Phosphodiesterase 10A Inhibition in Neuropsychiatric Disorders

Phosphodiesterase 10A (PDE10A) is a dual‐substrate enzyme that hydrolyses the intracellular messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). It is almost exclusively expressed in striatal medium spiny neurons, where it governs the balance between direct and indirect basal ganglia output pathways. Inhibition of PDE10A elevates levels of cAMP and cGMP in these neurons, enhancing corticostriatal transmission and modulating dopaminergic signalling without the motor side effects commonly associated with dopamine D2 receptor antagonists. Preclinical studies have shown that selective PDE10A inhibitors reduce psychotomimetic-induced hyperactivity, improve cognitive performance and attenuate behavioural deficits in models of schizophrenia, Huntington’s disease and bipolar disorder. Genetic and molecular analyses have uncovered mutations and novel isoforms of PDE10A linked to movement disorders and mood regulation, highlighting the enzyme’s complex regulation. Early clinical trials, however, have not demonstrated antipsychotic efficacy comparable to standard treatments, prompting deeper mechanistic investigations and efforts to refine compound potency, selectivity and translational biomarkers. Emerging strategies include optimisation of brain-penetrant ligands, exploration of combination regimens and in vivo imaging of PDE10A as a biomarker for patient stratification and target engagement.

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Phosphodiesterase 10A Inhibition in Neuropsychiatric Disorders publication trend

The graph below shows the total number of articles in phosphodiesterase 10a inhibition in neuropsychiatric disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Phosphodiesterase 10A (PDE10A): An enzyme that degrades cAMP and cGMP, predominantly located in striatal medium spiny neurons and critical for regulating intracellular cyclic nucleotide signalling.

Medium spiny neurons (MSNs): Principal projection neurons of the striatum that integrate cortical and dopaminergic inputs and control motor and cognitive functions via direct (D1 receptor) and indirect (D2 receptor) pathways.

cAMP/cGMP: Cyclic nucleotides acting as second messengers to regulate protein kinases, ion channels and gene transcription in neurons.

Indirect pathway: A striatal output route mediated by D2 receptor-expressing MSNs; its activation suppresses movement and is a target for antipsychotic interventions.

Positron emission tomography (PET): A neuroimaging technique that quantifies molecular targets in vivo using radiolabelled tracers to assess enzyme availability and drug occupancy.

References

1. Cloning and Characterization of a Novel Human Phosphodiesterase That Hydrolyzes Both cAMP and cGMP (PDE10A)*. Journal of Biological Chemistry (1999).
2. Facilitation of Corticostriatal Transmission following Pharmacological Inhibition of Striatal Phosphodiesterase 10A: Role of Nitric Oxide-Soluble Guanylyl Cyclase-cGMP Signaling Pathways. Journal of Neuroscience (2015).
3. PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?. Frontiers in Neuroscience (2021).
4. Characterization of Binding and Inhibitory Properties of TAK-063, a Novel Phosphodiesterase 10A Inhibitor. PLOS ONE (2015).
5. A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor. Psychopharmacology (2016).
6. De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions. American Journal of Human Genetics (2016).
7. Novel, primate-specific PDE10A isoform highlights gene expression complexity in human striatum with implications on the molecular pathology of bipolar disorder. Translational Psychiatry (2016).
8. Combined treatment with a selective PDE10A inhibitor TAK‐063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic‐like effects without affecting plasma prolactin levels and cataleptic responses in rodents. Pharmacology Research & Perspectives (2017).
9. Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study. Translational Psychiatry (2017).