A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity

Rita Balice-Gordon, Garry D Honey, Christopher Chatham, Estibaliz Arce, Sridhar Duvvuri, Melissa Graham Naylor, Wenlei Liu, Zhiyong Xie, Nicholas DeMartinis, Brian T Harel, Gabriel H Braley, Rouba Kozak, Lovingly Park, David L Gray, Rita Balice-Gordon, Garry D Honey, Christopher Chatham, Estibaliz Arce, Sridhar Duvvuri, Melissa Graham Naylor, Wenlei Liu, Zhiyong Xie, Nicholas DeMartinis, Brian T Harel, Gabriel H Braley, Rouba Kozak, Lovingly Park, David L Gray

Abstract

Background: Dopamine 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.

Methods: Using 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.

Results: Nominally 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.

Conclusions: PF-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 identifier: NCT02306876.

Keywords: dopamine D1 receptor D1R agonist; dopamine signaling; low working memory; motivation; reward.

© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Study design: planned 2-stage approach. POM, proof of mechanism.
Figure 2.
Figure 2.
Hypothetical target occupancy profile achieved following the dosing paradigm. IR, immediate release; MR, modified release.
Figure 3.
Figure 3.
Assessment schedule. CBS, Cambridge Brain Sciences; fMRI, functional magnetic resonance imaging; F/U, follow-up; HV, healthy volunteer; I/E, inclusion/exclusion.

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