PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action?

Frank S Menniti,Thomas A Chappie,Christopher J Schmidt

doi:10.3389/fnins.2020.600178

Frank S Menniti, Thomas A Chappie + Show 1 more

Open Access

https://doi.org/10.3389/fnins.2020.600178

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Abstract

PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.

Highlights

Dopamine D2 receptor antagonists have been the standard of care pharmacotherapy for the treatment of psychosis in schizophrenia since the 1950’s
We review the data on phosphodiesterase 10A (PDE10A) inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia
We review what is known about the role of PDE10A in regulating cyclic nucleotide signaling in medium spiny neurons (MSNs)

Summary

INTRODUCTION

Dopamine D2 receptor antagonists have been the standard of care pharmacotherapy for the treatment of psychosis in schizophrenia since the 1950’s. The effects of the PDE10A inhibitors were compared to antipsychotic dopamine D2 receptor antagonists and in some paradigms the effects of these two classes of compounds were very similar This similarity is consistent with the physiological data reviewed above indicating a biased efficacy of PDE10A inhibition for activation of indirect pathway MSNs, i.e., those expressing dopamine D2 receptors. These observations served as a significant part of the rationale for advancing PDE10A inhibitors into clinical trials for the treatment of psychosis in schizophrenia. As stated by Papa and colleagues—“MP-10- treated animals retained the ability to respond but did not engage tasks, whereas risperidone-treated animals retained the motivation to respond but were unable to perform the intended actions.”

DISCUSSION

Failure to suppress acute psychosis

SUMMARY AND CONCLUSION