Guiding principles: a preamble to specific recommendations

The risk/benefit ratio of pharmacological treatment of co-occurring psychiatric symptoms in those with ASD can be greatly enhanced by prescribing according to the following principles. Although not unique to psychiatric treatment, these principles are particularly important when prescribing neuropsychiatric medications due to the severity of possible side effects, and when prescribing in the ASD population due to the potential complexity of individuals’ medical, behavioral and communication profiles. The four simple principles are:

1.

Start Low and Go Slow

2.

Monitoring Matters

3.

One Size Does Not Fit All

4.

Back to the Basics

Start Low and Go Slow

In prescribing medications for individuals with ASD, the principle of "Start Low and Go Slow" guides initial dosing strategies. It advocates for commencing treatment at the lowest practical dose and gradually titrating upward to attain therapeutic efficacy. This approach minimizes the risk of adverse effects while allowing for careful observation of individual responses to medication.

Monitoring Matters

Consistent monitoring for side effects and continued efficacy is paramount in ASD medication management. Some medications may have serious side effects that are challenging to recognize in ASD individuals who may not be able to self-report issues or who may report side effects only through behavioral changes that may appear independent of the side effects listed on the drug insert. This necessitates a thorough understanding of the potential adverse effects of each prescribed medication and familiarity with the presentation of side effects in patients with ASD. Given that individuals with ASD may exhibit atypical responses to medications or difficulties in expressing adverse effects of medications due to challenges with communication, regular check-ups are essential for the timely detection of emerging side effects. Additionally, some medications may lose efficacy over time, or the need for continued treatment may decrease or increase due to factors such as an individual’s development or environmental changes. Periodic assessment ensures that the medication remains necessary and continues to have the desired effect.

One Size Does Not Fit All

Tailoring medication treatments to individual needs is essential in ASD management. Recognizing the diversity of ASD presentations, clinicians must acknowledge that "One Size Does Not Fit All." For example, understanding patients’ tolerability to different medication formulations is key. Clinicians should be aware of available dosage forms, such as liquids, sprinkles, crushable or chewable formulations, and consider the patient's ability to swallow pills [35]. Moreover, compounding medications into a liquid formulation may offer a tailored alternative when patients are unable to comply with available formulations. Certain medications require regular blood draws to monitor for therapeutic levels and serious side effects, so it is important to know how well your patient tolerates blood draws before considering such medications. Approaches that account for individual patient needs have the greatest potential for compliance and patient satisfaction, leading to more successful treatment outcomes.

Back to the Basics

Amidst the intricacies of ASD medication management, the principle of "Back to the Basics" serves as a crucial reminder to pay attention to fundamental healthcare needs. Sudden changes in a patient's behavior or the emergence of acute medical or psychiatric conditions may signify underlying basic healthcare issues that have been overlooked. It is imperative for healthcare providers to remain vigilant and consider the possibility of common health concerns that may underlie an individual with ASD’s behavioral changes. Regular dental exams, for instance, are indispensable, as issues such as decayed wisdom teeth can lead to significant pain and behavioral changes. Pain or discomfort from gastrointestinal (GI) issues such as constipation or gastroesophageal reflux disease (GERD), which are common in ASD, may manifest as irritability. It is important to ask about constipation and diarrhea, and some cases may warrant a kidney, ureter, and bladder X-RAY (KUB) study. Some additional evaluations to assess basic care needs that should be considered include metabolic panels, Thyroid-Stimulating Hormone (TSH) tests or thyroid function tests (TFTs), blood count, inflammatory markers, Lyme disease panel, and uric acid level. By addressing basic healthcare needs, clinicians can identify when there are underlying medical causes of psychiatric symptoms and behaviors, ensuring appropriate care and optimizing overall well-being for individuals with ASD.

By integrating these four principles into clinical practice, healthcare providers can navigate the complexities of ASD medication management and enhance patient care.

