Novel Treatments in Autism Spectrum Disorder

Danielle Baribeau; Jacob Vorstman; Evdokia Anagnostou


Curr Opin Psychiatry. 2022;35(2):101-110. 

In This Article

Abstract and Introduction


Purpose of Review: There are currently no approved medications for the core symptoms of autism spectrum disorder (ASD), and only limited data on the management of co-occurring mental health and behavioural symptoms. The purpose of this review is to synthesize recent trials on novel treatments in ASD, with a focus on research trends in the past 2 years.

Recent Findings: No new pharmacologic agents received regulatory approval for use in ASD. Several large randomized controlled trials (RCTs) had negative or ambiguous results (e.g. fluoxetine, oxytocin). A cross-over RCT of an oral cannabinoid suggested possible benefits for disruptive behaviours. Two large-scale multicentre trials of bumetanide were terminated early for lack of efficacy. Multicenter trials using repetitive transcranial magnetic stimulation are underway. Recent meta-analyses indicate that specific behavioural and psychological interventions can support social communication and treat anxiety. Numerous novel treatment targets informed by biological mechanisms are under investigation.

Summary: Recent data support the use of behavioural and psychological interventions for social communication and anxiety in ASD; data are more limited regarding pharmacotherapy for core and associated symptoms. Next steps include replication of early findings, trials of new molecular targets, and the identification of novel biomarkers, including genetic predictors, of treatment response.


Autism spectrum disorder (ASD) affects 1–3% of children.[1] The core symptoms are social communication deficits and restricted and repetitive patterns of behaviour.[2] Despite decades of effort to identify novel pharmacological treatments for core ASD symptoms, so far, few trials have met their primary endpoints or been replicated, and none have yielded sufficient evidence for regulatory approval or justified use in clinical practice. Several ambitious and comprehensive drug developmental programs in ASD and related disorders, informed by basic science and molecular research, have unfortunately yielded largely negative or ambiguous results in clinical trials (e.g. Fragile X[3]).

In addition to core symptoms, ASD is also associated with elevated risk for other co-occurring mental health and behavioural disorders.[4] Data suggest that the use of psychotropic medication to treat this comorbidity in ASD remains high.[5,6] In the past 2 years, no new agents have become available to treat associated mental health/behavioural symptoms in ASD either. Medication management options continue to consist of the atypical antipsychotics for irritability,[7–10] psychostimulants or atomoxetine for ADHD symptoms,[11,12] the alpha adrenergic agents, such as guanfacine for management of ADHD and/or disruptive behaviour (off-label for disruptive behaviour),[13,14] and N-acetyl cysteine for irritability (off-label).[15] A recent network meta-analysis concluded similar effectiveness of both risperidone and aripiprazole for irritability in ASD.[16] Selective serotonin reuptake inhibitors (SSRIs) are often used clinically for co-occurring anxiety, depression, or obsessive–compulsive disorder (OCD),[17] despite limited and at times conflicting data.[18] In 2019, a small trial of low-dose sertraline (2.5–5 mg) for preschool children with ASD did not identify a benefit on primary endpoints related to language, or secondary endpoints including anxiety.[19] For restricted/repetitive behaviour, a meta-analysis published in 2020 concluded there was no overall benefits from SSRIs.[20] A randomized controlled trial of fluoxetine in 7- to 18-year-olds with ASD published in 2020 identified clinical improvement in obsessive–compulsive and repetitive behaviour on their primary endpoint but the difference was not significant across prespecified sensitivity analyses adjusting for baseline demographic and clinical factors and there was a high drop-out rate. Secondary measures of anxiety also did not improve.[21] The clinical approach to management of associated mental health and behavioural symptoms with existing agents has been extensively reviewed elsewhere,[12,22,23] hence this review focuses on novel treatments and treatment targets (Figure 1, Table 1).

Figure 1.

Potential novel treatments and treatment targets under investigation in autism. ASD, autism spectrum disorder; E : I, excitatory : inhibitory; RNAi, RNA interference.

Despite a lack of novel treatment options, ongoing efforts to understand and target the underlying molecular mechanisms contributing to ASD continue.[24,25] A number of recent advances in the areas of autism genomics, neurophysiology, as well as the timing and approach of early behavioural interventions suggest that novel therapeutics and treatment strategies for ASD may be on the horizon. In this review, we discuss emerging treatments in the areas of genetically informed treatment targets, agents targeting transcriptional and epigenetic regulation, agents targeting excitatory: inhibitory neurotransmission, precision therapeutics, brain stimulation and targeted psychological and/or behavioural interventions.