Off-label psychopharmacological interventions for autism spectrum disorders: strategic pathways for clinicians

Abstract

The prevalence of autism spectrum disorder (ASD) continues to see a trend upward with a noticeable increase to 1 in 36 children less than 8 years of age in the recent MMWR. There are many factors linked to the substantially increased burden of seeking mental health services, and clinically these individuals are likely to present for impairments associated with co-occurring conditions. The advances in cutting-edge research and the understanding of co-occurring conditions in addition to psychosocial interventions have provided a window of opportunity for psychopharmacological interventions given the limited availability of therapeutics for core symptomatology. The off-label psychopharmacological treatments for these co-occurring conditions are central to clinical practice. However, the scattered evidence remains an impediment for practitioners to systematically utilize these options. The review collates the crucial scientific literature to provide stepwise treatment alternatives for individuals with ASD; with an aim to lead practitioners in making informed and shared decisions. There are many questions about the safety and tolerability of off-label medications; however, it is considered the best practice to utilize the available empirical data in providing psychoeducation for patients, families, and caregivers. The review also covers experimental medications and theoretical underpinnings to enhance further experimental studies. In summary, amidst the growing clinical needs for individuals with ASD and the lack of approved clinical treatments, the review addresses these gaps with a practical guide to appraise the risk and benefits of off-label medications.

Introduction

With the increased prevalence in the CDC’s recent MMWR surveys, there are trends of increasing the burden of individuals with ASD in clinical settings.¹ There is an expectation to provide evidence-based interventions to address serious impairments associated with ASD. Mitigating the impairments associated with the symptoms remains a key clinical reason for individuals and families seeking interventions. Given there are no approved psychopharmacological interventions for the core symptoms of ASD, the primary goal of pharmacotherapy in ASD is the treatment of comorbid mental disorders.² The experts overwhelmingly recommend empirically driven multimodal strategies, including primarily psychosocial treatments, psychopharmacological interventions, parenting sessions, and psychoeducation.³

In real-world clinical practice, the accessibility, higher cost, and questionable efficacies of many multimodal interventions remain a challenge, and therefore psychopharmacological treatments with parental psychoeducation on many occasions remain a mainstay of care planning.⁴ Among a limited repertoire of therapeutic options, risperidone was the first medication approved by the Food and Drug Administration (FDA) in 2006 for individuals aged 5 and above with irritability associated with ASD. Subsequently, aripiprazole (2009) was approved for the treatment of individuals 6 and over for similar indications.⁵

About 70% of individuals with ASD also have at least one comorbid psychiatric condition, and 41% also have two or more comorbidities.⁶ Taking into account the scope of the problem, there are many psychopharmacologic agents which are used safely and effectively for co-occurring conditions associated with ASD but have not undergone regulatory approval.⁷ These agents are referred to as “Off-label” for unapproved indications or age groups. A low or insufficient level of evidence is usually the basis for off-label. Off-label use is common and legal, unless it violates ethical guidelines or safety regulations, but carries legal liabilities due to potential health risks.⁸ The dearth of evidence-based psychopharmacological interventions has made off-label use of psychotropic medications common and upholds the right to health (1948 Universal Declaration of Human Rights). About 47% of psychopharmacological agents used in the children and adolescent (CA) population are off-label.⁹ Therefore, in this review, we appraise the empirical evidence supporting the use of off-label medications for co-occurring symptoms in ASD.

Methods

A comprehensive search of several databases including PubMed, PsychINFO, Cochrane Library, Google Scholar, Scopus, Medline, and web of science from inception to the date of the search was conducted. The search was designed using the following controlled vocabulary and keywords: “Autism*,” “SSRI” and other agents, “Oxytocin,” “Methylphenidate,” “Amphetamines,” “Aripiprazole,” “Risperidone,” “Antidepressants,” “Attention-Deficient Hyperactivity disorder,” “Propranolol,” “Valproic*,” “AcetylCysteine*,” “Amytriptiline” and other TCA’s, “Olanzapine,” Quetiapine,” “Ziprasidone,” “Clozapine,” “Lurasidone,” “Antipsychotic*,” “Lithium,” “Atomoxetine,” “Guanfacine,” “Clonidine,” Alpha-2-agonists,” “Lamotrigine,” “Benzodiazepine,” “Metformin,” “Melatonin,” “Trazodone,” “Mirtazapine,” “Buspirone,” “Amantadine,” “Memantine.” Keywords were selected by creating a list of the most commonly used psychotropic medications in the CA population in clinical practice.^{10, 11} The search was performed in all languages. A manual search was also conducted. We included any clinical studies or chart reviews examining the impact of psychopharmacology on the core symptoms of autism or associated comorbidities. Expert opinions and review articles were also included. “We used the following filter for age: Birth to 18 years.” 458 articles were identified after removing duplicates. Study abstracts were reviewed, and 96 of the studies meeting inclusion criteria were selected for this review. We attempted to encapsulate as many trials as possible in the review. We selected only those studies that were mutually agreed upon by the authors. 32 additional studies were added later by manual search. We also updated the material by reviewing reverse citations and added additional studies including numerous newer off-label use.

Results

We have summarized the findings in the following subsections of this narrative review.

Core symptoms

The hallmark of clinical presentations in ASD includes symptoms of restricted, repetitive behaviors and interests (RRBI) and social and communication impairment (SCI). The severity of the impairments is the rationale for multimodal interventions that include focused intervention practices (FIP) commonly used to teach specific skills to children with ASD. A few examples are behavioral strategies, pivotal response therapy, and picture exchange communication systems (PECS cards). A meta-analysis of 43 trials based on FIP found “medium positive effects” with a large effect size, especially with parent participation.¹²

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed medications for RRBI, but a 2013 Cochrane review of five RCTs concluded that SSRIs do not improve core symptoms, behavioral problems, self-injurious behaviors, or quality of life in individuals with ASD. The review further suggested behavioral activation and agitation due to SSRIs, and possible harm.¹³ Another meta-analysis found only modest benefits of fluvoxamine and no benefits with citalopram and fluoxetine in RRBI and, instead, found evidence supporting second-generation antipsychotics (SGA) like risperidone and aripiprazole. They concluded that SSRIs are not beneficial and that further studies are needed.¹⁴

Among the SGA, risperidone, the most vigorously studied medication, has shown some benefit in reducing RRBI in children with high irritability based on the secondary data analysis of the Research Units on Pediatric Psychopharmacology (RUPP) study,¹⁵ but the overall evidence for RRBI remains weak. Similarly, risperidone has weak evidence for SCI and it is attributed to indirect effects due to improvement in irritability.¹⁶

In our last section “Future directions,” we have discussed preliminary clinical trials on propranolol, divalproex sodium, oxytocin, sulforaphane, insulin growth factor 1, and acetylcysteine. Oxytocin deserves a special mention because initial studies have shown oxytocin to be promising, but recent meta-analyses¹⁷ have analyzed 12 RCTs on oxytocin and social cognition and on RRBI and found no significant effects of oxytocin on these two core symptoms.