A note on using the pharmacological treatment pathways

The treatment pathways defined later in Figs. 1, 2, 3, 4 and 5 involve a degree of context-dependent decision making due to the limited knowledge base in the literature. When deciding between medications within the same grouping, prescribers can consider factors such as how the medication side effect profiles will interact with patients’ unique clinical profiles. Prescribers may also want to consider prior familiarity with a medication as this may impact their proficiency with dosing, assessing efficacy and monitoring for side effects with a given medication.

Fig. 1

Pharmacological treatment pathway for sleep disturbances in patients with ASD

Fig. 2

Pharmacological treatment pathway for ADHD in patients with ASD

Fig. 3

Pharmacological treatment pathway for anxiety in patients with ASD

Fig. 4

Pharmacological treatment pathway for depression in patients with ASD

Fig. 5

Pharmacological treatment pathway for irritability in patients with ASD

Sleep disturbancesBackground

Sleep difficulties are more common in individuals with ASD than in non-autistics, with reported prevalence rates of 50–80% for children with ASD compared to 9–50% for control groups [36]. Children with ASD between the ages of 2–5 years, experience sleep problems twice as often as their peers in the general population, and sleep difficulties in children of all ages tend to persist compared to typically developing peers [37,38,39]. A systematic review and meta-analysis of sleep parameters found that adults with ASD also demonstrate significantly impaired sleep compared to controls in most subjective and objective measures of sleep [40]. The prevalence rate of sleep disturbances varies in ASD adults. In one study of adults with ASD, 85% had sleep problems [41] and in adults with ASD and intellectual disability (ID) about 45% were reported to have sleep problems [42]. Even though sleep disturbances are common in ASD across the lifespan, they are reported less often in adults due to adaptation to impaired sleep patterns, and adult ASD sleep disturbances are understudied [43]. Sleep problems in ASD can manifest in many different forms, including difficulties with sleep onset, sleep maintenance, parasomnias (e.g., nightmares, night terrors, enuresis), hypersomnia (excessive sleeping or sleepiness), sleep-related breathing or movement disorders, isolated symptoms like short sleep or early waking, abnormal sleep patterns, and circadian rhythm sleep disorders [36].

The psychiatric and medical co-occurring conditions that contribute to sleep problems in ASD include anxiety, depression, ADHD, GI problems, epilepsy, and certain medications that impact sleep [44]. Furthermore, children with ASD are more likely to have difficulty reporting pain, which can disrupt sleep [45]. Sleep issues can lead to challenging daytime behaviors like hyperactivity, inattention, and interfering ritualistic behavior [44]. Other co-occurring behavioral challenges include aggression, irritability, and self-injurious behavior (SIB). Sleep disorders have been correlated with daytime sleepiness, cognitive, attentional, behavioral, and emotional challenges, as well as poorer health-related quality of life for children with ASD [12, 13, 46]. Parents of children with ASD and sleep difficulties suffer a lower quality of life with heightened parent stress, anxiety, and depressive symptoms than average [14, 15]. In adults with ASD, sleep problems are associated with unemployment [47].

Diagnosis

Sleep disturbances can present in many ways (Table 1). Patients with ASD should be screened for insomnia. To best inform treatment strategy, it is important to differentiate between difficulty falling asleep (sleep onset insomnia) and difficulty staying asleep (sleep maintenance insomnia). An individual with problems falling asleep will often also have difficulties staying asleep. To help tease out behavior differences between sleep onset insomnia and sleep maintenance insomnia, the Sleep Habits Questionnaire for Children with ASD (CSHQ-Autism) [48] can be very useful. This questionnaire helps to better understand whether the sleep challenges relate to associations with falling asleep or sleep hygiene. Alternatively, the examiner can ask some key questions such as how long it takes to fall asleep, when the patient wakes up in the morning, when and how many times the patient wakes up during the night, how many hours the patient sleeps, is the patient well rested in the morning, and where does the patient sleep [49]. A sleep log can also be helpful in better understanding when and how frequently a patient sleeps.

