Emerging drugs for the treatment of irritability associated with autism spectrum disorder

ABSTRACT

Introduction

Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient.

Areas covered

After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action.

Expert opinion

Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.

KEYWORDS:

• Adverse drug reaction
• autistic disorder
• clinical trial
• combination drug therapy
• drug approval process
• neuroimmunomodulation
• psychiatric disorder
• state-of-the-art review

Article highlights

• The benefit-complication imbalance of irritability in current pharmacotherapies in some cases has necessitated the development of novel therapeutic approaches.

• Nineteen beneficial, safe, and well-tolerable medications were reviewed based on phase II and III clinical trials by describing the pathophysiology of irritability.

• The glutamatergic and γ-aminobutyric acidergic pathways with excitatory versus inhibitory effects are the most prominent mechanisms in the development of irritability.

• Another mechanism underpinning irritability is inflammation, usually accompanied by glutamate hyperactivity.

• More drugs with anti-inflammatory properties are emerging for autism-associated irritability.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Author contributions

A Shamabadi: Conceptualization, Project administration, Supervision, Data curation, Writing – original draft, Writing – review and editing; H Karimi: Data curation, Figure design, Writing – original draft; R A Bahri: Data curation, Writing – original draft, Writing – review and editing; M Motavaselian: Writing – original draft; and S Akhondzadeh: Conceptualization, Project administration, Supervision, Data curation. All authors approved the final version of the manuscript and had accountability for all work aspects.

Acknowledgments

The figure was created using BioRender.com with a publication license.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received consulting fees from Roche for projects related to autism clinical trials (though the primary outcomes in such trials were core features rather than irritability). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.