Submission: April 16, 2021; Published: May 11, 2021

*Corresponding author: Jonathan R. Stevens, M.D., M.P.H., Chief of Outpatient Services and Child & Adolescent Psychiatry, The Menninger Clinic, 12301 Main Street, Houston, TX 77035, United States

How to cite this article:Jonathan R S, Theodore A S. Pharmacologic Approaches for Autism Spectrum Disorder: Treatment Beyond Risperidone and Aripiprazole. Psychol Behav Sci Int J .2021; 16(5): 555950. DOI: 10.19080/PBSIJ.2019.10.555950.

Abstract

Psychopharmacology for children, adolescents, and adults with ASD with co-occurring psychiatric disturbances and behavioral issues is an emerging area of pharmacology. Although only risperidone and aripiprazole are FDA-approved for use in patients with ASD, numerous medications have been used to treat the symptoms of ASD, such as irritability, aggression, and aberrant social behavior. Limited clinical data have supported treatments with SSRIs, stimulants, NMDA-receptor antagonists and other agents, but well-designed studies and larger cohorts are needed. In general, psychopharmacology for these patients is prescribed by specialists familiar with ASD (e.g., developmental pediatricians, child psychiatrists, child neurologists). Because of shortages of these providers, primary care physicians often oversee the prescription of psychotropics for those with ASD and co-occurring psychiatric needs. Consultation with a specialist is often indicated.

Keywords: Autism spectrum disorder; Attention deficit hyperactivity disorder; Disruptive behavior disorders; Psychopharmacology; Psychiatrists; Neurologists; Psychotropics; Food and Drug Administration.

Introduction

Autism spectrum disorder (ASD) is a complex condition with significant heterogeneity that poses challenges related to assessment and treatment, even for experienced providers. Evidence suggests a high prevalence of co-morbid psychiatric conditions in ASD (70% have at least one, 41% have more than one) [1]. Common co-occurring conditions include attention deficit hyperactivity disorder (ADHD), disruptive behavior disorders, anxiety disorders, obsessive-compulsive disorder (OCD), mood disorders, and psychotic disorders. Other associated problems encountered frequently by providers include intellectual disability, seizure disorders, sleep disturbances, self-harm, irritability, and aggression (e.g., towards caregivers). The presence of co-occurring neurodevelopmental, medical, and psychiatric disorders often complicates manifestations of ASD, response to treatment, and overall prognosis. Therefore, evaluating and optimally-treating co-morbid conditions and/or associated problems is essential, for providers who work with autistic youth and adults.

Pharmacologic treatment may be a useful adjunct when behavioral and educational supports have been maximized in children with ASD [2]. Typically, early behavioral and educational interventions target improving language (i.e., comprehension and ability to communicate). Families who are considering pharmacologic treatment for their children should know that currently-available agents do not treat the core symptoms of autism and in general should be initiated only after educational and behavior interventions are in place and when general medical conditions have been addressed and psychosocial/environmental stressors considered. In general, the approach to pharmacologic management for individuals with ASD resembles the approach to pharmacologic intervention for individuals with other psychiatric conditions. Medications should target clearly-defined symptoms, and those symptoms should be measured over time (preferably using rating scales) to monitor treatment effectiveness. It is also important to periodically re-evaluate the need for continued treatment to avoid unnecessary or burdensome interventions that accumulate over time. It is crucial for individuals with ASD or their families to recognize that children with ASD are more likely to develop adverse effects than are children without ASD [3]. Moreover, given the difficulties such individuals have identifying and communicating emotions, it can be difficult to determine a primary target symptom or symptom cluster (e.g., anxiety, impulsivity, anger), and therefore, the most appropriate pharmacologic intervention. For similar reasons, it can be challenging to monitor side effects (e.g., dizziness, tachycardia, dry mouth) that may not be immediately obvious to prescribers. The potential benefits and risks of pharmacologic therapy for children with ASD must be weighed on a case-by-case basis. Although only risperidone and aripiprazole are the only drugs approved by the US Food and Drug Administration (FDA) specifically for irritability in children with ASD), these medications are often used off-label.

Here we review the pharmacotherapy for individuals with ASD. The literature supports the efficacy of risperidone, aripiprazole, methylphenidate (MPH), and some selective serotonin re-uptake inhibitors (SSRIs) for the treatment of problematic behaviors that co-occur with ASD. Despite being widely used, there is considerably less evidence for the use of divalproex sodium, atomoxetine, and other psychotropics. However, despite limited evidence, there may be a role for alpha2 agonists, glutamatergic agents, cholinergic agonists, and oxytocin; all of these agents require further investigation.

