Medical treatment of autism spectrum disorder in children: Current evidence, controversies, and clinical challenges

Table 1 Risperidone for pediatric autism spectrum disorder

Feature	Key findings
Indication	FDA-approved for irritability (aggression, self-injury, tantrums) associated with autistic disorder in ages 5-16 years
Efficacy	Strong evidence for reducing irritability, aggression, self-injury, and tantrums. Moderate evidence for reducing hyperactivity and stereotypy. Limited/inconsistent evidence for improving core social-communication symptoms
Key adverse effects	Weight gain: Significant, often rapid, linked to increased appetite; risk increases with duration and possibly younger age. Metabolic changes: Increased risk of insulin resistance, metabolic syndrome; changes in glucose, lipids, leptin, and adiponectin observed. Sedation/somnolence: Common, especially initially, often mild-moderate and transient. Hyperprolactinemia: Frequent, dose-dependent. Enuresis: Increased risk observed in long-term use. Tremor: Increased risk, though EPS is generally low
Cognitive effects	Appears to have no detrimental effect; some studies suggest potential minor improvements in attention/recognition memory in testable children
Pharmacokinetics/TDM	Sum trough concentration (risperidone + 9-hydroxyrisperidone-risperidone) correlates with efficacy and side effects (weight gain, sedation, prolactin). Proposed TDM target range: 3.5-7.0 μg/L to balance efficacy and weight gain. Simulation studies suggest TDM can improve achievement of the target range and potentially reduce side effects

FDA: Food and Drug Administration; EPS: Extrapyramidal symptoms; TDM: Therapeutic drug monitoring.

Table 2 Risperidone vs placebo in pediatric autism spectrum disorder (based on extracted data analysis)

Outcome measure	No. studies (pooled)	Result (pooled estimate)	95% confidence interval	I2 heterogeneity	P value	Notes
Efficacy (ABC change)		Mean difference (random-effects)				Negative mean difference favors risperidone
ABC Irritability	3	-11.08	(-14.39 to -7.78)	72% (substantial)	< 0.0001	Robust effect, but high heterogeneity
ABC Stereotypy	3	-3.91	(-6.37 to -1.44)	55% (moderate/substantial)	0.002
ABC Hyperactivity	3	-7.97	(-12.26 to -3.69)	81% (high)	0.0003
ABC Social Withdrawal	3	-0.55	(-0.85 to -0.24)	12% (low)	0.0005	Small but consistent effect
ABC Inappropriate Speech	3	-2.27	(-3.85 to -0.70)	41% (moderate)	0.005
Safety (adverse events)		Risk ratio (random-effects)				Risk ratio > 1 indicates higher risk with risperidone
Increased appetite	3	2.45	(1.29-4.65)	30% (moderate)	0.006	Common risk
Somnolence	2	4.14	(1.81-9.47)	0% (low)	< 0.001	Consistent, common risk
Drooling	2	4.70	(1.52-14.54)	65% (substantial)	0.005	Significant, but variable risk
Tremor	2	8.22	(1.56-49.82)	22% (low)	0.01	Significantly increased risk
Fatigue	3	2.18	(0.70-6.85)	78% (high)	0.18	Trend towards higher risk, high variability
Constipation	2	1.31	(0.10-16.38)	0% (low)	0.84	No significant difference
Weight gain (continuous)		Mean difference (kg) (random-effects)				Positive mean difference indicates more weight gain with Risperidone
Mean weight gain diff (kg)	3	1.97	(1.52-2.41)	0% (low)	< 0.0001	Significant and consistent weight gain over approximately 8 weeks

Pooled estimates are calculated using the random-effects model to account for clinical and methodological heterogeneity. The I² statistic explicitly quantifies heterogeneity. High heterogeneity (I² > 50%) suggests that the actual effect size varies significantly across studies, cautioning against a single, universal interpretation. These results highlight the trade-offs associated with risperidone: Its apparent efficacy in addressing challenging behaviors comes at the cost of significant, but variable, adverse effects, particularly metabolic ones (low I² for weight gain), which necessitate careful patient selection and monitoring. Therapeutic drug monitoring may offer a path to optimize this balance. ABC: Aberrant Behavior Checklist.

