Key result
In 77 healthy male volunteers, PF-06412562 (3 or 15 mg twice daily) did not improve cognitive function or motivation/reward processing more than placebo over 5 to 7 days.
Why the study?
Questions remain regarding functions of circuits modulated by dopamine D1 receptors because clinically viable, selective agonists have yet to be tested in humans.
Does PF-06412562 improve cognitive function or motivation/reward processing in healthy male volunteers with low working memory capacity?
RCT (n=77)
Does PF-06412562 improve cognitive function or motivation/reward processing in healthy male volunteers with low working memory capacity?
The selective D1/D5R partial agonist PF-06412562 did not improve cognitive function or motivation/reward processing more than placebo in healthy volunteers.
No benefit in healthy males cautions against cognitive use; challenges D1 agonism hypotheses and leaves open effects in clinical populations.
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.
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Balice‐Gordon et al. (2020) conducted an RCT in Low working memory capacity (n=77). PF-06412562 vs. placebo was evaluated on Working memory, executive function, and motivation/reward processing. In 77 healthy male volunteers, PF-06412562 (3 or 15 mg twice daily) did not improve cognitive function or motivation/reward processing more than placebo over 5 to 7 days.
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