at 10 mg daily) to two separate samples of healthy humans (total n = 50) for 7 days per condition. We assessed cognitive function using a computerised visuospatial working memory (VS-WM) task, and sustained attention and response inhibition using the Sustained Attention to Response Task (SART). We found that both amisulpride and aripiprazole caused impairments in VS-WM function compared to placebo on the Balanced Integration Score (amisulpride: p = 0.0079; aripiprazole: p = 0.015). Both antipsychotics impaired VS-WM performance in terms of response latency (amisulpride: p = 5.5 × 10⁻⁷; aripiprazole: p = 0.022), but did not affect response accuracy. Response latency deficits were not correlated with motor impairments induced by either drug, and we also found no effect of either drug on the SART measures, or on subjective alertness, suggesting that D2/D3 antagonism or partial agonism did not cause a generalised cognitive or motor deficit but specifically impaired cognition during VS-WM. This study provides the first causal evidence in healthy humans that working memory function is impaired following either sustained antagonism or partial agonism of D2/D3 receptors by antipsychotic drugs.