Comorbidities

According to many epidemiologic studies, approximately 70% of individuals with ASD also have at least one comorbid psychiatric condition, and 41% have two or more.⁶ Among the most associated psychiatric illnesses with ASD are ADHD, irritability, sleep disturbances, anxiety, and depression. There are many medical comorbidities that are also linked with ASD, which must be assessed and intervened in order to address confounding effects on overall outcomes.

Attention-deficient hyperactivity disorder

The symptoms of hyperactivity, impulsivity, and inattention are observed in 28% of individuals with ASD.⁶ Before the changes in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5), ADHD and ASD (APA, 2013) were not mutually exclusive diagnoses. Therefore, the treatment studies prior to 2013 focused on symptoms of hyperactivity, impulsivity, and inattention which were considered intrinsic to ASD, and measured response to the interventions with proxies.

In the 1990s there were two low-powered studies on the effects of methylphenidate (MPH)^{18, 19} that were inconclusive. MPH in variable doses (7.5 mg to 50 mg) was found to be superior to placebo for hyperactivity symptoms in individuals with ASD; however, there was marked variability in the response and a higher likelihood of adverse effects like a decrease in appetite and insomnia.²⁰ According to a recent Cochrane review, high doses of MPH (0.43 mg/kg/d- 0.60 mg/kg/d) showed significant improvement in hyperactivity. There was a “significant but not clinically relevant” benefit in attention span, but there was no conclusion on impulsivity due to lack of data.²¹ Furthermore, MPH did not affect any of the core symptoms such as social interactions, stereotypical behaviors, or impaired communication. Three out of the four trials on MPH^{18-20, 22} were included in the quantitative analysis. Since the three included trials were short-duration trials with small sample sizes, and children intolerant to MPH were excluded during testing, the overall quality of evidence was low and inconclusive.²¹ Another 6-week open-label trial (2017) found long-acting liquid MPH was beneficial for ADHD symptoms in 27 CA with ASD and comorbid ADHD.²³

A noteworthy trial found that MPH significantly improved performance in tasks requiring sustained attention, selective attention, and inhibition/impulsivity. In general, the relationship between dose and response was linear in the dose range studied, and there were no signs of deterioration at higher MPH dose levels.²⁴ Recent literature suggests that youth with high-functioning ASD respond linearly to MPH, but that might not be the case for low-functioning youth with ASD among whom experts recommend titrating the dose cautiously to avoid undesired effects, such as behavioral activation.²⁵ There are no published studies on amphetamine (AMP) in individuals with ASD and comorbid ADHD. A systemic review aimed at studying the effect of stimulants on irritability in ASD found that none of the trials on stimulants (MPH or AMP) studied the effect on irritability, and there is no evidence for or against the use of stimulants for irritability in ASD.²⁶

ATX is an inhibitor of the norepinephrine transporter, preventing the reuptake of norepinephrine, and is approved for use in ADHD in children 6 years and above. Atomoxetine has been studied, primarily for ADHD but secondary analyses of the data were conducted for the core symptoms of ASD. The initial studies on ATX in ASD (Troost et al.²⁷; Posey 2006²⁸) have shown that ATX (1.2–1.4 mg/kg/day) is beneficial for mild to moderate ADHD symptoms. Additionally, there were some benefits to social withdrawal and stereotypical and repetitive speech. However, it is associated with adverse effects like gastrointestinal symptoms, irritability, sleep disturbances (SD), and fatigue. About 42% of participants in a study²⁷ completed the trial and the rest dropped out due to side effects. A group of Dutch researchers in an 8-week trial compared ATX (1.2 mg/day) to a placebo in individuals with ASD and ADHD and found that besides the improvement in ADHD symptoms (primary outcome measure),^{29, 30} there were additional benefits with speech, stereotyped behaviors, and fear of change.³¹ In a 28-week follow-up study, the authors concluded that continued treatment improved ADHD symptoms, while adverse events decreased. Evidence, however, was weak, and higher-powered studies are necessary.³² Similarly, another 10-week double-blind multicenter randomized cross-over trial comparing ATX with or without Parental Therapy (PT) and a placebo of 128 CA participants with ASD and ADHD was conducted at three sites. The results suggested that ATX and PT were better than placebo for ADHD symptoms³³ with effects sustained over a 24-week extension study³⁴ and at 1.5 years follow-up.³⁵

Another medication that is less commonly used in ASD is bupropion which has no data from clinical trials. It is used as an off-label second-line medication for ADHD, although the effect is weaker than that of stimulants.³⁶ It is used for depression in individuals thought to have irritability due to bipolar disorder, and this use is through extrapolation of the data in the adult population which suggests that bupropion is least likely to worsen mood.³⁷ This clinical decision is not evidence-based in CA,³⁸ and even amongst the adult population, the evidence is weak.