Target Symptoms Versus Symptom Clusters

Pharmacologic therapy may be warranted in individuals with ASD if behavioral/environmental interventions are ineffective or are insufficient to successfully manage target symptoms. Target symptoms or symptom clusters that may respond to pharmacologic interventions include:

i. Inattention, hyperactivity, and impulsivity

ii. Maladaptive behaviors, including aggression, explosive outbursts, and self-injury.

iii. Restricted, repetitive behaviors and interests

iv. Insomnia and sleep disturbances

v. Social deficits

vi. Cognitive deficits

Inattention, Hyperactivity and Impulsivity

Individuals with ASD, particularly children, have higher rates of inattention, hyperactivity, and impulsivity occurring in one-third to one-half of affected persons [1]. Unfortunately, few controlled trials of pharmacotherapy to treat these symptoms (particularly in children with ASD) have been conducted [4]. The largest controlled trial involving the use of a stimulant, MPH, and was conducted by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network [5,6]. In this study, approximately one-half of children with ASD responded to MPH (as measured by a hyperactivity subscale, the Aberrant Behavior Checklist [ABC]); the effect size ranges from 0.20 to 0.54 depending on the dose or the rater, with greater improvement evident at higher dosages. Our own experience with MPH is that MPH produces highly variable responses in children with ASD and with co-morbid symptoms of ADHD. Responses range from marked improvement with few adverse effects to poor response with or without problematic adverse effects. Children with ASD, ADHD, and co-morbid intellectual disability can be effectively treated with MPH, though adverse effects tend to be more commonly reported than they are in children with only ADHD [7]. In general, when ADHD symptoms are severe and/or functionally impairing, it is reasonable to proceed with a trial of MPH. We warn parents of the lower likelihood of response in children with ADHD who are treated with stimulants and make note of the potential adverse effects. We typically start with a low initial dose (e.g., 0.125 mg/ kg three times daily, depending on the preparation), and increase the dose steadily thereafter. Treatment should be interrupted if the child’s behavior deteriorates or if other unacceptable adverse effects (e.g., insomnia, anorexia, increased self-harm) arise.

Despite the wide usage of amphetamines in children with ASD in the US, for those with ADHD there are no published data on the efficacy of amphetamines. Lisdexamfetamine (a pro-drug containing D-amphetamine found in the amino acid, lysine) is one of the most widely-prescribed stimulants; it has been effective and well-tolerated in treating ADHD in children and young people [8], however, there are no specific data about its use in those with ASD

Atomoxetine, a noradrenergic (non-stimulant) re-uptake inhibitor approved for the treatment of ADHD has infrequently been studied in those with ASD. Evidence from small, open-label trials and a handful of randomized double-blind trials suggests that it may be useful in children with ASD [9,10] but large-scale randomized controlled trials (RCTs) are lacking. Our experience is that atomoxetine has a marginal effectiveness in those with ASD and is best suited for children with milder ASD symptoms.

Alpha2 adrenergic agonists (e.g., guanfacine and clonidine, which are available in immediate-release and extended-release formulations) are useful in the management of symptoms of inattention, hyperactivity, and impulsivity in children with ASD. Although studies of alpha2 adrenergic agonists are limited, and sample sizes are small, these agents appear safe and effective in the management of hyperactivity and impulsivity in ASD. A multi-site, 8-week, RCT of extended-release guanfacine compared with placebo in children with ASD showed that it was welltolerated and effective [11]. Adverse effects of guanfacine include sedation, constipation, irritability, and aggression. Two small crossover trials using clonidine suggested that it decreased irritability, stereotypies, hyperactivity, inappropriate speech, and oppositional behavior [12,13]. However, side effects included hypotension and sedation. As a result, children treated with alpha2 adrenergic agonists should have their blood pressure and heart rate monitored at each office visit. The parents of affected children should also be warned against taking additional doses of this medicine during times of crisis as these agents could create significant harm if taken in excess. Parents should be counseled about the narrow therapeutic window of these medicines for safety; all medicines should be secured from children in the home.Alternatively, a transdermal form of clonidine, available as a onceweekly applied transdermal patch, can be effective.

