The present study is a systematic review and meta-analysis that investigated pharmacological and non-pharmacological interventions for irritability in ASD without any restrictions in terms of eligible interventions. We also evaluated the certainty of evidence for meta-analyzed interventions to determine the robustness of the treatment effects observed across the included studies. Our study found 60 RCTs with a total of 3531 participants, containing 45 different kinds of interventions. Our meta-analysis found that risperidone, aripiprazole, and parent training were effective for the reduction of irritable symptoms in ASD compared to placebo or inactive control. Risperidone and aripiprazole demonstrated a high certainty of evidence according to the GRADE assessment, whereas parent training exhibited a moderate certainty of evidence. We also identified several promising molecules for augmentation to risperidone, yet from one RCT each.

For pharmacological interventions, only two showed a statistically significant effect on reducing irritability in ASD: risperidone had a large size effect (Hedges' g − 0.857, 95% CI − 1.263 to − 0.450) and aripiprazole had a moderate size (Hedges' g − 0.557, 95% CI − 0.766 to − 0.348) compared to placebo, while other monotherapy interventions such as lurasidone and anti-epileptic drugs reported doubtful results. Notably, both risperidone and aripiprazole displayed a high certainty of evidence. The efficacy of risperidone and aripiprazole can be explained by their biological mechanisms. The core brain circuitry mechanism related to irritability is regulated and mediated by neurotransmitters such as serotonin (5-HT), dopamine, noradrenaline, and gamma-aminobutyric acid. Therefore, medications capable of modulating these neurotransmitters have been widely used to treat irritability in various psychiatric disorders including ASD, psychosis, and oppositional-defiant disorder [23, 24]. Risperidone, a serotonin-dopamine antagonist, is closely related to this mechanism. Specifically, its antagonistic mechanisms on both the 5HT2A receptor and dopamine D2 receptor have been reported to reduce irritable symptoms [25, 26]. Aripiprazole has distinctive receptor profiles compared to risperidone. It has not only a 5HT2A receptor antagonistic effect but also partial agonistic effects on the D2 dopamine receptor and 5HT1A serotonin receptor [27]. The effect of D2 receptor partial agonism can prevent hyperprolactinemia, thus improving compliance, especially in female patients [28]. Moreover, the 5HT1A receptor has been found to be a serotonin receptor that is closely related to aggression, which may contribute to reducing irritability [29].

Some trials investigated the effectiveness of risperidone + adjuvant therapy compared to risperidone monotherapy. Notably, numerous drugs have been examined for adjuvant therapy, and trials on such non-psychotropic adjuvant therapy seemed to be based on the evidence that immune dysfunction in ASD was related to behavior problems [30, 31]. However, meta-analysis was available only for risperidone + dietary supplementation and did not report significant results, showing very low certainty of evidence. Although not meta-analyzed, on the other hand, some candidate adjuvant medications with only one trial (sulforaphane, topiramate, pentoxifylline, memantine, celecoxib, minocycline, simvastatin, palmitoylethanolamide, and amantadine) showed significant effects on reducing irritability in ASD with moderate to very large effect sizes. Considering some adjuvant medications for risperidone showed a potential to significantly reduce irritability score compared to risperidone monotherapy, further research on this topic should be warranted to replicate findings.

