Immunoregulatory and/or Anti-inflammatory Agents for the Management of Core and Associated Symptoms in Individuals with Autism Spectrum Disorder: A Narrative Review of Randomized, Placebo-Controlled Trials

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a so far poorly understood underlying pathogenesis, and few effective therapies for core symptoms. Accumulating evidence supports an association between ASD and immune/inflammatory processes, arising as a possible pathway for new drug intervention. However, current literature on the efficacy of immunoregulatory/anti-inflammatory interventions on ASD symptoms is still limited. The aim of this narrative review was to summarize and discuss the latest evidence on the use of immunoregulatory and/or anti-inflammatory agents for the management of this condition. During the last 10 years, several randomized, placebo-controlled trials on the effectiveness of (add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, N -acetylcysteine (NAC), sulforaphane (SFN), and/or omega-3 fatty acids have been performed. Overall, a beneficial effect of prednisolone, pregnenolone, celecoxib, and/or omega-3 fatty acids on several core symptoms, such as stereotyped behavior , was found. (Add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, NAC, SFN, and/or omega-3 fatty acids was also associated with a significantly higher improvement in other symptoms, such as irritability , hyperactivity , and/or lethargy when compared with placebo. The mechanisms by which these agents exert their action and improve symptoms of ASD are not fully understood. Interestingly, studies have suggested that all these agents may suppress microglial/monocyte proinflammatory activation and also restore several immune cell imbalances (e.g., T regulatory/T helper-17 cell imbalances), decreasing the levels of proinflammatory cytokines, such as interleukin (IL)-6 and/or IL-17A, both in the blood and in the brain of individuals with ASD. Although encouraging, the performance of larger randomized placebo-controlled trials, including more homogeneous populations, dosages, and longer periods of follow-up, are urgently needed in order to confirm the findings and to provide stronger evidence.

Disease Course and Response to Immunotherapy in Children With Childhood Disintegrative Disorder: A Retrospective Case Series

“…7 More abundant pharmacotherapy data in autism spectrum disorder and that with regression 41 include >18 “immune pathway” drug studies, including corticosteroids and IVIG. 42–44 Small sample sizes, phenotypic and biochemical heterogeneity, and most important, subjective parent-reported outcomes greatly limit interpretation of these overwhelmingly positive results. Interestingly, IVIG was one of the few agents often showing no benefit.…”

Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy

“…429 Another narrative review of randomized controlled placebo trials summarizes how immunomodulatory/antiinflammatory therapeutic agents such as prednisolone, pregnenolone, celecoxib, minocycline, n-acetylcysteine, radicicic acid, and/or omega-3 fatty acids may be useful in the core management of (e.g., stereotypic behaviors) and related (e.g., irritability, hyperactivity, lethargy) symptoms in individuals with autism. 430 Likewise, a review based on RCTs concluded that myostatin, haloperidol, folinic acid, guanfacine, omega-3 fatty acids, probiotics, radicicic acid, sodium alginate, and sodium valproate showed some signs of improvement, but were imprecise and unreliable. 431 Overall, among the several intervention approaches described above, attention needs to be paid to individualization, targeting interventions to subgroups of ASDs with associations with these pathophysiological mechanisms, and improving the efficacy of interventions.…”

“…412,432 The literature on intervention efficacy is limited, and large-scale RCTs are still needed to provide strong evidence as well as the use of biomarkers. 430…”

“…(2) Other ASD therapies that have been used or are being studied that are initially characterized as neither anti‐inflammatory nor immunomodulatory at first, but exhibit immunomodulatory capabilities throughout the course of treatment: risperidone, vitamin D, omega‐3, ginkgo biloba, l‐creatinine, n‐acetylcysteine, and microbiome recovery 429 . Another narrative review of randomized controlled placebo trials summarizes how immunomodulatory/anti‐inflammatory therapeutic agents such as prednisolone, pregnenolone, celecoxib, minocycline, n‐acetylcysteine, radicicic acid, and/or omega‐3 fatty acids may be useful in the core management of (e.g., stereotypic behaviors) and related (e.g., irritability, hyperactivity, lethargy) symptoms in individuals with autism 430 . Likewise, a review based on RCTs concluded that myostatin, haloperidol, folinic acid, guanfacine, omega‐3 fatty acids, probiotics, radicicic acid, sodium alginate, and sodium valproate showed some signs of improvement, but were imprecise and unreliable 431 …”

“…Overall, among the several intervention approaches described above, attention needs to be paid to individualization, targeting interventions to subgroups of ASDs with associations with these pathophysiological mechanisms, and improving the efficacy of interventions 412,432 . The literature on intervention efficacy is limited, and large‐scale RCTs are still needed to provide strong evidence as well as the use of biomarkers 430 …”