Maladaptive Behaviors/Problem Behaviors, Including Irritability, Aggression, Explosive Outbursts, and Self-Injury

Aggression towards others and oneself are common and vexing problems for those who treat individuals with ASD. Although behavioral and environmental approaches should be firstline treatments, more severe and dangerous behaviors usually necessitate pharmacotherapy to avert inpatient psychiatric hospitalization, school expulsion, or involvement with law enforcement. The recommended duration of pharmacotherapy is difficult to derive from published evidence, but treatment appears to be beneficial for 6-12 months (evidence for longer durations of treatment, which is common in regular practice, is difficult to identify in the literature) [14]. Efforts to reduce and possibly discontinue such treatment at the end of this period should be considered.

Second-generation antipsychotics (SGAs) are first-line pharmacologic treatment for children and adolescents with ASD and irritability. Risperidone and aripiprazole have been reliably shown to reduce irritability, disruptive behaviors, aggression, and hyperactivity. Both have been approved by the FDA to treat irritability that is associated with ASD. A systematic review [15] carried out a meta-analysis of 46 RCTs comparing the efficacy of risperidone, aripiprazole, and other compounds with that of placebo. Risperidone and aripiprazole were the most effective agents in terms of effect size. Although other compounds showed some efficacy with perhaps better tolerability, these results were generally derived from single studies. Risperidone is currently FDA-approved for the treatment of irritability that presents with aggression, tantrums, and/or deliberate self-injury in children with ASD >5 years; aripiprazole has a similar indication for children aged 6-17 years.

Despite the initial promise and excitement elicited by the approval of risperidone and aripiprazole for treatment of irritability and ASD, the emergence of adverse effects has dampened initial enthusiasm. Commonly encountered side effects include increased appetite, weight gain, metabolic changes, and somnolence (risperidone more so than aripiprazole) [16,17]. One long-term, placebo-discontinuation study found that relapse rates did not differ between those who stayed on aripiprazole and those who were randomized to switch to placebo, suggesting that reevaluation of aripiprazole use after a period of stabilization and irritability symptoms is reasonable [18]. One study has made a head-to-head comparison that showed similar tolerability and efficacy profiles for risperidone and aripiprazole [19]. One side effect that differs between the two agents is asymptomatic hyperprolactinemia; in general, risperidone reliably increases prolactin levels in both boys and girls, whereas aripiprazole often lowers prolactin levels. Regular prolactin monitoring is advised with use of risperidone.

Other atypical antipsychotics are often used to treat disruptive behaviors in children with ASD. Evidence for clozapine, quetiapine, and ziprasidone primarily comes from open-label studies or case series. Additional research is needed before other agents can be recommended as the initial therapy for disruptive behaviors in children with ASD. However, parent preference, insurance formularies, or increasingly, results from pharmacogenomic studies lead families and practitioners to consider agents beyond risperidone and aripiprazole. In general, for severely aggressive or self-injuring patients, clozapine may hold promise for reducing aggressive, assaultive, and self-injurious behavior. Clozapine is currently FDA-approved for the treatment of schizophrenia and for reduction of suicidal behavior in those with schizophrenia or schizoaffective disorder. The drug acts as an antagonist at the alpha-adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors [20]. The efficacy of clozapine in limiting ASD-related disruptive behaviors has been the subject of a retrospective analysis, which found that treatment with clozapine resulted in a two-fold decrease in the number of days with aggression, a decrease in the number of psychotropics used, and a decrease in the dose of antipsychotic drugs [21]. Clozapine is associated with significant weight gain, metabolic syndrome, and asymptomatic tachycardia. Moreover, clozapine, at high doses, can cause seizures. For these reasons, it is rarely used as a first-line treatment in children or adults with autism; instead, it is usually reserved for more severe cases [22].