Table 1 Behavioral indications of and medical conditions associated with sleep disturbances in ASD

Sleep apnea should be ruled out by asking about snoring. The patient who wakes up with headaches and/or snores loudly should be referred for a sleep study (polysomnogram). Sleep studies are often not well tolerated in individuals with ASD. It is important to acknowledge that challenge. In some cases, it is possible to do a sleep study at home. If a sleep study is attempted, a social story, such as the one from the Kennedy Krieger Institute called “The Sleep Study Story” [50] or the one from Boston Children’s Hospital called “My Sleep Study” [51], may help patients and families in this process. Many otolaryngologists will preemptively perform surgery to remove the tonsils (tonsillectomy) in children with loud snoring and who are presumed to have sleep apnea. Consultation with a sleep specialist can help review all options.

Differential diagnoses

First, medical conditions that could present as sleep dysfunction should be ruled out. These include the common co-occurring conditions seen in ASD, such as GI disorders, including reflux and constipation, sleep apnea, pain, and neuropsychiatric disorders, such as anxiety, depression, and ADHD. Epilepsy can also present as sleep problems, so if this is a concern, a referral for a neurological evaluation is indicated. Medications, including psychostimulants such as methylphenidate and amphetamine salts or daytime cold/flu products, can also impair sleep onset and may be able to be adjusted. Patients with ASD can also have sleep disorders such as parasomnias and restless leg syndrome. Testing for iron deficiency (via a blood ferritin test) is recommended for suspected restless leg syndrome, especially because people with ASD commonly have dietary insufficiencies of vitamins and minerals, including iron, due to selective eating. A ferritin level below 50 mcg/dL suggests iron deficiency and can be addressed through diet changes and iron supplementation. Patients and families should be forewarned that iron supplementation products may have a strong smell and can cause constipation, which is a common concern in individuals with ASD.

Treatment

If a patient regularly requires more than 30 min to fall asleep, wakes up during the night and cannot return to sleep, or is not sleeping for an adequate duration, treatment should be considered. First, as stated above, any underlying medical conditions should be addressed. Then, sleep hygiene should be reviewed, including daytime habits, level of physical activity [52], consumption of food and beverages containing caffeine, sleep environment, and screen/device use close to bedtime.

Treatment to improve sleep habits should be established. A general recommendation is to start a brief bedtime routine (less than one hour) with quiet activities on a predictable schedule and ideally away from digital devices and bright lights. There are multiple sleep toolkits available that introduce strategies to improve sleep habits including the Autism Speaks Treatment Network’s “Sleep Strategies for Children with Autism” [53] and “Sleep Strategies for Teens with Autism Spectrum Disorder” [54], and the Stanford Medicine Center for Sleep in Autism Spectrum Disorder toolkit on “Interventions for Sleep Problems in Autistic Adolescents and Adults” [55]. For young children and those who are minimally verbal, a social story or a sleep toolkit video can be used, such as the ones available from the Autism Speaks Autism Treatment Network [56]. Importantly, how someone falls asleep is how someone stays asleep. The situation in which an individual falls asleep the first time should be maintained throughout the night. For example, if someone falls asleep in a room with a light on, that light should be on the whole night.

While improving sleep habits is sufficient in some cases, it may be necessary to consider a medication to help with sleep onset or maintenance. Typically, the stress experienced around sleep (or lack thereof) or the resulting challenges with school, learning or employment might help determine if medication is needed. In addition, if the individual or family is not able or willing to make behavior changes, medication can also be considered. Clinical experience reveals that, for many patients, altering the sleep routine is anxiety-producing, so medications may be a helpful adjunct.

In relation to non-autistic SOC

First-line treatment strategies for sleep disturbances in ASD align with non-autistic SOC, focusing on sleep hygiene and melatonin use.

