Cognitive deficits, particularly impairments in working memory and executive function, are a core problem of schizophrenia-spectrum conditions, as well as other serious psychiatric disorders (e.g., bipolar disorder, attention-deficit disorder). Moreover, working memory and executive function impairments predict functional outcomes, particularly in the schizophrenia-spectrum; however, conventional therapeutics have limited benefit for cognitive impairments, and, recent clinical trials of agents with preclinical promise have had disappointing results. We propose here to examine the effects of DAR-0100A -- a highly selective, full, dopamine-1 receptor (D1R) agonist -- on working memory impairments in patients with schizotypal personality disorder (SPD). SPD is a schizophrenia- spectrum condition that manifests a moderate and specific impairment in working memory, and related cognitive functions, which we have demonstrated can be reversibly ameliorated with dopaminergic agents, such as pergolide (a mixed D1/D2 receptor agonist) and amphetamine. An abundance of basic and preclinical neuroscientific data indicate the D1R is a highly promising pharmacological target to enhance working memory impairments in models of schizophrenia and aging. Currently, however, no published clinical human studies have evaluated a selective D1R agonist as a therapeutic agent for cognitive impairments of psychiatric disorders. We propose here to perform a 5-year, randomized, double-blind, placebo-controlled study in which DAR-0100A is administered intravenously at a dose of 15 mg over 30 minutes to 60 patients with SPD. Cognitive tests will be administered at baseline (Day 1) and on the third day of drug/placebo administration (Day 4). On Day 15, participants will return to repeat this sequence, but placed in a double-blind manner on the opposite agent (drug or placebo) initially administered. Cognitive testing, only, (i.e., no drug/placebo administration) will be performed on Day 1 and 4 to 60 healthy control participants. Primary outcome measures will consist of the following cognitive tests: modified AX-CPT, N-back, and Paced Auditory Serial Addition Task. Other cognitive tests of memory, executive function, and verbal learning will also be administered, as secondary outcome measures; and, comparison tests, not hypothesized to change with DAR-0100A treatment will also be given: Benton Judgment of Line Orientation Test (JLOT) and the Trail Making Test-A. We hypothesize that: 1. Baseline primary outcome measures will be impaired in SPD patients compared to controls. 2. SPD subjects on DAR100A will show improvement on primary measures greater than healthy controls and SPD patients randomized to placebo between baseline and Day 4. 3. SPD patients will show significant improvements on primary outcome variables on drug compared to placebo but not on comparison on perceptual (JLOT) and processing speed tasks (Trails A).
Functional outcomes in schizophrenia and related conditions are closely tied to impairments in working memory and executive function. SPD patients, who have less confounding variable and more readily reversible deficits than schizophrenia patients, appear an optimal population for studying proof of mechanism aimed at cognitive enhancement. Demonstrating, in human studies, proof-of-mechanism efficacy of DAR- 0100A -- a dopamine-1 receptor (D1R) agonist -- on working memory impairments in the schizophrenia spectrum will further catalyze research into a D1R-paradigm of working memory therapeutics and pathophysiology, and accelerate industry development of D1R agents that are better suited to routine clinical administration.
