Differential effect of amisulpride on cognition in schizotypy: validation of models for the early identification of cognitive enhancing agents

Abstract Background The cognitive impairment associated with schizophrenia is a major target for drug development but none of the drugs designed to address this problem has shown consistent efficacy. The most common causes for failure in the registration trials could be preempted by testing novel agents in milder forms of the disorder, such as schizotypy and assessing the effect with validated biomarkers. In this study we aimed to test this approach by comparing the effects of risperidone, amisulpride, and nicotine in a double-blind placebo-controlled three-centre study on the cognitive performance in schizotypy. Methods We recruited healthy volunteers who scored high and average on the Schizotypal Personality Questionnaire (122 in each group). 244 participants were randomised to an acute dose of risperidone (n=62, capsule plus placebo patch), amisulpride (n=62, capsule plus placebo patch), nicotine (n=61, placebo capsule plus nicotine patch), or placebo (n=59, placebo capsule plus placebo patch) and proceeded to complete cognitive tests (n-back, verbal fluency, and spatial working memory tasks). Primary outcome measures were percentage correct, errors of commission, and response latencies (n-back), number of correct words and category transitions (verbal fluency), and between-search and within-search errors (spatial working memory tasks). This trial has not been registered. Findings We found evidence for worse performance in the high schizotypy group on the n-back and verbal fluency tasks (p 2 =0·059 and p 2 =0·064, respectively). Amisulpride had a differential effect on the two groups in respect to these two tasks (p=0·02 and p=0·04, respectively): it improved performance in the high schizotypy group but impaired the controls. By contrast, risperidone impaired both groups while nicotine had a beneficial effect for the low baseline performers. There was a statistically significant increase in the reaction time latency in the n-back task in the risperidone arm compared with all other arms. Interpretation We attribute the effects of amisulpride to its presynaptic dopamine enhancing action at low doses. The deterioration of performance with risperidone on the other hand was probably due to sedation while nicotine showed signs of general vigilance improvement. Our findings confirm that cognitive abnormalities in schizotypy are replicable in multisite studies and responsive to drug challenges. Importantly, these results underline the importance of dopamine agonism in the pathophysiology of the cognitive deficits in the schizophrenia spectrum disorders. Funding P1vital Ltd.