Table 3 Comparison between risperidone vs aripiprazole in pediatric autism spectrum disorder

Feature	Risperidone	Aripiprazole
FDA approval	Approved in 2006 for irritability (aggression, self-injury, tantrums) in children with autistic disorder aged 5-16 years	Approved in 2009 for the same indication in children and adolescents aged 6-17 years
Mechanism of action	Dopamine D2 and serotonin 5-HT2A receptor antagonist	Dopamine D2 and serotonin 5-HT1A partial agonist, 5-HT2A antagonist
Core clinical target	Severe behavioral symptoms - irritability, aggression, self-injury, tantrums	Same behavioral symptoms; sometimes preferred for milder irritability or when metabolic risk is a concern
Efficacy (ABC-I)	Robust reduction (approximately 50%-60%) vs placebo in multiple RCTs (RUPP 2002, Shea 2004). Effects sustained up to 21 months	Similar magnitude of improvement (approximately 40%-60%) vs placebo; benefits evident within 1-2 weeks and maintained up to 52 weeks
Effects on other ABC subscales	Significant improvements in hyperactivity, stereotypy, and inappropriate speech; modest gains in social withdrawal	Moderate improvement in hyperactivity and stereotypy; inconsistent effects on social withdrawal
Effect on core ASD symptoms	Minimal or inconsistent improvement in social and communication domains; benefits, mainly indirect via behavior control	Similar - limited impact on core ASD features, though better adaptive engagement may follow behavioral improvement
Weight gain	Significant, often rapid (mean +2.7 to +5.4 kg in 8-24 weeks); linked to increased appetite and metabolic changes	Milder (mean +1.3 kg in 8-12 weeks); generally, not associated with metabolic syndrome
Metabolic effects	Marked rise in insulin, glucose, HOMA-IR, leptin, and fall in adiponectin; increased risk of metabolic syndrome	Minimal changes in glucose or lipid parameters; low metabolic liability overall
Prolactin	Increases prolactin (dose-dependent); may cause galactorrhea, gynecomastia	Usually reduces or normalizes prolactin due to partial D2 agonism
Sedation/somnolence	Common (40%-60%); often transient but dose-related	Mild to moderate; usually transient; less sedation than risperidone
EPS	Low-moderate risk; tremor approximately 8%-9%, dose-related	Low risk overall; akathisia slightly more frequent than with risperidone
Cognitive effects	No cognitive decline; some studies show mild improvement in attention/recognition	Neutral cognitive profile; no significant impairment reported
Pharmacokinetics	Metabolized by CYP2D6 → active metabolite 9-hydroxyrisperidone-risperidone; TDM useful (target sum trough 3.5-7 μg/L)	Metabolized by CYP2D6 and CYP3A4 → active dehydro-aripiprazole; TDM not routinely required
Pharmacogenetics	CYP2D6 poor metabolizers have higher active moiety levels; BDNF Val66Met linked to insulin resistance	CYP2D6 poor metabolizers show higher exposure; limited evidence of clinical impact from DRD2/HTR variants
Duration of benefit	Sustained efficacy with continued use; relapse on discontinuation	Sustained up to 1 year; relapse possible on abrupt discontinuation
Overall clinical impression	Highest efficacy for irritability and aggression, but greater metabolic and endocrine burden	Comparable efficacy, better metabolic profile, slightly higher akathisia risk; favorable long-term tolerability

This table provides a critical head-to-head comparison of the two Food and Drug Administration-approved atypical antipsychotics for pediatric autism spectrum disorder: Risperidone and aripiprazole. Both drugs are highly effective, demonstrating robust, comparable efficacy in reducing severe, challenging behaviors such as irritability, aggression, and tantrums (the primary target of Food and Drug Administration approval), with effects maintained over time. Their contrasting tolerability profiles primarily drive the choice between them. Risperidone is associated with a greater metabolic and endocrine burden, specifically significant weight gain and marked increases in prolactin (leading to potential side effects like gynecomastia). Aripiprazole, while showing comparable efficacy, has a significantly better metabolic profile (less weight gain, minimal change in glucose/Lipids) and tends to reduce prolactin levels. The trade-off is that aripiprazole carries a slightly higher risk of akathisia (a type of extrapyramidal symptom or extrapyramidal symptoms). Clinically, risperidone is often chosen for patients requiring the highest reduction in severe aggression. At the same time, aripiprazole is preferred for patients with pre-existing metabolic risk factors or those with milder symptoms, where the priority is to minimize metabolic side effects.

