Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242

Abstract

There is a need to develop treatments for cognitive impairment associated with schizophrenia (CIAS). The significant role played by N-methyl-d-aspartate receptors (NMDARs) in both the pathophysiology of schizophrenia and in neuronal plasticity suggests that facilitation of NMDAR function might ameliorate CIAS. One strategy to correct NMDAR hypofunction is to stimulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as AMPAR and NMDAR functioning are coupled and interdependent. In rats and nonhuman primates (NHP), AMPAR potentiators reduce spatial working memory deficits caused by the nonselective NMDAR antagonist ketamine. The current study assessed whether the AMPAR potentiator PF-04958242 would attenuate ketamine-induced deficits in verbal learning and memory in humans. Healthy male subjects (n=29) participated in two randomized treatment periods of daily placebo or PF-04958242 for 5 days separated by a washout period. On day 5 of each treatment period, subjects underwent a ketamine infusion for 75 min during which the effects of PF-04958242/placebo were assessed on ketamine-induced: (1) impairments in verbal learning and recall measured by the Hopkins Verbal Learning Test; (2) impairments in working memory on a CogState battery; and (3) psychotomimetic effects measured by the Positive and Negative Syndrome Scale and Clinician-Administered Dissociative Symptoms Scale. PF-04958242 significantly reduced ketamine-induced impairments in immediate recall and the 2-Back and spatial working memory tasks (CogState Battery), without significantly attenuating ketamine-induced psychotomimetic effects. There were no pharmacokinetic interactions between PF-04958242 and ketamine. Furthermore, PF-04958242 was well tolerated. ‘High-impact’ AMPAR potentiators like PF-04958242 may have a role in the treatment of the cognitive symptoms, but not the positive or negative symptoms, associated with schizophrenia. The excellent concordance between the preclinical (rat, NHP) and human studies with PF-04958242, and in silico modeling of AMPAR–NMDAR interactions in the hippocampus, highlights the translational value of this study.

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Acknowledgements

This study was sponsored by Pfizer. We acknowledge the contributions of (1) Angelina Genovese, RNC, MBA; Margaret Dion Marovitz, RN; Elizabeth O’Donnell, RN; Sonah Yoo, RPh; Rachel Galvan, RPh; and Willie Ford of the Neurobiological Studies Unit at the VA Connecticut Healthcare System, West Haven Campus; and (2) of Sylvester Pawlak, MD, and Kristy Macci MSN of the Pfizer Phase 1 Unit, New Haven, CT, as well as Mark Milad, PharmD of Milad Pharmaceutical Consulting and Stacey Boyer, PhD of Pfizer for their central contributions to the success of this project. We also acknowledge the contributions of William Lytton, MD, Professor of Neurology, Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, NY for his oversight of the in silico modeling research presented in this paper.

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Correspondence to M Ranganathan.

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MR has in the past 3 years or currently receives research grant support administered through the Yale University School of Medicine from Insys Therapeutics and Pfizer Inc. BH, JC, SG and MAS report no financial relationships with commercial interests. ND, FG, MMB, CLS, JM and LZ are full-time employees of Pfizer and own and/or hold options and/or restricted stock units for the company’s publicly traded shares. DCD has in the past 3 years or currently receives research grant support administered through Yale University School of Medicine from Pfizer. Pfizer had a role in the design and conduct of the study: collection, management, analysis and interpretation of the data; preparation, review and approval of the manuscript; and the decision to submit the manuscript for publication.

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Ranganathan, M., DeMartinis, N., Huguenel, B. et al. Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242. Mol Psychiatry 22, 1633–1640 (2017). https://doi.org/10.1038/mp.2017.6

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