Clinical Testing of a D1 Agonist for Cognitive Enhancement in Schizotypal Personality Disorder

Working memory deficits are central to the cognitive impairment of schizophrenia and other psychiatric disorders. The D1 receptor (D1R) is probably the best established mediator of working memory in neuroscience studies for over three decades and represents a highly promising therapeutic target for enhancing working memory in these disorders, yet this mechanism has never been tested in humans. Schizotypal personality disorder (SPD) patients who evidence moderate, focal impairments in working memory represent a unique population to test the effect of a D1 agonist on working memory impairment in humans. Cognitive impairment is the most salient predictor of functional outcome in schizophrenia (SCZ) and is essentially refractory to conventional treatments. Identifying pharmacologic agents that target the cognitive deficits of SCZ is thus the top priority in SCZ research, but so far, clinical trials of a number of drugs with preclinical promise have yielded disappointing results. Currently, no study to date has directly tested a selective D1R agonist in relation to the cognitive impairment of SCZ without the confound of neuroleptics. The investigators propose to examine the efficacy of DAR-0100A, a highly selective, full D1R agonist supported by pre-clinical and preliminary pilot clinical data, in ameliorating the cognitive deficits in SPD subjects receiving no medications including antipsychotics. SPD will be classified as a schizophrenic disorder in DSM-5 and ICD-10. The investigators have characterized the cognitive deficits of SPD and demonstrated that, as with chronic SCZ, a core component consists of impairments in working memory. Studies of SPD obviate confounds associated with SCZ, such as the effects of overt psychotic episodes, medication history, severe, persistent functional impairment and multiple treatments. Furthermore, the cognitive deficits of SPD are less global and more readily reversible than those of chronic SCZ, providing a unique opportunity to test the D1 mechanism of cognitive enhancement. DAR-0100A, which is the active enantiomer of dihydrexidine (DHX), is a full D1R agonist with a10-60 fold selectivity over the D2R. DHX administration improves cognition in single doses in young adult and aged monkeys and rodents. A single treatment with DAR-0100A in adult humans with SCZ was demonstrated to enhance prefrontal perfusion. Pilot data from our group and Columbia suggest DAR-0100A improves cognitive performance, particularly working memory, in the schizophrenia spectrum.

Primary Aims: 1. To perform a 5-year study in which three consecutive days of DAR-0100A at a dose of 15 mg or placebo are administered intravenously over 30 minutes to 60 patients with SPD (12/yr) in a between-groups, randomized, double-blind design. Cognitive testing will be performed at baseline (Day 1) and on the third day of drug/placebo administration (Day 4). Subjects will return at Day 15 to receive drug (if randomized initially to placebo) or placebo (if randomized to drug) in a double blind fashion in an identical protocol. This allows all patients to receive drug for Secondary Aim 1 while maintaining the blind. Baseline (Day 1) and repeat cognitive testing (Day 4) is also administered to 60 healthy controls per year (12/yr). The cognitive tests of working memory serving as primary outcome measures will include the modified AX-CPT (d'), the N-back (% correct at the 2-back condition), the DOT Task (distance error at 30 second delay - no delay), and the Paced Auditory Serial Addition Task (PASAT)( correct responses). The investigators will also include other tests of memory, executive function, and verbal learning for secondary outcome measures (see Methods) as well as comparison tests not hypothesized to change with drug: the Benton line orientation test (JLOT) and the Trail Making Test A. 2. To compare changes on the primary outcome measures from baseline to Day 4 testing between drug and placebo administration in SPD subjects. 3. To compare primary outcome variables at baseline and change from baseline to Day 4 testing between patients groups and healthy controls. 4. To obtain plasma DHX concentrations on Day 4 to evaluate plasma concentrations in relation to cognitive changes as a potential covariate.

Secondary Aims: 1. To evaluate the change between baseline and Day 4 cognitive testing in all SPD patients receiving drug in the first or second phase. 2. To evaluate secondary outcome and comparison variables between SPD patients on placebo and drug.

Primary Hypotheses: 1. Baseline primary outcome measures will be impaired in SPD subjects compared to controls. 2. SPD subjects on DAR-0100A 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 comparis¬on perceptual (JLOT) and processing speed/attentional tasks (Trails A).

It is critical to establish efficacy for cognitive enhancement with a selective D1 agonist in a schizophrenic disorder with cognitive impairment and without concomitant neuroleptic treatment to provide momentum for these efforts. The more readily reversible cognitive impairment of SPD provides a unique opportunity for this critical study of the D1 hypothesis to pave the way for development for more severe schizophrenic disorders with their inevitable complicating artifacts.