FDA: Food and Drug Administration; 5-HT₂A: Serotonin 5-hydroxytryptamine receptor type 2A; 5-HT₁A: Serotonin 5-hydroxytryptamine receptor type 1A; ABC-I: Aberrant Behavior Checklist-Irritability subscale; RCTs: Randomized controlled trials; RUPP: Research Units on Pediatric Psychopharmacology (a study group); ABC: Aberrant Behavior Checklist; ASD: Autism spectrum disorder; HOMA-IR: Homeostasis model assessment of insulin resistance; EPS: Extrapyramidal symptoms (motor side effects like tremor or dystonia); CYP2D6: Cytochrome P450 2D6 (a liver enzyme involved in drug metabolism); TDM: Therapeutic drug monitoring (measuring drug levels in blood); CYP3A4: Cytochrome P450 3A4 (a liver enzyme involved in drug metabolism); BDNF: Brain-derived neurotrophic factor; Val66Met: Valine to Methionine substitution at position 66 (a polymorphism in the brain-derived neurotrophic factor gene); DRD2: Dopamine D2 receptor; HTR: 5-hydroxytryptamine receptor (serotonin receptor).

Table 4 Comparison of methylphenidate vs atomoxetine in children with autism spectrum disorder and attention-deficit/hyperactivity disorder symptoms

Feature	Methylphenidate	Atomoxetine
Evidence base	5 placebo-controlled crossover RCTs (total n = 146)	2 placebo-controlled RCTs included in pooled analysis (total n = 113)
Effect on hyperactivity	Significant improvement (teacher-rated SMD approximately -0.78, P < 0.001)	Significant improvement (pooled SMD approximately -0.68, P = 0.0004)
Effect on inattention	Small but significant reduction (P = 0.04); not clinically large	Significant reduction on ADHD-RS in parallel trial (MD: -6.7, P < 0.001)
Effect on core ASD symptoms	No primary benefit; secondary signals for joint attention/self-regulation	No primary benefit; possible improvement only when combined with risperidone
Tolerability profile	Higher risk of irritability, emotional lability, decrease appetite (RR: 8.28)	Generally well tolerated; nausea, decrease appetite, fatigue most common
Risk of behavioral activation	Higher (especially at higher doses)	Lower
Trial duration	Very short: 1 week per dose	6-8 weeks
Clinical role	Often first-line if tolerated	Alternative when stimulants are not tolerated or contraindicated

This table compares the two most common pharmacological treatments for attention-deficit/hyperactivity disorder symptoms, primarily hyperactivity and inattention, when they co-occur in children with autism spectrum disorder: Methylphenidate, a stimulant, and atomoxetine, a non-stimulant. Both drugs demonstrate significant and comparable efficacy in reducing hyperactivity, which is the primary behavioral target. Methylphenidate, while often chosen as the first-line agent for attention-deficit/hyperactivity disorder in the general population, has been shown to have a higher risk of behavioral activation (increased irritability, emotional lability) in children with autism spectrum disorder compared to neurotypical peers, potentially leading to discontinuation. Atomoxetine, a selective norepinephrine reuptake inhibitor, offers a generally well-tolerated alternative with a lower risk of behavioral side effects, though side effects like nausea and decreased appetite are still common. Crucially, neither drug shows a primary benefit on core autism spectrum disorder symptoms (social or communication deficits). The choice between them balances potent efficacy (methylphenidate) against a better tolerability profile (atomoxetine). Atomoxetine is often preferred when methylphenidate is not tolerated or contraindicated, or as a co-treatment when combined with atypical antipsychotics like risperidone. RCTs: Randomized controlled trials; SMD: Standardized mean difference (a measure of effect size); ADHD-RS: Attention-Deficit/Hyperactivity Disorder Rating Scale; MD: Mean difference; ASD: Autism spectrum disorder; RR: Relative risk (ratio of probability of an event occurring in an exposed group vs unexposed group).

