A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity
| Autor: | Gabriel H Braley, Rita Balice-Gordon, Zhiyong Xie, Melissa Naylor, Brian T. Harel, Wenlei Liu, Rouba Kozak, Lovingly Park, Estibaliz Arce, Garry D. Honey, David Gray, Sridhar Duvvuri, Christopher H. Chatham, Nicholas DeMartinis |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male medicine.medical_specialty AcademicSubjects/MED00415 Adolescent dopamine signaling dopamine D1 receptor D1R agonist low working memory Placebo Partial agonist Regular Research Articles 050105 experimental psychology Drug Administration Schedule 03 medical and health sciences Executive Function Young Adult 0302 clinical medicine Physical medicine and rehabilitation Cognition motivation Double-Blind Method Medicine Humans 0501 psychology and cognitive sciences Pharmacology (medical) Receptors Dopamine D5 Adverse effect reward Pharmacology business.industry Working memory AcademicSubjects/SCI01870 Receptors Dopamine D1 05 social sciences Brain Middle Aged Magnetic Resonance Imaging Healthy Volunteers Discontinuation Drug Partial Agonism Psychiatry and Mental health Memory Short-Term Tolerability Dopamine receptor Dopamine Agonists business 030217 neurology & neurosurgery |
| Zdroj: | International Journal of Neuropsychopharmacology |
| ISSN: | 1469-5111 1461-1457 |
| Popis: | BackgroundDopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans.MethodsUsing a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons.ResultsNominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562–treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate.ConclusionsPF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period.ClinicalTrials.gov IdentifierNCT02306876 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|