Clonidine and guanfacine both activate the alpha-2 receptors at the prefrontal cortex, preventing the secretion of norepinephrine, which helps with cognitive and emotional functioning. Clonidine binds to all three types of alpha-2 receptors A, B, and C, while guanfacine is specific for alpha-2 receptor type A. The long-acting form of both, clonidine extended-release (CXR) and guanfacine extended-release (GXR), are FDA-approved in the pediatric population both as monotherapy for ADHD and as an adjunct to stimulants. The shorter-acting clonidine and guanfacine are used off-label for insomnia associated with (hyperarousal effects of) stimulants.³⁹ A recent systematic review found limited evidence for clonidine’s ability to treat behavioral problems in ASD. They found that most data are from case reports and limited guidance is available. However, it continues to be clinically used, and given the due paucity of pharmacological options for challenging behaviors in ASD, a clonidine trial may be an appropriate and cost-effective option. Daytime sedation related to clonidine is a common adverse effect affecting its overall effectiveness.⁴⁰

In a multisite RCT,⁴¹ extended-release guanfacine (GXR) was compared to a placebo in children with ASD (mean age, 8.5 years) over 8weeks, and was found to be safe and effective in treating hyperactivity in this group of children. GXR was found to reduce oppositional behavior and repetitive behaviors, but not to improve anxiety or sleep, in an analysis of secondary outcomes.⁴²

Interestingly, SGA may also be effective in treating ADHD in ASD, and one open-label pilot RCT showed that both aripiprazole and risperidone showed improvement in ADHD symptoms after 24 weeks of treatment.⁴³

Irritability, aggression, self‐injurious behavior, and disruptive behaviors

Antipsychotics are the most prescribed medications for individuals with ASD irritability, aggression, and disruptive behaviors. Second-generation antipsychotics, which offer additional serotonin receptor blockade, are generally preferred in the CA population over typical antipsychotics due to less likelihood of extrapyramidal side effects. Risperidone and aripiprazole are FDA-approved for irritability associated with ASD.⁵

Risperidone was FDA-approved in 2006 after two positive double-blinded, placebo-controlled, randomized controlled trials (DB-PC-RCTs) of 8 weeks in CAP with ASD.^{44, 45} Risperidone at a mean dose of 1.8 mg/ day was found to be safe and effective for irritability.¹⁵ The safety and efficacy were maintained for up to 6 months.⁴⁶ Similarly, aripiprazole’s safety and efficacy for irritability associated with ASD were established by two DB-PC-RCTs for a duration of 8 weeks^{47, 48} which guided FDA approval in 2009.

In many cases of risperidone-induced hyperprolactinemia and galactorrhea, a small dose of aripiprazole in addition to risperidone is highly effective.⁴⁹

One study suggests 59.8% of antipsychotics used are off-label in CAP with ASD.⁵⁰ Much of this use is through extrapolation of research in pediatric bipolar disorder where lurasidone and asenapine were recently approved in addition to risperidone and aripiprazole. However, other SGAs, such as olanzapine, quetiapine, asenapine, ziprasidone, and clozapine, have not been evaluated by adequately powered RCTs. Small trials with lurasidone were negative while there are no trials on asenapine.

Lurasidone has a chemical structure similar to aripiprazole but did not demonstrate statistically significant efficacy on the primary outcome measures compared to placebo. However, overall Clinical Global Impressions, (CGI–I) scores improved when fixed doses of 20 and 60 mg/day of Lurasidone were used in this study. Loebel et al.⁵¹ conducted a multicenter RCT with 150 participants and found that once-daily, fixed doses of 20 and 60 mg/day of lurasidone were not effective for treating short-term moderate-to-severe irritability associated with ASD. There are reports of response at higher doses which may be considered as an alternative when approved medications are not effective.⁵² In an 8-week small open-label trial of 11 adolescents with ASD-associated aggression, quetiapine was found to be effective and well tolerated with improvement in aggression and SD.⁵³ A 6-week head-to-head trial of olanzapine and haloperidol found that both olanzapine (mean dose 7.9 mg/day) and haloperidol (mean dose 1.4 mg/day) provided a statistically significant clinical improvement on the clinical global impression scale (CGI-S) and children’s psychiatry rating scale (CPRS) (p = 0.0008).⁵⁴ 6 out of 8 participants in another small open-label trial on olanzapine responded to a mean dose of 7.8 mg, improving hyperactivity, social relatedness, affectual reactions, sensory responses, and language. There were no changes in repetitive behaviors, however, and sedation and weight gain were the most common side effects.⁵⁵ In another 8-week DB-PC-RCT of 11 participants, 50% responded to olanzapine compared to 20% placebo, with weight gain (7.6 +/− 4.8 lbs. vs 1.5 +/− 1.5 lbs. on placebo) as the common side effect.⁵⁶ In another open-label trial, 13 weeks of olanzapine treatment led to improved CGI-S scores in 30% of participants. There was an additional significant reduction in aberrant behavior checklist (ABC) sub-scores of irritability, lethargy, stereotypical behaviors, hyperactivity, and inappropriate speech.⁵⁷ There has been a lack of research on clozapine due to its potentially serious side-effect profile, and monitoring requirements and evidence are limited to case reports⁵⁸ and retrospective chart reviews,⁵⁹ which are not generalizable. An interesting secondary analysis of an 8-week open-label trial showed no difference in response rates or tolerance between risperidone, aripiprazole, ziprasidone, olanzapine, and quetiapine in those with bipolar disorder and ASD comorbidity.⁶⁰

Lithium and sodium valproate are effective mood stabilizers in treating persistent aggression in children, but data about ASD are scarce. While they are commonly prescribed to individuals with ASD and persistent aggression, data indicates that they may not be as effective as SGA at treating irritability.⁶¹ It may be helpful to use divalproex sodium when there are seizures and abnormal EEGs associated with ASD,⁶² but it should be used with caution due to adverse effects. In a 12-week double-blind placebo-controlled RCT of 55 individuals with a mean age of 9.63 years and mean non-verbal-IQ of 63.3 points, 62% showed improvement in the ABC-I scale with depakote, compared with 9% with placebo, with higher blood valproic acid levels showing a better response. Even though the results were optimistic, the study was small, and more research is needed.⁶³ In another study, the author found that divalproex sodium reduced repetitive behavior.⁶⁴ However, in a DB-PC-RCT involving 30 participants with a pervasive developmental disorder (PDD) and aggression, there was no difference between valproic acid and placebo. This was thought to be due to heterogeneity, small sample size, and large placebo response.⁶⁵

Mitochondrial diseases are more common in ASD⁶⁶ and divalproex sodium should be avoided in any individual with mitochondrial dysfunction due to the possibility of fulminant liver failure⁶⁷ In addition, divalproex sodium requires monitoring and has a side-effect profile that may cause long-term harm. Likewise, Rezaei et al.⁶⁸ found that risperidone plus topiramate was superior to risperidone alone. It is important to carefully evaluate the risks, benefits, and side-effect profiles before combining mood stabilizers.

