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.

Emerging research has begun to underline PDEs as potential therapeutic targets in ASD. Resveratrol, found in red wine and peanuts and known for its health benefits, inhibits PDEs 1, 3, and 4. A double-blind, placebo-controlled randomized Phase 3 clinical trial showed that, although resveratrol combined with risperidone didn’t reduce irritability as a primary outcome measure in autistic children (62 subjects aged 4–12 years), it significantly improved hyperactivity/non-compliance as a secondary outcome measure (Cohen’s d = 0.52) [5]. Additionally, a double-blind, placebo-controlled randomized Phase 2–3 clinical trial with autistic children (61 subjects aged 5–11 years) suggested benefits of the PDE3 inhibitor cilostazol in managing participants with higher hyperactivity as a primary outcome measure (partial eta squared = 0.14) [6]. The interest in PDE inhibitors extends to fragile X syndrome (FXS), the most common inherited intellectual disability and a major ASD contributor. A double-blind, placebo-controlled randomized Phase 2 clinical trial (30 male subjects aged 18–41 years) demonstrated safety and tolerability as primary outcome measures for the PDE4 inhibitor BPN14770 in FXS individuals. The study also demonstrated significant improvements in secondary outcomes, such as language function cognitive tests, as well as parent/caregiver perceptions of improvement in language and daily function (Cohen’s d = 0.7–0.9) [7].

While further research involving larger patient cohorts is essential, current studies underscore the potential of PDE inhibitors to elevate cyclic nucleotide levels in the brain, which could potentially rectify dysfunctional brain circuits in ASD. However, the challenge of targeting PDEs in the central nervous system comes from their broad distribution [8]. Therefore, a deeper understanding of specific PDE isoforms and their brain locations could significantly enhance pharmacological strategies for ASD. One strategy is to focus on PDE families with fewer isoforms and a more limited tissue distribution. For instance, PDE10A, comprising a single isoform family with most prevalent expression in the striatum, meets these criteria.

The striatum, the primary input nucleus of the basal ganglia, receives extensive neural inputs from the cortex and other regions. Recent research underscores the basal ganglia’s key role in ASD pathophysiology, moving beyond their traditional association with neurodegenerative diseases like Parkinson’s and Huntington’s diseases [9]. Molecular pathway and brain circuit studies in ASD have shown mutations predominantly in genes with high expression levels in the striatum [10]. Striatal enlargement, often observed in autistic individuals, frequently correlates with repetitive behaviors and motor performance impairments [11]. Moreover, striatal dysfunction in ASD is linked to cognitive inflexibility and impulsive behaviors [12].

Given the striatum’s pivotal role in mediating behaviors associated with ASD, targeting its activity with PDE inhibitors presents a promising therapeutic avenue. Genome-wide association studies have linked microRNA miR-137, a key player in neuropsychiatric disorders in humans, with PDE10A and ASD etiology. Mice with reduced miR-137 exhibit repetitive behaviors and sociability and learning impairments due to increased PDE10A levels. Notably, the PDE10A inhibitor papaverine mitigated these ASD-like behaviors, highlighting PDE10A as a promising target [13]. In 2019, the European Medicines Agency granted orphan drug status to the PDE10A inhibitor balipodect, which is intended to be studied as a treatment for FXS. This highlights the potential of PDE inhibitors as a pharmacological tool in this condition (EMADOC-628903358-742).

Notably, PDE1B, part of the PDE1 family, is highly expressed in the striatum and the dentate gyrus of the hippocampus. Intriguingly, an inherited missense variant of PDE1B has been identified in individuals with ASD [14]. Preclinical studies have shown that the PDE1 inhibitor vinpocetine can ameliorate ASD-like behaviors [15]. Although vinpocetine has considerable off-target activity, the development of more selective PDE1 inhibitors underlines the potential of modulating PDE1B activity in ASD-related behaviors. Nonetheless, considering other PDE sub-families with significant expression in the striatum and key brain areas is crucial.

This commentary highlights the potential of PDE inhibitors as a promising yet underexplored treatment avenue for ASD, acknowledging the lack of conclusive evidence for their effectiveness. Challenges such as adverse drug reactions and insufficient efficacy persist. Drug development could explore adjunctive regimens that pair PDE inhibitors with other treatments to improve ASD-related symptoms without increasing side effects. Focusing on enhancing isoform specificity offers another pathway to minimize adverse reactions and improve therapeutic outcome. Specifically targeting PDE isoforms associated with ASD neural dysfunctions could refine this pharmacological strategy. Developing and assessing both existing and novel PDE inhibitors is essential for advancing our pharmacological knowledge and improving ASD treatments.