Table 5 Clinical algorithm for selecting methylphenidate vs atomoxetine in children with autism spectrum disorder and attention-deficit/hyperactivity disorder symptoms

First-line medication choice
MPH is recommended as initial pharmacotherapy in most children with ASD and comorbid ADHD symptoms, provided that no major tolerability concerns are present. MPH demonstrates the largest pooled effect size for hyperactivity reduction (SMD: -0.78) and has rapid onset of action (within days)
ATX is recommended as first-line therapy when:
The child has a history of stimulant-induced irritability, behavioral activation, or emotional dysregulation
Comorbid anxiety, tics, or sleep disturbance is present
Parents prefer a non-stimulant medication
Cardiac risk factors delay or preclude stimulant use
Stepwise treatment approach
Initiate MPH at low dose and titrate gradually based on response and tolerability
Reassess after 2-4 weeks. If inadequate response or intolerable adverse effects occur, switch to ATX
If ATX is started first and response remains suboptimal after 6-8 weeks of optimized dosing, switch to MPH
Combination therapy (MPH + ATX) may be considered only in specialist care after monotherapy failure, with clear target symptoms and close monitoring
Clinical considerations
MPH is associated with a higher risk of appetite suppression and irritability but provides faster and stronger symptom reduction
ATX offers more stable behavioral control, is better tolerated in emotionally reactive children, and may improve global ASD severity when combined with risperidone
Both agents require monitoring of appetite, sleep, heart rate, blood pressure, and behavioral changes at baseline and follow-up visits

MPH: Methylphenidate; ASD: Autism spectrum disorder; ADHD: Attention-deficit/hyperactivity disorder; SMD: Standardized mean difference; ATX: Atomoxetine.

Table 6 Emerging immunotherapies in autism spectrum disorder

Intervention	Ref.	Population	Key findings	Status/safety
Low-dose IL-2	Case reports/series (Chen et al[159] in 2025, Li et al[253] in 2024)	Small N (children)	Positive: Improvements in speech, social interaction, sleep. Mechanism: Corrected Th1/Treg immune imbalance	Experimental. No adverse events reported in these cases
M2 macrophage secretome	Clinical trial (Shevela et al[171], 2024)	n = 71 (3-13 years)	Positive: Reduced language impairment and autistic-like behavior via intranasal delivery	Experimental. Reported as safe and well-tolerated
GcMAF	In vitro study (Siniscalco et al[172], 2014)	Macrophage cells	Mechanistic: Normalized endocannabinoid gene expression in cells	Unproven/risky. Unlicensed; no clinical evidence provided
Allergy immunotherapy	Case report (Sood et al[174], 2016)	n = 1 (8 years)	Feasibility: Behavioral strategies allowed successful treatment of comorbid allergies	Standard therapy for atopy (not ASD core symptoms)

Table 6 presents highly experimental and emerging immunotherapies for autism spectrum disorder, based on the hypothesis that a subset of autism spectrum disorder is driven by immune dysregulation or neuroinflammation. The current evidence base is extremely low certainty, relying primarily on case reports/series and preclinical studies rather than large-scale randomized controlled trials. Low-dose interleukin-2 and the M2 macrophage secretome show POSITIVE initial signals in small human trials, demonstrating improvements in symptoms like speech, social interaction, and language impairment. The mechanism is hypothesized to involve correcting the imbalance between Th1 and Treg cells. These interventions are highly experimental but have been reported as safe in the limited cases studied. Gc protein-derived macrophage activating factor is listed primarily for its mechanistic interest (in vitro), but it is generally considered unproven and risky due to a lack of clinical evidence and issues surrounding its licensing and production. Allergy immunotherapy is relevant for treating comorbid atopy (allergies), not core autism spectrum disorder symptoms, though managing comorbidities can indirectly improve behavior. Overall, these interventions target specific biological pathways (e.g., T-cell differentiation, macrophage function) that are hypothesized to be dysfunctional in autism spectrum disorder, but they remain far from clinical recommendation and require extensive, rigorous double-blind randomized controlled trial validation. IL-2: Interleukin-2 (a type of cytokine); M2 macrophage: A type of macrophage (immune cell) associated with tissue repair and anti-inflammation; GcMAF: Gc protein-derived macrophage activating factor; Th1: T helper type 1 cell (an immune cell); Treg: Regulatory T cell (an immune cell that suppresses immune responses); In vitro: Experiment performed in a test tube or culture dish (outside a living organism); ASD: Autism spectrum disorder.

