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.

Inclusion Criteria:

- Currently meeting DSM-IV-TR criteria for Schizotypal Personality Disorder

- Males and Females 18 ≤ age ≤ 60

- Medically and neurologically healthy

- Willing and having capacity to provide informed consent

Exclusion Criteria:

- Currently bipolar I disorder, schizophrenia or current psychosis

- Clinically significant cardiovascular or neurological conditions, uncontrolled
hypertension, clinically significant EKG abnormalities, or serious general medical
illness

- Clinical evidence of dehydration or significant hypotension

- Currently meeting DSM-IV-TR criteria for Major Depressive Disorder

- Current substance abuse or past dependence within the last six months (other than
nicotine)

- Currently taking psychotropic medications

- Currently pregnant or lactating

- Non-English speaking

Socio-economically disadvantaged people will be included in our research study.