Lithium may also be used for ASD, but the evidence is limited. In a retrospective chart review, 73.7% (n = 14) of patients with ASD and maladaptive behaviors showed improvement (CGI-I ratings of 3) when lithium was added to their treatment regimens.⁶⁹ The effects of lithium on individuals with ASD and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency) will be investigated in a future pilot study.⁷⁰ Monitoring lithium levels and lithium’s side-effects profile is also of concern, but at lower dosages, it is quite safe for individuals with intellectual disabilities.⁷¹ A study⁷² comparing placebo with lamotrigine for 16 weeks on 27 children (mean age 5.8 years) with ASD found no benefits.

Gabapentin is another commonly prescribed medication for ASD but lacks evidence. The only evidence available includes 1 case report for disruptive and compulsive behaviors⁷³ and 1 retrospective chart review for refractory insomnia in 23 CA with various neurodevelopmental disorders, 9 of whom had ASD. They found that 8 out of the 9 participants reported improvement in insomnia and was tolerated well.⁷⁴

Sleep disorders

ASD is associated with issues with sleep onset, sleep maintenance, and irregular sleep–wake cycles. Many causes have been discovered, including genetic abnormalities that disrupt the melatonin pathway. A meta-analysis found that, besides being very well tolerated, was beneficial for improving sleep characteristics, improving daytime behavior, and producing minimal side effects at doses ranging from 1 to 10 mg. The meta-analysis expressed concern about the small sample sizes in five of the included studies.⁷⁵ Additional studies indicate that children sleep longer and faster with good tolerability on melatonin.⁷⁶ Children’s PedPRM, prolonged-release melatonin, was also effective.⁷⁷ Long-term data on prolonged-release melatonin showed promise as well.⁷⁸ PedPRM was found to be safe and effective for children with ASD after a 3-month double-blind, placebo-controlled study. This study aimed to determine whether long-term use of PedPRM would affect sleep, growth, body mass index, and pubertal development. For the long-term treatment of CA with ASD and insomnia, PedPRM at a dose of 2, 5, or 10 mg was found to be safe and effective. In addition to the lack of adverse effects on growth and pubertal development, there was no withdrawal or safety concern related to the use or discontinuation of the drug.⁷⁹

The effectiveness of trazodone, a sedating antidepressant, in treating pediatric sleep disorders is lacking in both typically developing children and those with neurodevelopmental disorders; however, the drug is commonly used in clinical practice to treat insomnia. A retrospective review reported on trazodone’s use for the treatment of sleep problems associated with the opsoclonus-myoclonus syndrome, although no studies have specifically examined children with ASD or other neurodevelopmental disorders (NDDs).⁸⁰ There is the potential for priapism with trazodone⁸¹ and behavioral activation, given the similarities between trazodone and SSRIs.

Antidepressants may be beneficial for children who are anxious or depressed, but they should be used with caution as discussed above. There is also some evidence supporting mirtazapine in insomnia associated with ASD and it is discussed in the anxiety and depression section below. There is weak evidence that risperidone may help insomnia in ASD,⁸² especially in individuals with extreme irritability. However, the Canadian Academy of Child and Adolescent Psychiatry recommends against using SGA as a first-line medication for insomnia.⁸³

Anxiety and depression disorders

Polymorphism of serotonin transporter genes like SLC6A4 has been linked to ASD.⁸⁴ Also, depressive and anxiety disorders are common in ASD. A Stockholm cohort study found that 19.8% of individuals with ASD without intellectual impairment experienced depression by age 27 compared to 6% in the general population,⁸⁵ and 20.1% had anxiety compared to 8.7% in the controls.⁸⁶ In addition to depression and anxiety, they are often prescribed for RRBI which is a core symptom of ASD and can be distressing. OCD is another frequent comorbidity with ASD and is associated with worse outcomes in individuals with ASD compared to individuals without ASD.⁸⁷ OCD has a similar developmental pattern to RRBI, but it can be differentiated based on the characteristics of anxiety; obsessions may worsen anxiety while sameness and restricted communication may reduce anxiety symptoms. In a 2019 multicenter RCT among 146 individuals with ASD and obsessive-compulsive behaviors, fluoxetine (20–30 mg/day) was compared with a placebo over 16 weeks. They found a significant change in children’s Yale-Brown obsessive-compulsive scale modified for pervasive developmental disorders (CYBOCS-PDD) with fluoxetine, but it had a high dropout rate. Additionally, the study suggested the potential of confounders in the baseline measurement. They concluded that the efficacy remains uncertain.⁸⁸ Sample heterogeneity has been an issue in most clinical trials with SSRIs in ASD. Additionally, fewer trials are available on escitalopram, paroxetine, and sertraline, which may be more effective, and therefore there is a need for large RCTs.⁸⁹

One naturalistic open-label trial of mirtazapine⁹⁰ showed modest improvement to a mean dose of 30.3 mg. Of 26 participants, only 9 showed improvements in aggression, hyperactivity, and insomnia. The results of a DB-PC-RCT conducted over 10 weeks with 30 participants with ASD aged 5–17 found mixed results with mirtazapine for anxiety in ASD. An improvement in Pediatric Anxiety Rating Scale (PARS) was observed within the group (p = 0.001), but not when compared with the placebo group (p = 0.64).⁹¹

Buspirone is a partial agonist of pre-and post-synaptic 5HT1A receptors which was originally developed as an antipsychotic but was found ineffective. In subsequent studies, it was found to be mostly serotonergic with antianxiety effects due to presynaptic 5HT1A receptor agonism with some dopamine affinity. Although no dopamine affinity was found, some early research on buspirone in ASD was initially focused on hyperactivity.^{92, 93} In 1986, buspirone got FDA approval for generalized anxiety disorder in adults, but its use in CA is still off-label. Several studies have examined the effectiveness of buspirone in treating anxiety and irritability among individuals with ASD.^94-96 Low-dose buspirone may prove to be a safe alternative, especially in younger children, due to its favorable safety and side-effect profiles.⁹⁵ Since SSRIs are at risk for behavioral activation and akathisia; buspirone may be a suitable alternative. No clinical trials have been conducted on hydroxyzine in individuals with ASD. Benzodiazepines should not be used to treat irritability and aggression in ASD with a risk for behavioral disinhibition, which could worsen aggression.⁹⁷ Benzodiazepines may, however, be necessary to manage acute aggression.

