ReviewFrontiers in neuroscience2020
PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action?
Review in Frontiers in neuroscience, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed, 48 citations in OpenAlex.
- Trial
- Efficacy and Safety of Roluperidone for the Treatment of Negative Symptoms of Schizophrenia.Schizophrenia bulletin · 2022Trial
- Revealing the genetic mechanisms underpinning the parasite-induced water-seeking behaviour of insects through RNA-seq.Proceedings. Biological sciences · 2026Article
- Antipsychotic Drug Action, Novel Treatment Targets, and the Failure of Current Clinical Trial Designs in Evaluating New Target Molecules.Biological psychiatry · 2026Review
- Family-Wide Dysregulation of Phosphodiesterases Alters cAMP/cGMP Microdomains in Thoracic Aortic Aneurysm.Journal of cardiovascular development and disease · 2026Article
- Development of Selective and Soluble Mitochondrial Complex 1 Inhibitors Derived from Papaverine for Radiosensitization of Cancer.Journal of medicinal chemistry · 2025Article
- A single-cell genomic atlas for the effects of chronic ethanol exposure in the mouse dorsal striatum.Molecular psychiatry · 2025Article
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- The Missing Enzymes: A Call to Update Pharmacological Profiling Practices for Better Drug Safety Assessment.Journal of medicinal chemistry · 2025Review
- In the Brain of Phosphodiesterases: Potential Therapeutic Targets for Schizophrenia.Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology · 2025Review
- PDE10A as a novel diagnostic and therapeutic target in cancer: insights and challenges.Frontiers in oncology · 2025Review
- Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.Annual review of pharmacology and toxicology · 2025Review
- THPP-1 PDE10A inhibitor reverses the cognitive deficits and hyperdopaminergic state in a neurodevelopment model of schizophrenia.Schizophrenia research · 2024Article
- Article
- First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline.Journal of medicinal chemistry · 2023Article
- Article
- Insights into the Mechanism of Action of Antipsychotic Drugs Derived from Animal Models: Standard of Care versus Novel Targets.International journal of molecular sciences · 2023Review
- Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons.Nature neuroscience · 2023Article
- Article
- Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia.Journal of medicinal chemistry · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.