Medication management and dosing for sleep disturbances

When a pharmacological intervention is required, there are several options to consider (Fig. 1, Table 2). Melatonin is generally the first-line approach to treating sleep disruption pharmacologically. Melatonin is produced in the pineal gland and is released as it gets dark. Children with ASD have lower urinary melatonin secretion than typical children, suggesting possibly lower production levels [57, 58]. There are numerous randomized controlled trials (RCTs) of melatonin in people with ASD, including children, showing that melatonin can help with sleep onset and is generally well tolerated with minimal side effects [59, 60]. Out of 18 studies, the average overall improvement rate from melatonin for sleep disturbances in individuals with ASD was over 84% [58]. Melatonin has been shown to reduce sleep latency (the amount of time it takes to fall asleep) [61]. The effects of melatonin typically last 4–6 h, so while it is helpful for sleep onset, its effect on sleep maintenance is variable [38]. Long-acting melatonin has been shown to increase total sleep time in individuals with ASD across multiple studies [62], but many long-acting formulations require swallowing a pill that is not sized for children. This limitation has led to the development of pediatric-appropriate prolonged-release melatonin (PedPRM), which is a mini-tablet (diameter ≤ 3 mm) designed for children with neurodevelopmental disorders who have difficulty swallowing pills [63]. PedPRM has been shown to be efficacious and safe for the long-term treatment of insomnia in children with ASD in initial research [63]. However, the product is not yet available in the U.S.

Table 2 Medication options and dosing for sleep disturbances in patients with ASD

It is generally recommended to start with 1–3 mg of melatonin about 30 min prior to the desired onset of sleep. Doses can be increased every 5–7 days in 1–3 mg increments up to 10 mg at bedtime. If no effect is seen after giving 10 mg, melatonin should be discontinued, and a new medication should be considered.

Since melatonin is considered a dietary supplement instead of a drug in the U.S., melatonin products are not subject to FDA oversight. Studies have found considerable variation in product concentrations and ingredients [64, 65]. Because of this, it is important that clinicians educate patients and families to look for supplement products that have received third-party certification from a reputable, independent organization, such as the USP (United States Pharmacopoeia) or NSF (National Sanitation Foundation) International.

Clonidine, an α2-adrenergic agonist, has been studied for sleep onset, and the long-acting preparation can be used for sleep maintenance [66]. Short-acting clonidine is effective in improving sleep onset. The long-acting formulation however, has not been adequately studied and requires swallowing a pill whole [66]. For sleep onset, it is generally recommended to start with half of the short-acting clonidine 0.1 mg tablet (0.05 mg) 30 min before bedtime and increase the dose by half a pill every 3 to 5 days as tolerated. Typically, if the patient does not fall asleep within 30 min after lights out after increasing their dose up to 0.3 mg, then clonidine should be discontinued, and a different medication should be tried. If the short-acting preparation is effective with sleep onset and the patient can swallow a pill, then clonidine ER can be tried. Dosing of clonidine ER for sleep disturbances should start with 0.1 mg (these tablets cannot be broken or chewed) and can be increased every 5–7 days until achieving the desired clinical response or reaching a maximum daily dose of 0.3 mg.

Guanfacine is a medication in the same drug class as clonidine (α2-adrenergic agonist), and some practitioners may prefer trying guanfacine before clonidine. Guanfacine is FDA-approved for ADHD in children but is used off-label for sleep disturbances. The short-acting guanfacine can be prescribed at a starting dose of half of a 1 mg tablet (0.5 mg) and can be increased by 0.5–1 mg every 3 to 5 days as tolerated up to 2 mg for sleep disturbances. Long-acting guanfacine preparations can be effective for sleep maintenance. If the short-acting preparation is effective with sleep onset and the patient can swallow a pill, then guanfacine ER can be tried. Dosing of guanfacine ER should start with 1 mg (these tablets cannot be broken or chewed) and can be increased every 5–7 days until achieving the desired clinical response or reaching a maximum dose of 4 mg/day.