Avoidant/restrictive food intake disorder and other feeding difficulties

ARFID is another condition that frequently co-occurs with ASD. One study estimated a prevalence of ARFID in up to 21% of individuals with ASD.⁹⁸ ARFID shares many symptoms with ASD including feeding problems and sensory aversions.⁹⁹ One meta-analysis estimates individuals with ASD are five times more likely to have feeding difficulties compared to TDY.¹⁰⁰ The treatment of ARFID is limited to modified behavioral therapies, and there is no medication that has evidence to support its benefits.¹⁰¹ Some case reports have suggested the benefits of mirtazapine but need further empirical support¹⁰² (Table 1).

Table 1. Key Studies Included in the Review

Discussion

ASD remains a highly heterogeneous condition, with a myriad range of genetic variations and developmental phenotypes. With a higher-than-ever prevalence of 1:36 (under the age of 8) in the United States, it is imperative to screen given in a proportion of individuals with ASD the signs and symptoms are often overshadowed by comorbidities. Late diagnostics are not uncommon and are often previously treated for co-occurring conditions without the awareness of underlying ASD and modifications wherein. Therefore, given its high comorbidity with both psychiatric and medical disorders, multiple interacting variables often challenge clinical diagnostics, and it often takes a deep understanding of the developmental aspects of ASD in deciding what, how, and when to treat (Figure 1).

Figure 1. A flowchart of a complex clinical pathway for diagnostics of ASD and assessment of co-occurring conditions. (a) Autism is a clinical diagnosis that incorporates levels of dysfunction and support needed in various contexts. (b) Testing is an aid to clinical diagnosis but is not necessary. ADOS-2 is an excellent test but is far from being the gold standard. (c) Testing should incorporate various elements including intellectual functioning, adaptive functioning, ADOS-2, ADI-R, and others. (d) ADOS-2 alone may only provide a 60-minute snapshot of symptoms and supplemental detailed parent interviews like ADI-R are helpful in improving sensitivity and specificity. (e) Given the high rates of false negatives, negative testing should be interpreted based on context and dysfunction. (f) In case of negative testing, consider diagnostic overshadowing or “Multiple Complex Developmental Disorder” which could lead to masking of symptoms, especially in HFA individuals. (g) If testing continued to be negative but clinical symptoms are suggestive of autism, consider diagnosing ASD. (h) Aggression in ASD can be complex and multimodal interventions have better outcomes. Interventions include considerations of sensory and food insensitivities along with ruling out any medical causes like constipation. (i) Although a linear dose–response was reported with MPH for higher-functioning ASD youths; however, experts suggest using caution with dose titration in lower-functioning ASD youths to avoid undesired side effects including behavioral activation. (j) Slow-dose titration of SSRI is recommended due to the risk of behavioral activation. There is a high risk of partial response and no response due to poor metabolism and precision medicine is recommended. (k) Could be secondary to sensory insensitivities or medical reasons.

Guiding principles of treatment with off-label medications

Due to these multilayered complexities, the diagnosis and treatment of ASD and its comorbidities is often a clinical conundrum requiring astute medical decision-making. It is not uncommon, and many symptoms associated with ASD are transdiagnostic and do not meet the threshold for a DSM diagnosis; however, the severity of symptoms (associated with impairments) continues to necessitate treatment despite a lack of evidence-based psychopharmacological interventions. Therefore, with marked variability in the clinical phenotypes, interacting risks, perpetuating factors, and limited resources, the onus is on synthesizing and sequencing the best available therapeutics with shared decision-making.

The off-label use of psychotropics may have better outcomes when clinicians are aware of the following guiding principles that apply to CA and more specifically to ones with ASD. Given the challenge of diagnostic uncertainty, it may be prudent to target symptoms since it takes a developmental course for the illness to develop. The knowledge of the quality, efficacy, safety, and intended use of therapeutics for unlicensed applications (“off-label” use) is critical prior to interventions. Always start low and go slow but may need a higher dose based on the pharmacokinetic profiles; also, multiple medications may be needed which requires an adequate duration of trial with optimal dosing before switching. While switching it is advised to change one drug at a time to gather information about the responses and adverse effects.

The incorporation of screening tools and standardized diagnostic tools under measurement-based care (MBC) is a recommended step to discriminate and identify co-occurring conditions. The clinical outcomes must be measured in two settings, with one preferably structured like a school, that could guide the need for titration or change. The knowledge of black box warnings, pharmacogenetics profiles, pharmacokinetics, gender difference, and so forth further advances the likelihood of response under the core strategies of precision psychiatry. Therefore, integrating psychiatric decision-making with MBC, and precision medicine approaches are the cornerstone for sequencing the psychiatric management of these highly complex clinical presentations. Although some advanced precision medicine tests might not be cost-effective or widely available, these could be considered for non-responders or partial responders. Lastly, psychoeducation about these off-label medications should be provided with NbN-2-based classification to effectively convey underlying mechanisms and rationale.¹⁰⁴

Synthesizing and sequencing treatments for multiple comorbidities

With the widely spread and scattered but rich literature on off-label therapeutics for ASD, there is a need to develop processes in how and when to target specific symptoms, diagnoses, and impairments. There are many moving targets, confounders, and caveats which we discuss in the subsequent sections.

