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

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.

Modulating D1 rather than D2 receptor-expressing spiny-projection neurons corresponds to optimal antipsychotic effect

“…Next we asked whether we could use these dynamics to distinguish between three antipsychotic drugs with different clinical efficacies and side-effect profiles. We compared clozapine, a highly efficacious antipsychotic with few motor side effects, to haloperidol, a moderately efficacious antipsychotic with a high motor side effect propensity, and MP-10, an antipsychotic drug candidate that recently failed in a clinical trial for schizophrenia 26,27 .…”

“…Given the strong linkage between striatal D2R binding and antipsychotic effect, MP-10 was predicted to be antipsychotic, with possibly fewer of the adverse effects associated with brain-wide D2R antagonism. Although this prediction is logical within a receptor-symptom conceptual framework, MP-10 had no antipsychotic effect in patients with schizophrenia 9 .…”

“…Initially we sought to use this readout to determine whether we could distinguish between antipsychotic drugs or drug candidates with varying clinical efficacies and side-effect profiles. Specifically, we compared two effective antipsychotics (clozapine and haloperidol) and one ineffective antipsychotic drug candidate (MP-10) 9,21 . Presently, the different efficacies and side-effect propensities of antipsychotic drugs are best understood by their different brain receptor binding profiles 22 .…”

Pivotal role of phosphodiesterase 10A in the integration of dopamine signals in mice striatal D1 and D2 medium‐sized spiny neurones

“…This D 2 /D 1 imbalance was consistent with PDE10A inhibitors mimicking the D 2 antagonistic action of antipsychotic agents. PDE10A inhibition has therefore been largely studied as a therapeutic strategy for the treatment of schizophrenia or Huntington's disease (Chappie et al, 2009;Harada et al, 2020;Kehler et al, 2007;Kehler & Nielsen, 2011;Menniti et al, 2007Menniti et al, , 2020Schülke & Brandon, 2017). While clinical results did not confirm these expectations, a better understanding of PDE10A involvement in dopamine action may eventually reveal the cellular underpinnings of schizophrenia (Menniti et al, 2020).…”

Cellular context shapes cyclic nucleotide signaling in neurons through multiple levels of integration

“…This D2/D1 imbalance was consistent with PDE10A inhibitors mimicking the D2 antagonistic action of antipsychotic agents, which had sparked considerable interest in PDE10A as a potential therapeutic target to treat schizophrenia (Kehler and Nielsen, 2011;Schülke and Brandon, 2017;Harada et al, 2020). So far, this hope has not met clinical success (Menniti et al, 2020), possibly because inhibiting such an essential signaling enzyme profoundly destabilizes signal integration in MSNs (Mota et al, 2021). Compared to PDE10A, PDE2A and PDE4 display much lower affinity for cAMP and therefore preferentially regulate high cAMP concentration.…”