A D1 Agonist For Working Memory

A D1 Agonist For Working Memory Enhancement In The Schizophrenia Spectrum

The purpose of the study is to examine the effects of the administration of a drug called DAR-0100A on attention and memory in persons with schizotypal personality disorder (SPD). DAR-0100A has not been FDA approved, however in recent studies has been used to treat cognitive deficits, meaning problems in the way you organize your thinking, in people diagnosed with schizophrenia.

Many people who carry a diagnosis of schizotypal personality disorder have trouble with attention and memory. Increasing the presence of a brain chemical called dopamine has been found to help people with schizophrenia with their attention and memory problems. This study will investigate whether the same is true for people with schizotypal personality disorder by using DAR-0100A, a drug that has been shown to help with the cognitive deficits of people with Parkinson's disease by increasing dopamine effects. Information collected in this experiment may lead to a better understanding of the brain mechanisms involved in schizotypal personality disorder and improve treatments for the psychological problems associated with this condition.

Study Overview

• Status: Completed
• Conditions: Schizotypal Personality Disorder; SPD
• Intervention / Treatment: Drug: DAR 0-100A; Drug: Placebo

Detailed Description

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 (Visit 1) and on the third day of drug/placebo administration (Visit 4). Subjects will return a minimum of two weeks later for Visit 5 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 (Visit 1) and repeat cognitive testing (Visit 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 (accuracy scores for AX, AY and BX and ANOVA), the N-back (delta difference 0-back-2-back), and the Paced Auditory Serial Addition Task (PASAT) (% correct and ANOVA). Other tests included are tests of working and verbal memory, executive function, and verbal learning for secondary outcome measures as well as comparison tests not hypothesized to change with drug.
2. To compare changes on the primary outcome measures from baseline to Visit 4 testing between drug and placebo administration in SPD subjects.
3. To compare primary outcome variables from baseline to Visit 4 between patients groups and healthy controls.
4. To obtain plasma DAR-0100A concentrations on Visit 4 to evaluate plasma concentrations in relation to cognitive changes as a potential covariate.

Secondary Aims:

1. To evaluate the change between baseline and Visit 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 Visit 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).

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Currently meeting DSM-IV-TR criteria for Schizotypal
• Personality Disorder
• Males and Females 18 ≤ age ≤ 65
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DAR 0-100A then Placebo; 15 mg is dissolved in 150 cc NS administered over 30 minutes x 3 consecutive days. Subjects will return a minimum of two weeks later for Visit 5 to receive drug (if randomized initially to placebo) or placebo (if randomized to drug).	Drug: DAR 0-100A; 15 mg DAR 0100A is dissolved in 150 cc NS administered over 30 minutes intravenously.; Other Names: DHX; dihydrexidine; Drug: Placebo; 15 mg DAR placebo is dissolved in 150 cc NS administered over 30 minutes intravenously.
Placebo Comparator: Placebo then DAR 0-100A; 15 mg dissolved in 150 cc NS saline is administered over 30 minutes x 3 consecutive days. Subjects will return a minimum of two weeks later for Visit 5 to receive drug (if randomized initially to placebo) or placebo (if randomized to drug).	Drug: DAR 0-100A; 15 mg DAR 0100A is dissolved in 150 cc NS administered over 30 minutes intravenously.; Other Names: DHX; dihydrexidine; Drug: Placebo; 15 mg DAR placebo is dissolved in 150 cc NS administered over 30 minutes intravenously.
No Intervention: Healthy Control; patients without diagnosis of SPD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Modified AX-CPT (d')	A cognitive test of working memory	Baseline performance