Trazodone, a 5-HT2 antagonist, was initially FDA-approved for the treatment of depression in adults and was found to be too sedating. It is thus frequently used for sleep disturbance in adults and children with mood and anxiety disorders. There are no RCTs of trazodone in children with ASD, yet clinically, it is a very effective medication for improving sleep onset and maintenance. Side effects, including prolonged erection of the penis (priapism), should be explained to patients and families. Start with half of a 50 mg tablet (25 mg) at bedtime and increase weekly by 25 mg to a maximum dosage of 100–150 mg at bedtime, depending on body weight.

Mirtazapine is a central presynaptic α2-adrenergic antagonist and serotonin (5-HT)2,3 antagonist and is FDA-approved for the treatment of major depressive disorder in adults. There are no RCTs of mirtazapine for sleep, yet this also can be effective for sleep onset and maintenance. Some of the common side effects of mirtazapine include drowsiness, increased appetite, weight gain, and irritability. See the anxiety section for dosing and titration recommendations.

Sleep medications, which are sometimes prescribed for adults with insomnia, such as benzodiazepines or even antihistamines, can cause activation or agitation in some children and should be used with caution. There are no FDA-approved medications for sleep for pediatric insomnia. Antihistamines, such as hydroxyzine, are frequently used by pediatricians for the management of sleep onset difficulties, although they might have a paradoxical effect in children under the age of 5 years. Since the long-term use of these medications in young children has yet to be studied, they are not recommended for long-term use for young children [67]. Hydroxyzine can be started at a dose of 10 mg at bedtime and increased up to a maximum dose of 25 mg.

Zolpidem is a gamma-aminobutyric acid (GABA) A agonist that has received FDA approval for short-term treatment of insomnia in individuals 18 years and older; it can be considered for sleep in teens and adults. Zolpidem is less useful for children who may be at risk for a paradoxical reaction from benzodiazepines. Zolpidem IR can be dosed at 5–10 mg at bedtime, and zolpidem ER can be dosed at 6.25–12.5 mg at bedtime.

Amitriptyline is a tricyclic antidepressant. While there is no data in the literature for children, the use of amitriptyline in low dosages is often effective for insomnia for children and adults with ASD. Start with a low dose of 5 mg at bedtime and increase weekly by 5 mg. Typically, it is effective in doses ≤ 50 mg at bedtime. Amitriptyline can cause constipation, which is common in individuals with ASD. Patients with prior heart disease will need an electrocardiogram (ECG) before they take amitriptyline, as it can prolong the time that the heart muscle takes to contract and relax (QTc cardiac interval).

For the patient who does not respond to medication for sleep disturbances, referral to a sleep specialist or psychiatrist is recommended. See Fig. 1 for pharmacological approaches to the treatment of sleep disturbances in individuals with ASD.

Attention-Deficit/Hyperactivity DisorderBackground

The DSM-5-TR defines ADHD as functionally impairing symptoms of inattention and/or hyperactivity and impulsivity, with onset before age 12 years and which occur in two or more settings [68]. While the DSM, Fourth Edition (DSM-IV) [69] and DSM, Fourth Edition, Text Revision (DSM-IV-TR) [70] precluded the co-occurring diagnosis of ADHD in individuals with ASD, the DSM-5, released in 2013, removed this restriction [71]. ADHD is one of the most common co-occurring diagnoses in individuals with ASD, with prevalence estimates ranging from 40–70% [72, 73]. In a 2021 meta-analysis, the pooled current and lifetime prevalence rates of ADHD among those with ASD were 38.5% (95% CI 34.0–43.2) and 40.2% (95% CI 34.9–45.7), respectively [74].

