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Beyond traditional pharmacology: evaluating phosphodiesterase inhibitors in autism spectrum disorder

Neuropsychopharmacology (2024)Cite this article

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Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions characterized by differences in social communication and interaction, coupled with repetitive behaviors and interests. Its features vary widely, from speech and language delays to sensory hypo- or hypersensitivity and stereotypic behaviors that can include aggression or self-harm. These often coincide with psychiatric and medical co-occurring conditions such as attention-deficit/hyperactivity disorder, anxiety, and irritability. Current psychopharmacological treatments, including atypical antipsychotics, serotonergic agents, alpha-2 agonists, and psychostimulants, primarily address these associated symptoms. While useful, these medications frequently require polypharmacy, posing challenges due to potential drug interactions and side effects.

Despite progress in understanding the brain circuitry associated with ASD [1], effective diagnostic biomarkers or treatments for its core symptoms remain elusive. Interest in cyclic nucleotide phosphodiesterase (PDE) inhibitors has grown. Approved indications for PDE inhibitors include respiratory, cardiovascular, inflammatory, and nervous system disorders [2]. PDE5 inhibitors such as sildenafil, vardenafil, avanafil, and tadalafil have been used as therapeutic options for individuals with erectile dysfunction. Cyclic nucleotides cAMP (3′,5′-cyclic adenosine monophosphate) and cGMP (3′,5′-cyclic guanosine monophosphate) act as crucial second messengers in the brain, transforming neuromodulatory signals into functional responses that modulate neuronal activity. Their intracellular concentrations are regulated by PDE enzymes, which are categorized into 11 families. Each family’s affinity for cyclic nucleotides varies; PDEs 1, 2, 3, 10, and 11 target both cAMP and cGMP, whereas PDEs 4, 7, and 8 are cAMP-specific, and PDEs 5, 6, and 9 are cGMP-specific. These families comprise multiple genes, yielding over 100 human isoforms and splice variants [3]. While preclinical studies suggest that modulating PDE activity could benefit ASD [4], clinical trials for autistic individuals remain limited.

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Funding

The authors were funded by the grants #2019/04188-0 (DLR), and #2017/00003-0 (FEP-N) from the São Paulo Research Foundation (FAPESP) and grant # 312009/2022-4 (FEP-N) from the National Council for Scientific and Technological Development (CNPq).

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  1. Department of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Fernando E. Padovan-Neto, Ana Júlia de Oliveira Cerveira, Aline da Silva & Danilo Leandro Ribeiro

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  1. Fernando E. Padovan-Neto
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  2. Ana Júlia de Oliveira Cerveira
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  3. Aline da Silva
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  4. Danilo Leandro Ribeiro
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Contributions

FEP-N: Conceptualization, literature review, writing- original draft preparation, writing- reviewing and editing. AJOC, AS, and DLR: Literature review, writing- original draft preparation.

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Correspondence to Fernando E. Padovan-Neto.

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Padovan-Neto, F.E., Cerveira, A.J.d.O., da Silva, A. et al. Beyond traditional pharmacology: evaluating phosphodiesterase inhibitors in autism spectrum disorder. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01860-z

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