Conventional antipsychotics are also used to treat behavioral dyscontrol in those with ASD. RCTs suggest that haloperidol, a typical antipsychotic, is more effective than is placebo but less effective than is risperidone [23]. In addition, the risk of dyskinesia and other extrapyramidal symptoms (EPS) (that occur in approximately one-third of patients) limits its use [24]. Despite having risks, the more favorable metabolic profiles of these first-generation antipsychotics continue to generate interest. In severe cases, use of chlorpromazine is often effective in reducing severe aggressive, assaultive, or self-injurious behavior. Compared to haloperidol, chlorpromazine is less likely to cause EPS or dyskinesias. It is, however, more sedating and can induce sedation, urinary retention, constipation, and, in rare cases, druginduced hepatitis. There is considerable interest in other agents, which may be effective and safer than antipsychotics in those with ASD having dysregulated or aggressive behavior. Alpha2 adrenergic agents and N-acetylcysteine have led to improvement in symptoms with fewer side effects than antipsychotics in small studies (additional research is needed) [15]. Anti-seizure medicines and mood stabilizers (e.g., divalproex sodium [25] and lithium, respectively), SSRIs, stimulants, and beta-blockers are also used to treat disruptive behaviors in children and adolescents with ASD, albeit with a limited literature in support of these agents.

The effectiveness of other atypical antipsychotics (such as olanzapine, quetiapine, ziprasidone, and clozapine) has not been tested in adequately-powered RCTs. Controlled trials support the use of mood stabilizers (such as lithium and divalproex sodium) as effective in the treatment of persistent aggression in pediatric patients, although data suggest that mood stabilizers and anticonvulsants may not be as effective as SGAs in the treatment of irritability in ASD. Additional RCTs are warranted on brain-derived neurotrophic factor (BDNF) stimulators, such as loxapine and amitriptyline [26]. Use of benzodiazepines in ASD, to manage irritability and aggression is common, although it is not recommended by the literature or our experience. Although, use of a benzodiazepine may be necessary to manage a variety of conditions, worsening behavioral dysregulation is a common side effect of benzodiazepines in ASD (particularly children).

Repetitive Behaviors and Rigidity

Repetitive behaviors, stereotypies, and rigidity in individuals with ASD often interfere with functioning. The treatment for this symptom cluster often involves weighing the risks and benefits. Sometimes aggressive, assaultive, or self-injurious behaviors prompt pharmacologic treatment, even in the absence of evidence for effective treatment for repetitive behaviors. As with ASD in general, there is significant heterogeneity in the presentation of specific restrictive and repetitive behaviors. Pharmacologic research on these behaviors typically often does not account for this heterogeneity (i.e., high within-group variability in the experimental design), which may explain mixed findings and smaller effect sizes [27]. That said, investigators have studied potential treatments (including SSRIs, clomipramine, atypical antipsychotics, divalproex sodium, and buspirone) for repetitive behaviors in children with ASD.

Currently, there is marginal evidence from RCTs showing that SSRIs are beneficial for repetitive behaviors and rigidity [28]. Fluoxetine is an SSRI used for acute and maintenance treatment of major depressive disorder (MDD), acute maintenance treatment of OCD, acute maintenance treatment for bulimia nervosa, and acute treatment for panic disorder with or without agoraphobia. One study showed improvement in repetitive behaviors among adults with ASD treated with fluoxetine treated with doses of 20 mg to 80 mg daily. The most common adverse events were mild-tomoderate insomnia, headache, and dry mouth. However, a followup study in children showed that fluoxetine was no more effective than was placebo in treating repetitive behaviors. Citalopram, another SSRI currently approved for treatment of depression, was studied in a RCT; it was ineffective in reducing repetitive behaviors in children with ASD [29]. Moreover, citalopram was significantly more likely to be linked with adverse effects (particularly increased energy level, impulsiveness, decreased concentration, stereotypies, diarrhea, insomnia, and skin problems) than was placebo [28]. Clomipramine in the serotonin selective tricyclic antidepressant (TCA). The use of clomipramine for repetitive behaviors/stereotypies in those with ASD is based on its effectiveness in treating individuals with OCD. However, studies of clomipramine for repetitive behavior in children with ASD offered inconsistent findings [30]. Moreover, use of clomipramine has often been limited by side effects, including lethargy, tremors, tachycardia, insomnia, diaphoresis, nausea, decreased appetite, urinary retention, and severe constipation [31].

