A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia

Ragy R. Girgis, Jared X. Van Snellenberg, Andrew Glass, Lawrence S. Kegeles, Judy L. Thompson, Melanie Wall, Raymond Y. Cho, Cameron S Carter, Mark Slifstein, Anissa Abi-Dargham, Jeffrey A. Lieberman

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)428-435
Number of pages8
JournalJournal of Psychopharmacology
Volume30
Issue number5
DOIs
StatePublished - 2016

Fingerprint

Dopamine Agonists
Schizophrenia
Randomized Controlled Trials
Dopamine Receptors
Short-Term Memory
Cognition
Primates
Magnetic Resonance Imaging
Pharmaceutical Preparations
Pharmacokinetics
Placebos
dihydrexidine
Brain
Therapeutics

Keywords

  • cognitive enhancement
  • DAR-0100A
  • dopamine-1 agonist
  • randomized controlled trial
  • schizophrenia

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Girgis, R. R., Van Snellenberg, J. X., Glass, A., Kegeles, L. S., Thompson, J. L., Wall, M., ... Lieberman, J. A. (2016). A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia. Journal of Psychopharmacology, 30(5), 428-435. https://doi.org/10.1177/0269881116636120

A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia. / Girgis, Ragy R.; Van Snellenberg, Jared X.; Glass, Andrew; Kegeles, Lawrence S.; Thompson, Judy L.; Wall, Melanie; Cho, Raymond Y.; Carter, Cameron S; Slifstein, Mark; Abi-Dargham, Anissa; Lieberman, Jeffrey A.

In: Journal of Psychopharmacology, Vol. 30, No. 5, 2016, p. 428-435.

Research output: Contribution to journalArticle

Girgis, RR, Van Snellenberg, JX, Glass, A, Kegeles, LS, Thompson, JL, Wall, M, Cho, RY, Carter, CS, Slifstein, M, Abi-Dargham, A & Lieberman, JA 2016, 'A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia', Journal of Psychopharmacology, vol. 30, no. 5, pp. 428-435. https://doi.org/10.1177/0269881116636120
Girgis, Ragy R. ; Van Snellenberg, Jared X. ; Glass, Andrew ; Kegeles, Lawrence S. ; Thompson, Judy L. ; Wall, Melanie ; Cho, Raymond Y. ; Carter, Cameron S ; Slifstein, Mark ; Abi-Dargham, Anissa ; Lieberman, Jeffrey A. / A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia. In: Journal of Psychopharmacology. 2016 ; Vol. 30, No. 5. pp. 428-435.
@article{091ec40bc4934424881739806d5f334c,
title = "A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia",
abstract = "Background: 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. Methods: 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. Results: 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. Conclusion: 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.",
keywords = "cognitive enhancement, DAR-0100A, dopamine-1 agonist, randomized controlled trial, schizophrenia",
author = "Girgis, {Ragy R.} and {Van Snellenberg}, {Jared X.} and Andrew Glass and Kegeles, {Lawrence S.} and Thompson, {Judy L.} and Melanie Wall and Cho, {Raymond Y.} and Carter, {Cameron S} and Mark Slifstein and Anissa Abi-Dargham and Lieberman, {Jeffrey A.}",
year = "2016",
doi = "10.1177/0269881116636120",
language = "English (US)",
volume = "30",
pages = "428--435",
journal = "Journal of Psychopharmacology",
issn = "0269-8811",
publisher = "SAGE Publications Ltd",
number = "5",

}

TY - JOUR

T1 - A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia

AU - Girgis, Ragy R.

AU - Van Snellenberg, Jared X.

AU - Glass, Andrew

AU - Kegeles, Lawrence S.

AU - Thompson, Judy L.

AU - Wall, Melanie

AU - Cho, Raymond Y.

AU - Carter, Cameron S

AU - Slifstein, Mark

AU - Abi-Dargham, Anissa

AU - Lieberman, Jeffrey A.

PY - 2016

Y1 - 2016

N2 - Background: 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. Methods: 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. Results: 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. Conclusion: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusion: 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.

KW - cognitive enhancement

KW - DAR-0100A

KW - dopamine-1 agonist

KW - randomized controlled trial

KW - schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=84964355629&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964355629&partnerID=8YFLogxK

U2 - 10.1177/0269881116636120

DO - 10.1177/0269881116636120

M3 - Article

C2 - 26966119

AN - SCOPUS:84964355629

VL - 30

SP - 428

EP - 435

JO - Journal of Psychopharmacology

JF - Journal of Psychopharmacology

SN - 0269-8811

IS - 5

ER -