Firstly, one of the most common presentations requiring interventions in individuals with ASD is emotional dysregulation. The term emotional dysregulation (ED) is a broad construct defined as a failure to regulate emotions appropriately with an excessive response to stimuli. The transdiagnostic symptoms of irritability (which is a proneness to anger) are a feature of several different DSM diagnoses and are difficult to discriminate from other mental disorders. It is also recommended to use broad, nonspecific, validated tools like the overt aggression scale (OAS), and the strengths and difficulties questionnaire (SDQ) to assess these symptomatologys. There are also more specific scales for ED in ASD like the affective reactivity index (ARI) and the aberrant behavior checklist (ABC). The applications of these measurement tools could assist in differentiating between persistent non-episodic irritability and frank mania (which tends to present as distinct episodes). It has been widely accepted that with the advances in MBC, it is useful to develop strategies using objective scales validated for symptoms and disorders in question. In the last decade, narrow scales have been developed, that have a propensity to detect salient features to discriminate when overlapping symptoms are present. When a decision is made to target impairing symptoms, multimodal interventions must be part of the treatment plan to maximize efficacies. While ABA and other evidence-based interventions are not widely accessible in all geographical areas, educating patients and families about the limitations of off-label interventions is necessary.

In individuals with ASD with chronic persistent irritability, the highest effect size is for risperidone and aripiprazole which are also considered the first line of treatment. Due to the difference in the half-lives, the response with risperidone is earlier as compared to aripiprazole, but they have similar effect sizes and must be considered as first-line interventions. The agents with shorter half-lives reach a steady state earlier, whereas ones with longer half-lives may take longer to achieve a response based on their pharmacokinetics profiles. Many studies have also shown that variable dose schedules have better outcomes as compared to the fixed-dose. This underscores the need for both optimal drug titration to a therapeutic dose and waiting for an adequate duration for a clinical response prior to the switch or if the agent is deemed ineffective.

In individuals with ASD with comorbid ADHD symptoms, chronic persistent non-episodic irritability could be a challenging symptom to treat. Unlike typically developing children, treatment of ADHD symptoms only after the titration of stimulant medication with or without alpha agonists and psychosocial interventions was not found to be statistically significant. In these individuals (with ASD with ADHD) who do not respond to conventional regimes (stimulants with or without alpha agonists), the addition of risperidone or divalproex sodium to the stimulants has been empirically supported.

About 50% of individuals with ADHD also have irritability or emotional dysregulation, and it is the most commonly co-occurring condition associated with ASD. It is highly challenging to differentiate the emotional dysregulation of ADHD from the irritability associated with ASD. Therefore, the decision to treat ED due to ADHD symptoms or irritability associated with ASD remains critical for overall outcomes. At the same time, the knowledge of the presence and absence of atypical sensory problems (ASP), co-occurring anxiety, tics, sleep disturbances, cognitive impairments, seizures, gastrointestinal problems, and RRBI is critical to incorporate into the choice of interventions.

The late diagnosis of ASD is common with many presenting with new onset problems after being stable for years on previous treatments for ADHD (with stimulants with or without alpha agonists). Interestingly studies of risperidone and aripiprazole targeting irritability measured on the subscale of the ABC also found improvement in the “hyperactivity/defiance and stereotyped behaviors” subscales in individuals with ASD.¹⁰⁵ In contrast, most of the studies on MPH in individuals with ASD failed to distinguish between hyperactivity and irritability.²⁵ This compelling evidence provides an overarching guide to avoiding a priori assumptions. Therefore, this specific group of individuals who were chronologically diagnosed late with ASD (as compared to ADHD) needs further assessment if they require titration of ADHD medication or switch to a different class of medications.

In disorders when higher comorbidities like ASD, it is a widely accepted general principle to treat an established clinical diagnostic than nonspecific irritability or aggression. However, in the case of the treatment of ADHD in individuals with ASD, there is a caveat in dosing stimulants for specific developmental phenotypes. Emerging literature has reported a linear dose–response with MPH for higher-functioning ASD youths;²¹ however, experts suggest using caution with dose titration in lower-functioning ASD youths to avoid undesired side effects, including behavioral activation. The knowledge of curve linear dose–response with MPH in lower-functioning ASD children is crucial to avoid adverse effects like iatrogenic insomnia with higher doses and therefore slow, gradual titration of MPH remains key for optimizing response in these subgroups.²⁵ Treatment-emergent mood lability (ie, mood dysregulation and mood-related adverse event) are also associated with MPH in individuals with ASD, and caution is needed during slow titration in lower-functioning ASD individuals. When only a partial response is observed with stimulants on ADHD symptoms, in the absence of any verbal or physical outburst or aggression the addition of alpha agonists like guanfacine¹⁰⁶ and clonidine¹⁰⁷ is recommended.

In a highly significant 2014 study “Treatment of Severe Childhood Aggression” (The TOSCA Study), there were additional benefits of adding risperidone to individuals with ADHD optimized on stimulants and parent training.¹⁰⁸ Although ADHD medications like MPH may partially reduce irritability in some individuals with ASD and co-occurring ADHD, on many occasions, dose-optimized ADHD treatments may not be sufficient. Therefore, at that point, assessment for combination treatment with additional psychotropics like risperidone or aripiprazole may be considered, given these agents have established efficacy and comparable effect sizes.

Uncovering confounders with emerging evidence and neuroscientific context of SSRIs controversies

Counterintuitively psychosis is also common (0–60%) in individuals with ASD, but unlike schizophrenia, it presents at an earlier age and has atypical presentations like behavioral disorganization, often suggestive of psychosis in individuals with ID and ASD.^{109, 110} About one in five individuals with subclinical psychotic symptoms were found at risk of conversion to psychosis.¹¹¹

SSRIs have commonly prescribed medications in CAP, although there have been many controversies related to black box warnings. Low-dose SSRI has been better tolerated; however, the risk and benefits rationale is yet to be empirically substantiated. In mouse models, the disruption of the excitatory/inhibitory (E/I) balance of cortical circuits is thought to underlie the pathophysiology of ASD¹¹² and the imbalance of the neuronal circuity in the prefrontal cortex (PFC). To understand the relationship between the serotonin transporter gene (SLC6A4) and the serotonin receptor 2A gene (HTR2A), the serotonin-transporter-linked polymorphic region (5HTTLPR)¹¹³ of SLC6A4 and SSRI response in ASD has been the area of interest.¹¹⁴ Studies comparing allele 5-HTTLPR (long (l) or short(s)) and response to SSRIs found the LL and SL groups showed a greater reduction in irritability scores than did the SS group.¹¹⁵

Serotonin systems have been dysregulated in ASD individuals and a study found a statistically significant decrease in serotonin transporters (5-HTT) within the anterior cingulate cortex (ACC). A decrease in 5-HT2 receptor density in the ACC in the adult cohort was found but not in child postmortem ASD cases as compared to controls. This suggests a deficit in 5-HTT within the ACC in individuals with ASD, while reductions in 5-HT2 density are age-dependent.