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Modified AX-CPT (d')	A cognitive test of working memory	Day one
The Modified AX-CPT (d')	A cognitive test of working memory	Day three
The Modified AX-CPT (d')	A cognitive test of working memory	One month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
the N-Back	A cognitive tests of working memory - the N-Back (% correct at the 2-back condition)	Baseline
the N-Back	A cognitive tests of working memory - the N-Back (% correct at the 2-back condition)	Day one
the N-Back	A cognitive tests of working memory - the N-Back (% correct at the 2-back condition)	Day three
the N-Back	A cognitive tests of working memory - the N-Back (% correct at the 2-back condition)	One month
the DOT Task	A cognitive tests of working memory - the DOT Task (distance error at 30 second delay--no delay)	Baseline
the DOT Task	A cognitive tests of working memory - the DOT Task (distance error at 30 second delay--no delay)	Day one
the DOT Task	A cognitive tests of working memory - the DOT Task (distance error at 30 second delay--no delay)	Day three
the DOT Task	A cognitive tests of working memory - the DOT Task (distance error at 30 second delay--no delay)	One month
the Paced Auditory Serial Addition Task (PASAT)	A cognitive tests of working memory - the Paced Auditory Serial Addition Task	Baseline
the Paced Auditory Serial Addition Task (PASAT)	A cognitive tests of working memory - the Paced Auditory Serial Addition Task	Day one
the Paced Auditory Serial Addition Task (PASAT)	A cognitive tests of working memory - the Paced Auditory Serial Addition Task	Day three
the Paced Auditory Serial Addition Task (PASAT)	A cognitive tests of working memory - the Paced Auditory Serial Addition Task	One month

Collaborators and Investigators

• Sponsor: Antonia New
• Collaborators: National Institute of Mental Health (NIMH); New York State Psychiatric Institute
• Investigators: Principal Investigator: Antonia S. New, MD, Icahn School of Medicine at Mount Sinai

Publications and helpful links

General Publications

• Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS. Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl). 1994 Oct;116(2):143-51. doi: 10.1007/BF02245056.
• Abi-Dargham A. Probing cortical dopamine function in schizophrenia: what can D1 receptors tell us? World Psychiatry. 2003 Oct;2(3):166-71.
• Castner SA, Williams GV, Goldman-Rakic PS. Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science. 2000 Mar 17;287(5460):2020-2. doi: 10.1126/science.287.5460.2020.
• Fici GJ, Wu H, VonVoigtlander PF, Sethy VH. D1 dopamine receptor activity of anti-parkinsonian drugs. Life Sci. 1997;60(18):1597-603. doi: 10.1016/s0024-3205(97)00126-4.
• Kirrane RM, Mitropoulou V, Nunn M, New AS, Harvey PD, Schopick F, Silverman J, Siever LJ. Effects of amphetamine on visuospatial working memory performance in schizophrenia spectrum personality disorder. Neuropsychopharmacology. 2000 Jan;22(1):14-8. doi: 10.1016/S0893-133X(99)00075-5.
• Koenigsberg HW, Reynolds D, Goodman M, New AS, Mitropoulou V, Trestman RL, Silverman J, Siever LJ. Risperidone in the treatment of schizotypal personality disorder. J Clin Psychiatry. 2003 Jun;64(6):628-34. doi: 10.4088/jcp.v64n0602.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): January 12, 2018
• Study Completion (Actual): January 12, 2018

Study Registration Dates

• First Submitted: July 22, 2015
• First Submitted That Met QC Criteria: July 22, 2015
• First Posted (Estimate): July 23, 2015

Study Record Updates

• Last Update Posted (Actual): April 9, 2018
• Last Update Submitted That Met QC Criteria: April 5, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Dementia; Mental Disorders; Cognition Disorders; Delirium; cognitive impairment; Amnestic; working memory; schizotypal personality disorder; Dopamine Agonists; Personality Disorders; Cognitive Disorders; Dihydrexidine; Dopamine A
• Additional Relevant MeSH Terms: Mental Disorders; Personality Disorders; Schizotypal Personality Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Dopamine Agonists; Dopamine Agents; Dihydrexidine
• Other Study ID Numbers: GCO 11-1279; 5R01MH097799-02 (U.S. NIH Grant/Contract)