Table 7 The different biotic interventions to modulate the gut-brain axis

Intervention type	Definition/source	Key mechanisms on gut-brain axis	Examples	Observed effects (general and specific)
Probiotics	Live microorganisms (e.g., bacteria or yeast) that, when administered in adequate amounts, confer a health benefit on the host	Directly modulate the gut microbial composition. They produce short-chain fatty acids like butyrate, which can cross the blood-brain barrier. They also modulate the production of neurotransmitters (e.g., gamma-aminobutyric acid, serotonin) and reduce systemic inflammation	Bacteria: Lactobacillus species (Lactobacillus rhamnosus, Lactobacillus acidophilus), Bifidobacterium species (Bifidobacterium longum, Bifidobacterium infantis)	General: Improved mood, reduced anxiety, improved gut health (e.g., reduced IBS symptoms). Specific: Probiotics with Fructo-oligosaccharide in children with autism spectrum disorder were found to improve autism-related symptoms, increase beneficial bacteria, and reduce the hyper-serotonergic state and dopamine metabolism disorder
Prebiotics	Selectively fermented ingredients (often non-digestible fibers) that nourish and result in specific changes in the composition and/or activity of the beneficial gastrointestinal microbiota	Indirectly influences the brain by serving as food for beneficial gut bacteria, thereby increasing short-chain fatty acid production (especially butyrate). They enhance gut barrier function and indirectly influence the nervous system by reducing inflammation and modulating short-chain fatty acid signaling	Fibers: Fructans (inulin, Fructo-oligosaccharides), Galacto-oligosaccharides	General: Selective growth of beneficial bacteria (Bifidobacteria, Lactobacillus), enhanced mineral absorption, reduced constipation. Specific: Fructo-oligosaccharide used in combination with probiotics in children with autism spectrum disorder was associated with improved symptoms and beneficial gut change
Synbiotics	A product containing both Probiotics (live microorganisms) and Prebiotics (their selectively utilized food substrate) in a combined form	Combines the direct seeding and modulating effects of probiotics with the selective nourishment and short-chain fatty acid-boosting effects of prebiotics, potentially offering a synergistic effect on the gut-brain axis	Commercial blends containing strains such as Bifidobacterium and a fiber source such as Fructo-oligosaccharides or inulin	Effects are similar to or enhanced versions of those observed with single-agent interventions, often formulated to maximize the survival and activity of the probiotic strain

This table provides a clear taxonomy of interventions targeting the microbiota-gut-brain axis, a critical communication pathway between the central nervous system and the gut. These interventions aim to correct microbial dysbiosis, which is hypothesized to contribute to neurodevelopmental conditions like autism spectrum disorder. Probiotics are live microbial supplements that directly modulate the gut's composition and function, producing crucial metabolites like short-chain fatty acids (e.g., butyrate) that can influence the brain and modulate neurotransmitter systems (e.g., serotonin). Prebiotics are non-digestible fibers that indirectly support brain health by selectively feeding beneficial bacteria, thereby boosting short-chain fatty acid production and enhancing the intestinal barrier. Synbiotics combine both components to produce a synergistic effect potentially. In the context of autism spectrum disorder, specific studies on the combination of probiotics and fructo-oligosaccharides have shown promise, not only improving gut health but also reducing autism-related symptoms and correcting key metabolic issues, such as reducing the hyper-serotonergic state and dopamine metabolism disorder. This highlights a targeted strategy to manage autism spectrum disorder-associated symptoms and comorbidities by leveraging the connection between the gut and the brain. IBS: Irritable bowel syndrome.