These findings also correlate with the behavioral activation associated with SSRI, observed in almost a third of the individuals with ASD.¹¹⁶ Younger children are more affected as compared to adolescents;¹¹⁷ likewise, poor-metabolizer with regard to P450-2D6, serotonin-transporter-linked polymorphic region (5HTTLPR)¹¹³ variability, and increase in the plasma concentration due to rapid medication titration are also linked to the activation.¹¹⁷

Another study reviewed messenger RNA expression in the HTR and found that the expression of excitatory glutamate serotonin 2A receptors HTR2A appears earlier than inhibitory GABA interneurons serotonin 2C receptors.¹¹⁸ These ontological delays could potentially contribute to the E/I imbalance.

While SSRI use is linked to some benefits in the reduction of RRBI, caution is required while using them in younger children. While there is a risk of dose-related activation, it is imperative to slow titration and discontinue if behavioral activation develops. Also, the role of precision medicine and pharmacogenetics data could clarify the nuanced individual variability. With emerging data linking higher deaths by suicide in ASD individuals it is paramount to be informed about the limitation of SSRIs and controversies about its association with black box warnings.¹¹⁹ Buspirone could be a non-SSRI alternative for anxiety disorders and mirtazapine for depressive illness.

Distinct sleep issues need special attention

Last, but not least, sleep disturbances have been extensively reported and studied and prevalence rates fall between 64% and 93% without much gender differences (girls may have stronger links between SD and RB). This section has been extensively covered in our earlier articles. SD is also known to be independently linked with worsening of the core symptoms and requires screening specifically for SD. The relationship is bidirectional and accounts for at least 22–32% variance in behavioral problems. The role of ASP in regulating arousal and over-responsivity to environmental stimuli has been found to be associated with SD. There is a strong neurobiological basis for SD in ASD, including genetic mutations in the circadian clock and non-circadian genes. Besides screening, it is also important to evaluate and identify if presentations and symptoms are consistent with subcategories like sleep-related breathing disorders, circadian rhythm sleep–wake disorders, sleep-related movement disorders (SLMD), and/or parasomnias. On some occasions, further gold-standard testing like polysomnography and expert evaluation with sleep specialists is required. With highly complex clinical phenotypes, the presence of comorbid disorders like ADHD could further add to the complexity, requiring knowledge of pharmacokinetics, safety, medication efficacy, available efficacy data, agent safety, dosing, and drug–drug interactions with concomitant medications. There is overwhelming empirical support for prolonged-release melatonin (PedPRM), an easy-to-use formulation that is efficacious, and a safe option for long-term treatment that improves caregivers’ quality of life. Interestingly, in individuals with ASD and SLMD, there is weak evidence for iron supplementation to augment ferritin levels to more than 50 ng/dl (Figure 2).

Figure 2. Overarching principles and multimodal interventions to mitigate impairments associated with ASD.

Conclusion

ASD is a heterogeneous neurodevelopmental disorder with varied phenotypic manifestations and co-occurring conditions. The presence of debilitating symptoms and impairments is often the reason for pharmacologic interventions. The rich but scattered literature on the off-label psychotropic agents in ASD alludes to the rationale, efficacy, and risks associated. Treatment aims to initiate the minimal effective dose while carefully considering the psychopharmacological agent’s risks, benefits, and side effects. Most medications being used for CA with mental health conditions are prescribed off-label, and therefore patient assent and parental informed consent are paramount. Although psychopharmacological interventions are no panacea, whenever available, behavioral and cognitive interventions along with parent training must be tried alone or in combination for improved efficacies.

It is recommended to start at a lower-than-usual dose and increase the dose every five half-lives of the drug, given the increased susceptibility to side effects in individuals with ASD. ASD populations are at a higher risk of experiencing side effects, including EPS and weight gain, and should be carefully monitored. An individual’s metabolic profile, waist circumference, and weight should be monitored regularly. In the event of weight gain, various interventions such as lifestyle modifications may be useful. It is important to monitor closely for side effects since there could be medical conditions that result in more severe side effects, such as GERD, and consultation with other subspecialties may be needed.

Limitations

Although we have endeavored to provide a comprehensive overview of the existing evidence, it is important to note that this is a narrative literature review. Our interpretation of the studies and conclusions drawn from them may be influenced by selection biases. To avoid any possibility of misleading conclusions, we not only reviewed clinical trials for objective data but also tried to include expert opinions or any other narrative reviews. This information must be used carefully, and clinical judgment must be exercised as the overall evidence supporting it is either low or insufficient and it continues to be off-label. There are many overlapping symptoms in the co-occurring disorders, which could be difficult to differentiate. The review also does not focus on multimodal treatments often recommended for these conditions.

Future directions

There are many ongoing trials to empirically test the scientific hypothesis that continues to provide guidance and hope for the future of therapeutics for ASD. Metformin is commonly used for the treatment of antipsychotic-induced weight gain is metformin¹²⁰ but it is also beneficial in rodent models (AMPK activator-related neuro-protective effects) for spatial and verbal memory. The early use of postnatal metformin improved social interactions and reduced repetitive behavior in Black and Tan Brachyury (BTBR) mice.¹²¹ Despite its neuroprotective effects, a 2018 meta-analysis found no further improvement in mini mental status exam (MMSE) scores, and though metformin may be helpful, no data supports its use in individuals without diabetes.¹²² A 32-week, two-phase study was conducted examining the effects of metformin on spatial and verbal memory in 51 patients with atypical antipsychotics-associated weight gain; results showed no difference in spatial or verbal memory over 32 weeks, although there was nominally better spatial memory on the NSPSY-II in 16 weeks.¹²³

