ABSTRACT: Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well 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, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.