Table 8 Level of evidence of the common pharmacological and biomedical interventions in pediatric autism spectrum disorder

Intervention type	Mechanism of action	Evidence level	Recommended dose (pediatric)	Common side effects	Key clinical notes
Antipsychotics
Risperidone	Antagonist of D2 (dopamine) and serotonin 2A receptors	High (FDA-approved for irritability)[1]	Initial: 0.25-0.5 mg/day. Target: 0.5-3.0 mg/day (weight-based)[2]	Weight gain, increased appetite, sedation, hyperprolactinemia, enuresis, tremor[3]	Most effective for irritability/aggression. Requires monitoring of weight, metabolic profile, and prolactin[4]
Aripiprazole	Partial agonist of D2 and serotonin 1A; antagonist of serotonin 2A	High (FDA-approved for irritability)[5]	Initial: 2 mg/day. Target: 5-15 mg/day[6]	Sedation, vomiting, tremor, akathisia, weight gain (less than risperidone)[7]	Metabolic profile generally better than risperidone. Can lower prolactin levels[8]
Psychostimulants
Methylphenidate	Blocks reuptake of norepinephrine and dopamine	Moderate[9]	Start low (e.g., 2.5-5 mg/day) and titrate. Max 2 approximately mg/kg/day or 60 mg/day[10]	Appetite suppression, insomnia, irritability, emotional lability[11]	Effective for ADHD symptoms but less tolerated in ASD than in pure ADHD. “Irritability” is a dose-limiting side effect[12]
Non-stimulants
Atomoxetine	Selective norepinephrine reuptake inhibitor	Moderate[13]	0.5 mg/kg/day to 1.2-1.4 mg/kg/day[14]	Nausea, fatigue, decreased appetite, early morning awakening[15]	Good alternative if stimulants aren’t tolerated. Effects may take weeks to appear[16]
Alpha-2 agonists
Guanfacine	Selective alpha-2A adrenergic receptor agonist	Moderate (RCTs available)[17]	1-4 mg/day (extended release)[18]	Drowsiness, fatigue, hypotension, dry mouth[19]	Effective for hyperactivity and impulsivity. Monitor BP and pulse[20]
Clonidine	Non-selective alpha-2 adrenergic agonist	Low/moderate (small RCTs)[21]	Oral/transdermal. Approximately 0.1-0.2 mg/day (titrated)[22]	Sedation (prominent), dizziness, hypotension, irritability[23]	Useful for hyperarousal and sleep. More sedating than guanfacine[24]
Mood stabilizers
Valproate	Increases GABA; blocks Na+ channels; epigenetic modulation	Low/moderate (mixed RCTs)[25]	Titrated to serum levels (50-100 μg/mL)[26]	Weight gain, GI upset, tremor, hair loss, thrombocytopenia, hepatotoxicity (rare)[27]	May reduce irritability/aggression. Avoid in metabolic disorders (mitochondrial)[28]
CBD	Modulates endocannabinoid system (low affinity CB1/CB2)	Low/emerging (one positive RCT)[29]	Variable. e.g., 20:1 CBD:THC oil or pure CBD[30]	Somnolence, decreased appetite, restlessness, diarrhea[31]	Shows promise for severe behavioral problems. Long-term safety data in kids is limited[32]
SSRI/antidepressants
Fluoxetine	SSRI	Low/negative for core symptoms[33]	Low dose start (e.g., 2.5-5 mg)[34]	Behavioral activation (hyperactivity, agitation), insomnia, GI upset[35]	Not effective for core RRBs in large trials. Use for comorbid anxiety/depression[36]
Sertraline	SSRI	Low/negative for core symptoms[37]	Low dose start (e.g., 25 mg)[38]	Hyperactivity, insomnia, GI disturbance[39]	May benefit a subgroup with specific genetic profile (solute carrier family 6 member 4 long/Long genotype)[40]
Metabolic/dietary
Methyl B12	Cofactor for methionine synthase; supports methylation	Low (small RCTs)[41]	64.5-75 μg/kg subcutaneous injection every 3 days[42]	Generally safe. Hyperactivity/agitation possible. Cobalt accumulation[43]	May improve clinical global impression in some children[44]
Folinic Acid	Reduced folate; supports methylation/DNA synthesis	Low/moderate (one positive RCT)[45]	High dose (up to 2 mg/kg/day; max 50 mg)[46]	Excitement, insomnia, aggression (rare)[47]	Improved verbal communication in FRAA-positive children[48]
L-Carnitine	Transports fatty acids for mitochondrial oxidation	Low (small/pilot studies)[49]	50-100 mg/kg/day (up to 400 mg/kg used in pilots)[50]	Fishy body odor, diarrhea/GI upset[51]	May help a subset with mitochondrial dysfunction. Odor is a limiting side effect[52]
Sulforaphane	Upregulates antioxidant response (Nrf2 pathway)	Low/moderate (mixed RCTs)[53]	Derived from broccoli sprout extract (variable potency)[54]	GI upset, insomnia, smell/taste aversion[55]	showed benefit in young adults; results in children are mixed[56]
Gut-brain axis
Probiotics	Modulate gut microbiota and gut-brain signaling	Low/moderate (mixed)[57]	Strain-dependent (e.g., Lactobacillus plantarum, Lactobacillus reuteri)[58]	GI bloating, gas (usually mild)[59]	Some strains improve GI symptoms and potentially some behavioral symptoms (anxiety)[60]
Fecal Transplant (FMT)	Restores diverse/healthy gut microbiota	Low/emerging (open label/small RCTs)[61]	Oral capsules or rectal enema (experimental protocols)[62]	GI symptoms (diarrhea, pain), fever (transient)[63]	Promising long-term data on GI and core symptoms in small cohorts. Investigational[64]
Experimental
Bumetanide	Diuretic; reduces intracellular chloride (restores GABA inhibition)	Low/controversial (failed phase 3)[65]	0.5-1.0 mg twice daily[66]	Hypokalemia (frequent), diuresis, dehydration[67]	Phase 3 trials terminated for futility. May benefit specific biological subgroups[68]
Oxytocin	Neuropeptide; enhances social cognition/bonding	Low/negative (large RCT negative)[69]	Intranasal spray (various doses, e.g., 24 IU)[70]	Nasal irritation, epistaxis[71]	Large trial showed no benefit over placebo[72]
Immunotherapy (IVIG)	Modulates immune system; neutralizes autoantibodies	Very low (case series/uncontrolled)[73]	Intravenous (hospital based)[74]	Headache, fever, aseptic meningitis, risk of infection/thrombosis[75]	Reserved for rare cases with identifiable autoimmune encephalitis/markers[76]