Buspirone is a non-addictive anxiolytic and partial serotonin agonist. In a small trial that compared low doses of buspirone to placebo in children with ASD, low-dose buspirone had no effect on the core symptoms of ASD but improved scores on the Autistic Diagnostic Observation Schedule Restricted and Repetitive Behavior Score (a secondary outcome) [32]. Although these results suggest that buspirone may be a useful adjunct to behavioral interventions for the treatment of repetitive behaviors, additional study, perhaps at more therapeutic doses, is necessary. Bumetanide, a potent loop diuretic indicated for the treatment of edema associated with congestive heart failure (CHF), hepatic disease, and renal disease (including nephrotic syndrome) was used in a small, double-blind, randomized placebo-controlled study in children with ASD. It showed significantly reduced scores of repetitive behaviors on both the CARS and Clinical Global Improvement (CGI) index [33]. The only adverse effect of active treatment was occasional mild hypokalemia (that may be treated by supplemental potassium). In our experience, bumetanide can cause profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required during drug treatment, and the dose should be adjusted based on the individual’s needs and laboratory values.

Insomnia and Sleep Disturbance

Many individuals with ASD, particularly children, have sleep disturbance, including frequent awakening, and restlessness [34]. The etiologies of sleep disturbances in ASD are currently unknown but may be related to abnormalities in melatonin, serotonin, or gamma-aminobutyric acid (GABA). The evaluation of sleep disturbance in children with ASD should include taking a thorough sleep history and screening for obstructive sleep apnea (OSA) or other sleep disorders. A referral to a specialist (e.g., a sleep specialist, psychiatrist, neurologist, or otolaryngologist) may be warranted if a specific sleep disorder is suspected or identified. It is also important to ensure appropriate sleep hygiene by using behavioral interventions. That said, medications are often used for insomnia, at times prompted by family members or by a consultation with a provider.

Melatonin is probably the most common agent used for insomnia today. The benefits of melatonin for sleep onset and maintenance in children with ASD has been noted by observational, open-label studies, and RCTs. A meta-analysis [35] of several randomized crossover trials of melatonin use in children with ASD suggested an increased sleep duration (by 73 minutes) and decreased sleep-onset latency (by 66 minutes, compared to placebo) but it did not affect night-time awakenings. Side effects were generally minimal. Therefore, over the short term (i.e., up to six months), 1-10 mg of melatonin may be effective in helping children with ASD to fall asleep and sleep well when administered 30 minutes before bedtime. However, dosing guidelines for administration are lacking as is information about the longterm use or side effects of melatonin. Our experience suggests that side effects of melatonin include difficulty with waking up in the morning, daytime sleepiness, and occasionally, enuresis [36]. Melatonin is sold over-the-counter and does not require a prescription. It is not regulated by FDA. In our experience, parents/ caregivers purchase melatonin and become attached to a specific brand and formulation. We often recommend that parents seek a formulation that contains melatonin as the only active ingredient.

Beyond the use of melatonin, research has shown that other agents have some utility. Mirtazapine is a tetracyclic antidepressant that enhances a central noradrenergic and serotonergic activity. While antidepressants are associated with an increased risk (compared to placebo) of suicidal thinking and behavior in children, adolescents, and adults with MDD and other psychiatric disorders, the risk of initiating an antidepressant agent for sleep must be balanced against the patient’s needs when mirtazapine (or any other antidepressant) is used to treat ASD. However, on at least one open-label study [37] of mirtazapine (with doses ranging from 7.5 mg to 45 mg nightly) showed that it was effective in improving insomnia in children, adolescents, and young adults with ASD and other developmental disorders. Of note, the treatment also did significantly improve aggression, self-injury, or irritability scores measured on the CGI. Adverse events included increased appetite and transient sedation. Some data suggests that low serum ferritin levels in children with ASD may contribute to restless sleep (even in children with normal iron levels). In one observational study, oral iron supplementation was beneficial in improving restless sleep in children with ASD and decreased serum ferritin levels [38].

Treatment of Social Deficits

Potential therapies to treat social deficits have long been sought in pharmacologic treatments of individuals with ASD. Social deficits, apart from other symptoms discussed thus far, represent a core component of autism. Thus far, pharmacologic agents that have demonstrated a potential for benefit of social deficits in those with ASD come from smaller, open-label, studies. Oxytocin, an endogenous hormone best known for its role in lactation and parturition, has been found to play a role in relationship formation and social functioning in both humans and animals [39]. Because ASD is associated with impaired social interaction and impaired communication, investigators have looked at the ability of intranasal oxytocin to reduce these deficits. A systemic review [40] of RCTs of intranasal oxytocin in those with ASD concluded “potentially promising” findings in measures of emotional recognition and eye gaze, which are impaired early while ASD and may disrupt the learning of social skills in developing children. Secretin is another endogenous hormone that regulates exocrine secretions in the stomach, pancreas, and gallbladder. It also acts as a neuropeptide in the central nervous system (CNS) [41]. A report from the Agency for Healthcare Research and Quality identified a publication that addressed treatment with human, porcine, biologic secretin in children with ASD [42]. According to the authors, none of these trials demonstrated significantly greater improvements in measures of language, cognition, or autistic symptoms (when compared with placebo). Another review [43] of 16 clinical trials of intravenous (IV) secretin in a total of 900 children with ASD found no evidence that the hormone was effective in this setting. As a result, secretin should not be recommended or administered as an ASD treatment.

