T38. DOPAMINE ENHANCEMENT OF VERBAL LEARNING IN THE SCHIZOPHRENIA SPECTRUM

Abstract

Background: Cognitive impairment is a prominent feature that is closely linked to functional outcome in schizophrenia-spectrum patients, such as those with schizotypal personality disorder (SPD). Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate these cognitive deficits, although there have been few controlled experiments of this mechanism. Methods: Twenty-seven medication-free patients with SPD who demonstrated cognitive impairment (i.e., scoring more than 1 SD below healthy control means of measures of cognition) were enrolled in a randomized, double-blind, placebo-controlled trial of the full D1 receptor agonist, dihydrexidine (DAR-0100A; 15 mg/150 ml of normal saline administered intravenously over 30 min). We administered the MATRICS Clinical Consensus Battery (MCCB) during drug/placebo infusion. Using a crossover design, study procedures occurred over four consecutive days, with MCCB testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4; administration of drug/placebo order was randomly assigned, with 14 participants receiving DAR-0100A first. Results: Compared with cognitive performance during placebo, administration of DAR-0100A was associated with significantly better verbal learning (HVLT score, F(1, 24)=5.1,p=.03). DAR-0100A was adequately tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, e.g., co-administered normal saline. Discussion: These findings lend further clinical support to the potential D1 receptor agonists to treat cognitive impairments in schizophreniaspectrum disorders. Future research, including in schizophrenia samples, is warranted.