FDA: Food and Drug Administration; ADHD: Attention-deficit/hyperactivity disorder; ASD: Autism spectrum disorder, RCT: Randomized controlled trial; GABA: Gamma-aminobutyric acid; BP: Blood pressure; GI: Gastrointestinal; CBD: Cannabidiol; THC: Tetrahydrocannabinol; SSRI: Selective serotonin reuptake inhibitor; RRBs: Restricted and repetitive behaviors; FRAA: Folate receptor-α autoantibodies; Nrf2: Nuclear factor erythroid 2-related factor 2; FMT: Fecal microbiota transplantation.

Table 9 Summary decision matrix for common associated disorders frequently met in children with autism spectrum disorder

Primary symptom	1st line intervention	2nd line/alternative	Monitoring key
Irritability/aggression	Aripiprazole or risperidone	Valproate, cannabidiol	Weight, glucose, lipids, prolactin (risperidone)
Hyperactivity	Methylphenidate	Guanfacine, atomoxetine	Irritability, sleep, appetite
Anxiety/depression	CBT (behavioral)	Sertraline or fluoxetine	Behavioral activation (agitation)
Core social deficits	Behavioral therapy	Lactobacillus plantarum PS128 (probiotic)	Nonspecific
Language/speech	Speech therapy	High-dose folinic acid (if FRAA+)	Sleep disturbance (excitement)

CBT: Cognitive behavioral therapy; FRAA: Folate receptor-α autoantibodies.