title: A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia.
abstract: Evidence from preclinical and human studies indicates the presence of reduced dopamine-1 receptor (D1R) signaling in the cortex, where D1Rs predominate, in patients with schizophrenia (SCZ), which may contribute to their cognitive deficits. Furthermore, studies in nonhuman primates (NHP) have suggested that intermittent administration of low doses of D1R agonists produce long-lasting reversals in cognitive deficits. The purpose of this trial was to test whether a similar design, involving subacute intermittent administration of low doses of a full, selective agonist at D1Rs, DAR-0100A, would improve cognitive deficits in SCZ.
  
  
  
  We randomized 49 clinically stable individuals with SCZ to three weeks of intermittent treatment with 0.5 mg or 15 mg of DAR-0100A, or placebo (normal saline). Functional magnetic resonance imaging (fMRI) BOLD was used to evaluate the effects of drug administration on brain activity during a working memory (WM) task. Effects on cognition were also assessed using the MATRICS and the N-back task as primary endpoints. The CogState battery was used as a secondary endpoint.
  
  
  
  There were no observed treatment effects on either the BOLD fMRI signal during WM tasks or the WM domains of the MATRICS. Moderate improvement was detected on the CogState battery and on the attention domain of the MATRICS.
  
  
  
  These results suggest that low doses of D1 agonists that do not result in measureable occupancy of the D1R do not reliably improve cognition in SCZ, unlike the observations in NHP. As this drug is limited by its pharmacokinetic profile, better D1R agonists that can achieve adequate levels of D1R occupancy are needed to test the efficacy of this mechanism for cognitive enhancement in SCZ.
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Ragy R
authors.initials: RR
authors.lastname: Girgis
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Jared X
authors.initials: JX
authors.lastname: Van Snellenberg
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Glass
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kegeles
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA Rutgers University, New Brunswick, NJ, USA.
authors.forename: Judy L
authors.initials: JL
authors.lastname: Thompson
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wall
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Cho
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of California-Davis, Sacramento, CA, USA.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Carter
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA Department of Radiology, Columbia University, New York, NY, USA.
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA jlieberman@nyspi.columbia.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001288:Attention / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000627:therapeutic use*; D010617:Phenanthridines / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018697:Nootropic Agents; D010617:Phenanthridines; D017447:Receptors, Dopamine D1; C061532:dihydrexidine; D004298:Dopamine
keywords: DAR-0100A; cognitive enhancement; dopamine-1 agonist; randomized controlled trial; schizophrenia