Fragile X syndrome (FXS) is one of the most common genetic conditions associated with ASD. A case report of two individuals with FXS who had been treated with metformin clinically for 1 year showed significant cognitive and behavioral improvements, as well as normalizing their weight percentiles.¹²⁴ In a DB-RCT currently underway at the University of California, Davis (2022), for individuals with FXS ages 6–25, metformin will be evaluated for the treatment of language deficits, behavior problems, and obesity/excessive appetite.¹²⁵

There are many preliminary trials of propranolol to study its effects on cognitive functioning in ASD, which includes improvement in verbal problem-solving¹²⁶ verbal decision-making,¹²⁷ and category fluency.¹²⁸ A series of trials tested the short-term effect of administration of propranolol and found improved working memory,¹²⁹ reduction in oral fixation,¹³⁰ and conversational reciprocity.¹³¹ Propranolol led to faster performance in verbal problem-solving, and there was an improvement in autonomic activity and anxiety, which can be potential biomarkers for response to propranolol.¹³² Two studies used fMRI and found increased functional connectivity, which could be a potential image marker of cognitive effects of propranolol in ASD.^{127, 133} London did a retrospective study on 46 adults and adolescents with ASD with adjunct propranolol and found that 85% of participants had much or very much improved CGI scale.¹³⁴

Based on mouse models, the IGF-AKT–mTOR signaling network is over-active at synapses, making neurotrophic factors like IGF-1 potentially useful for the treatment of ASD by reducing neuroinflammation. Researchers have found that IGF-1 may restore function in Retts and ASD caused by SCHANK3 gene deficiency, but these are preliminary findings that require further testing for their efficacy and safety.¹³⁵

A promising agent has been oxytocin, which is responsible for the formation of monogamous bonds in prairie vole rats. Research has indicated low blood oxytocin levels in ASD children as compared with those with typically developing youths.¹³⁶ Ooi et al.¹⁷ reviewed 12 RCTs in a meta-analysis of oxytocin and its effect on social cognition and on restricting repetitive behaviors and found no significant effects of oxytocin on these two core symptoms. One of the proposed explanations is the incapacity of oral or intranasal oxytocin to penetrate the blood–brain barrier. Newer molecules such as Melanotan II are being studied to improve oxytocin delivery to the brain.¹³⁷ Similarly, Horvath compared 5 RCT in his meta-analysis of omega 3 fatty acids in ASD and found no effects of omega 3 in individuals with ASD with a limited number of studies and a small sample size.¹³⁸

Another proposed etiology of ASD is inflammation and oxidative stress, and multiple agents have been investigated. Some initial evidence suggested low levels of carnitine, a cofactor for carnitine Acyltransferase enzyme, are associated with more severe symptoms of ASD.¹³⁹ A review of clinical studies on levocarnitine¹⁴⁰ found low evidence but suggested a subgroup of ASD with altered mitochondrial metabolism who responded to levocarnitine. This is noteworthy as mitochondrial diseases are more common in ASD compared to TDY.⁶⁶

Another theory related to mitochondria is the dysfunctional cell danger response and integrated stress response. When under stress, mitochondria cannot regulate oxidative metabolism and the release of purine and pyrimidine nucleotides. Suramin, an inhibitor of purinergic signaling, was tested based on this hypothesis in a small (n = 10) 6 weeks pilot trial which indicated a small but significant change in ADOS-2 comparison scores with some improvement in core symptoms.¹⁴¹ NAC can modulate free radical pathways and help treat ASD but a DB-PC-RCT¹⁴² found NAC 500 mg for 6 months ineffective.

Gluten and casein have also been implicated as potential etiologies of autism since they show excess opioid activity and permeability in the gut. Multiple reviews have examined the efficacy of GCFC diets.^{143, 144} and found no evidence to support it. Quan suggests GCFC is “promising”, but evidence levels were low as the studies were not double-blinded, and most had performance bias. We need more high-quality studies.¹⁴⁵

Sulforaphane, another potent antioxidant found in cruciferous vegetables, has been studied for its effect on autism.¹⁴⁶ looked at three RCTs and two open-label trials, which may offer some benefits, but the quality of evidence is low due to the small size of studies that were poorly reported and moderately biased.

An open-label 12-week study¹⁴⁷ studied add-on loxapine (BDNF stimulator) doses of 5–15 mg in 16 participants with ASD who were on one or more psychotropics of different types. Most improved in their Clinical Global Impression-Improvement scale (CGI-I) scores and their Aberrant Behavior Checklist- irritability (ABC-I) subscale scores with minimal side effects. They measured loxapine and metabolites 7-hydroxyloxapine, 8-hydroxyloxapine, and amoxapine concentrations in addition to using the brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation and found that the concentration of BDNF increased statistically significantly. Low-dose loxapine is a medium potency antipsychotic with D2 and 5HT2 receptor blockage, mostly resembling SGA at low dosages,¹⁴⁸ and may be an option for irritability. A retrospective chart review of 50 CA with ASD and hyperactivity and impulsivity who have been prescribed amitriptyline (mean dose of 1.3 mg/kg/day). The results showed that 60% of the participants improved in their CGI-I scores.¹⁴⁹ The use of brain-derived neurotropic factor stimulators, such as loxapine or amitriptyline, deserves further study.¹⁵⁰

NMDA receptor antagonists memantine and amantadine have also been studied. Initially, memantine showed promise,^{151, 152} but later trials have been negative.^{153, 154} Open-label trials in adults with ASD¹⁵⁵ found some benefits. A recent small study found that memantine improved verbal recognition memory as measured by Narrative Memory-Recognition (NEPSY-II) (p = .03).¹⁵⁶ The tolerability of memantine was not a concern in any of the studies. As with amantadine, early studies showed promise, either as a monotherapy¹⁵⁷ or in combination with risperidone,¹⁵⁸ but the quality of the evidence is low. Based on a retrospective cohort study conducted at Baylor University in Texas between 2014 and 2018 on 297 children ages 6–18 years with psychiatric disorders (ADHD being the most common 251/297), amantadine (median dose 200 mg daily) resulted in favorable clinical outcomes in 67.8% (40/59) of individuals with ASD, suggesting its benefits in individuals with ADHD comorbid with ASD.¹⁵⁹