Treatment of Cognitive Disorders

Research has examined the potential benefit of pharmacotherapy in the treatment of cognitive disorders associated with ASD. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist that is indicated for the treatment of moderate-to-severe dementia of the Alzheimer’s type has been studied in this regard. System activation of NMDA is believed to contribute to the symptoms of Alzheimer’s disease. A pilot study of memantine in children with ASD showed significant improvement from baseline in the Children’s Memory Scale Dot Learning Subtest memory evaluation [44]. However, there were no significant deficits from baseline in measures of expressive language, receptive language, or non-verbal IQ. Our experience suggests that patience is required when using memantine as a short-term agent; its benefits are elusive. That said, memantine is a usually well tolerated aside from the occasional emergence of diarrhea. Several of our patients have taken memantine for more than one year, and caregivers have reported slow, but sustained language acquisition and improvements with concentration.

The acetylcholinesterase inhibitor, rivastigmine, is indicated for treatment of mild-to-moderate dementia of the Alzheimer’s type and mild-to-moderate dementia associated with Parkinson’s disease. Although the drug’s precise mechanism of action is unknown, it is thought to exert its therapeutic effects by enhancing cholinergic function [45]. Rivastigmine has been evaluated in children with ASD to determine whether it improved cognition (including significant improvements in cognition at week 12 on the Gardner’s Expressive One-Work Picture Vocabulary Test) in patients during a 12-week study using oral rivastigmine [46]. Further investigation is warranted. Adverse effects (e.g., nausea, diarrhea, irritability, hyperactivity) were like those reported in adults.

Conclusion

Psychopharmacology for children, adolescents, and adults with ASD with co-occurring psychiatric disturbances and behavioral issues is an emerging area of pharmacology. Although only risperidone and aripiprazole are FDA-approved for use in patients with ASD, numerous medications have been used to treat the symptoms of ASD, such as irritability, aggression, and aberrant social behavior. Limited clinical data have supported treatments with SSRIs, stimulants, NMDA-receptor antagonists and other agents, but well-designed studies and larger cohorts are needed. In general, there is a paucity of long-term safety and efficacy data for psychopharmacologic agents in youth and adults with severe developmental disorders. Regular follow up with the prescriber as well as planned, supervised trials of medication discontinuation may be warranted to avoid polypharmacy. Psychopharmacology for these complex patients is best prescribed by specialists familiar with ASD (e.g., developmental pediatricians, child psychiatrists, child neurologists). Because of shortages of these providers, primary care physicians often oversee the prescription of psychotropics for those with ASD and co-occurring psychiatric needs. Consultation with a specialist is often indicated.

In general, individuals with ASD who are receiving pharmacologic therapy for target symptoms should be monitored regularly for efficacy and for side effects. Additional precautions and psychoeducation may be necessary for those receiving more than one psychoactive medication. After carefully considering a patient’s presentation and discussing potential risks and benefits, clinicians and parents/patient agree that pharmacotherapy is indicated for cognitive symptoms only after the potential benefits and risks have been weighed on a case-by-case basis. We recommend that the target symptoms for pharmacotherapy in those with ASD should be defined clearly. Medical causes for the behaviors should be excluded, and behavioral interventions should be maximized before pharmacotherapy is prescribed. More research is needed around psychopharmacology in individuals with ASD. In general, pharmaceutical companies have shied away from investing in ASD treatments and treatment of developmental disorders. This risk aversion to conducting research may be related to the condition’s unclear physiology, high level of heterogeneity, lack of few clear biomarkers, and poorly developed outcome measures for clinical studies [47]. Nonetheless, several clinical trials are ongoing [48]. Of these, oxytocin nasal spray is a popular therapeutic approach with other compounds under investigation

Acknowledgements:

We would like to thank Tina Holmes and Tiffany Tran for their assistance.

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