Concerning non-pharmacological interventions, parent training showed a promising effect in reducing irritability in ASD (Hedges’ g − 0.892, 95% CI − 1.184 to − 0.601) compared to inactive control with moderate certainty of evidence. Note that in this study, based on previously suggested classification of parent training for ASD [22], the term ‘parent training’ specifically refers to parent training aimed at addressing maladaptive behaviors (parent implementation), which emphasize skill development of parent and directly benefit the child. Our results are quite meaningful when considering the safety issues of pharmacotherapies [32]. Firstly, pharmacotherapies, including atypical antipsychotics, still have safety and tolerability issues. Even though a recent meta-analysis pointed out that antipsychotics are generally tolerable [33], numerous studies have reported adverse events related to pharmacotherapies such as extrapyramidal symptoms, somnolence, and weight gain, leading to poor compliance. Secondly, atypical antipsychotics, which were approved by the FDA for irritability, have an age limitation for use: risperidone is approved for those aged \(\ge\) 5, and aripiprazole is for those aged \(\ge\) 6. Therefore, non-pharmacological interventions such as parent training seem to be essential for children who have not yet reached the permitted age. Moreover, while not reaching statistical significance, our meta-regression analysis suggested that younger age may be associated with better outcomes of parent training (k = 4, meta-regression coefficient for the mean age of intervention group = 0.1793, P = 0.0877), which indicates early initiation of parent training may possibly be beneficial. We hypothesized that the nonsignificant result in this instance may be attributed to the limited number of studies and participants (four studies with a total of 222 participants), which consequently reduced the statistical power to detect the genuine effect. However, when considering early intervention is highly recommended for patients with ASD, the strategies that initiate early parent training before reaching the permitted age and combining parent training and pharmacological treatment when pharmacotherapies become available would be beneficial. Nevertheless, the notable efficacy of parent training should be interpreted in the context of limited evidence, as 5 out of 6 (83.3%) meta-analyzed estimates were associated with a high risk of bias, primarily due to a non-blind design of trials (open), which calls for future trials with double-blinded design.

While our study identified parent training, specifically the implementation aspect that emphasizes skill development of parent with the child as the primary beneficiary [22], it is important to note the existence of another form of parent training known as parent support (e.g., care coordination and psychoeducation) for addressing problematic behaviors [34,35,36]. However, parent support seemed to have lower efficacy compared to parent implementation. A previous RCT involving 180 children with ASD compared the efficacy of parent training (i.e., parent implementation) with parent education (i.e., parent support) and found that the former was superior to the latter in reducing problematic behaviors, including irritability [37].

For dietary supplementation, none of them exhibited a significant effect on the reduction of irritability in ASD except for sulforaphane. Sulforaphane was quite noticeable considering its large effect size even though only one trial was conducted. Notably, although not meta-analyzed, risperidone + sulforaphane also showed a better effect than risperidone monotherapy. Regarding N-acetylcysteine, whereas a previous meta-analysis reported that N-acetylcysteine may be efficacious [38], our analysis yielded nonsignificant results. Moreover, a pooled estimate on risperidone + N-acetylcysteine compared to risperidone monotherapy was also found to be nonsignificant. However, rather than interpreting these results as they are not helpful to alleviate irritability in ASD, the viewpoint that evidence is not yet enough to determine their effect and further studies are needed seems to be appropriate.

Due to the challenging nature of irritability in patients with ASD, it is a significant concern for both patients themselves and their caregivers. As a result, it has been a primary target of interventions including pharmacological agents such as risperidone and aripiprazole. However, due to the potential for adverse events, numerous studies have been done to extend the indication of existing medications for alleviating irritable symptoms in patients with ASD. A comprehensive systematic review with meta-analysis by Salazar de Pablo et al. investigated various pharmacological interventions in this context [7]. While re-affirming the efficacy of antipsychotics and identifying the potential of ADHD medications, the study did not cover the non-pharmacological interventions. Interestingly, our study revealed that the parent training demonstrated comparable efficacy to antipsychotics (risperidone and aripiprazole), suggesting that non-pharmacological interventions are as important as pharmacological interventions in managing irritability in patients with ASD. Notably, the strength of our study lies in its broad range of examined interventions, enabling the comparison of efficacy across different interventions using effect sizes of Hedge’s g.

In addition, our study went beyond the previous meta-analysis by utilizing the GRADE approach to evaluate the certainty of evidence for each meta-analyzed intervention. Since the GRADE approach addresses multiple dimensions of evidence such as risk of bias, imprecision, inconsistency, indirectness, and publication bias, it could provide a more comprehensive and nuanced perspective on the identified interventions compared to solely providing pooled effect size. For example, our study revealed parent training exhibited a comparable effect size to antipsychotics with moderate certainty of evidence. Interventions in other categories (risperidone + adjuvant therapy and dietary supplementation) yielded a certainty of evidence ranging from ‘very low’ to ‘low.’ These findings suggested that there is limited confidence in the reported efficacy of these interventions, indicating the need for further studies to establish robust evidence. By utilizing the GRADE approach to assess the certainty of evidence, our study enabled a more informed understanding of the efficacy of various interventions for irritability in patients with ASD. This approach guides future research and helps in making more evidence-based decisions in clinical practice.