Diagnosis

Due to the overlapping features between ASD and ADHD (e.g., social impairment, executive dysfunction), diagnosing ADHD in patients with ASD can be challenging even for experienced clinicians [75]. A 2020 BMC Medicine publication from Young et al. focused on co-occuring ASD and ADHD offers thorough guidance on identifying and treating ADHD in the ASD population [31]. The diagnosis of ADHD in people with ASD requires a comprehensive, multi-modal evaluation. This determination relies on clinical interviews in combination with reports from collateral sources including rating scales and objective supporting assessments, which are appropriate based on the individual’s age and unique presentation [31]. The Strengths and Difficulties Questionnaire (SDQ) and National Institute for Children’s Health Quality (NICHQ) Vanderbilt Assessment Scales can be helpful for collecting information from individuals or caregivers and teachers. Whenever possible, neuropsychological testing is highly recommended for its ability to combine direct observation and real-time neurocognitive data (e.g., standardized measures of sustained attention, impulsivity, and executive functioning, such as the Conner’s Continuous Performance Test, 3rd Edition) with parent/teacher rating scales and a comprehensive medical record review.

Differential diagnoses

A thorough differential diagnosis should assess for factors that may contribute to the clinical presentation and/or mimic symptoms of inattention, hyperactivity, and impulsivity. These may include other neuropsychiatric conditions, such as anxiety, mood disorders, and tic disorders; medical conditions, such as sleep disturbance and hyperthyroidism; adverse effects of medications, such as movement disorders like akathisia due to an antipsychotic medication; or environmental considerations, such as an unbefitting school placement. In some cases, a medical workup may be indicated to assess for medical causes, such as thyroid function tests to check for endocrine disorders like hyperthyroidism. See Table 3 for signs and symptoms to assist with recognition of ADHD in individuals with ASD.

Table 3 Signs and Symptoms of ADHD in ASDTreatment

There are differences of opinion as to whether to first initiate pharmacologic or non-pharmacologic interventions in the treatment of ADHD [76]. The American Academy of Pediatrics (AAP) Clinical Practice Guideline on ADHD in the general population identifies parent-training behavior management (PTBM) as the first-line approach for preschool-aged children and medication management in conjunction with PTBM and behavioral classroom interventions for youth ages six years or older [77]. Young et al. outline many non-pharmacological avenues through which to support children and adults with co-occuring ASD and ADHD and how to tailor these to meet the needs of the individual [31]. Their practice recommendations echo the AAP guideline’s focus on education for parents, along with career and occupational skills training, cognitive behavioral therapy (CBT), and other behavioral and educational approaches both for individuals with ASD and ADHD and their families [31].

Medications approved by the FDA to treat ADHD include psychostimulants (methylphenidate, amphetamine salts), selective norepinephrine reuptake inhibitors, and α2-adrenergic agonists (Fig. 2, Table 4). The data examining the effectiveness of these medications in patients with ASD and ADHD is more limited.

Table 4 Medication options and dosing for ADHD in patients with ASD In relation to non-autistic SOC

While stimulants are the first-line pharmacological treatment for ADHD in non-autistic populations, non-stimulants may be more suitable than stimulants for many autistic patients based on their unique clinical profiles.

Medication management and dosing for ADHD

Whether a stimulant or a non-stimulant should be the first-line pharmacotherapy approach for managing ADHD in ASD depends on the profile of the individual patient. Methylphenidate (MPH) and amphetamine (AMP) are the first-line treatments for ADHD in typically developing children and adolescents. Clinicians can choose from among a variety of immediate-release (IR) and extended-release (ER) formulations of MPH and AMP.

Non-stimulants such as α2-adrenergic agonists may be preferable for patients with any of the following: significant behavioral or emotional dysregulation beyond ADHD symptoms, anxiety, sleep disturbance, tics, or medical contraindications such as cardiovascular disease or low body weight that stimulants could exacerbate. Although FDA labeling on stimulants warns of their association with the onset or worsening of tics, a 2015 meta-analysis did not substantiate this relationship [