Practitioner’s review: medication for children and adolescents with autism spectrum disorder (ASD) and comorbid conditions

Anticonvulsants may be used to treat epilepsies, bipolar disorders, and externalizing behavioral problems⁷. Anticonvulsant treatment of children with ASD [83, 133, 261], like in other patients with convulsions, depends on the type of convulsions and should always be combined with psychosocial support [261].

The most commonly used pharmacotherapeutics are valproic acid, lamotrigine, levetiracetam, and ethosuximide [96], cf. Table 6. In select syndromes such as Landau–Kleffner syndrome or ESES⁸, corticosteroids, ACTH, or immunoglobulin therapy may be considered [303]. Additional nonpharmacological therapeutic options for therapy-resistant epilepsies include vagus nerve stimulation [184], ketogenic diet, and neurosurgical interventions [114]. It is not clear whether an interictal epileptiform EEG may be a cofactor contributing to neurologic deterioration or progressing developmental retardation [310]. Pharmacologic treatment should always be considered if symptoms get worse.

ASD and ADHD share genetic, neurophysiological, and clinical similarities [10, 181]. Both disorders affect attention, flexibility, planning, and response inhibition, have a high heritability, early onset, overlapping comorbidities, and prevail in males [50, 58]. Hans Asperger already described attention problems as “almost regularly occurring in children of this type” [13]. Ronald et al. [265] found significant correlations between ASD and ADHD pheno and genotypes in their twins’ early development study, and a probability of 41% for co-occurrence ADHD in ASD patients. Nijmijer et al. [225] found genetic linkages between ASD and ADHD on chromosomes 7, 12, 15, 16, and 18. The “dual disorder” is characterized by increased psychopathology and psychosocial stress, more compromised cognitive and daily functions, including maladaptive behaviors, and poorer effects of therapy [48, 125, 147, 160, 246, 251]. ASD and ADHD share multiple comorbidities, such as dysexecutive problems, increased anxiety, sensory integration, sleep, affective and central hearing processing disorders, developmental delay, OCD, and epilepsy [187, 223, 281]. These comorbid conditions will largely determine the clinical picture. Unfortunately, ADHD in autistic patients is generally not appropriately treated [160]. This could be due to the fact that ADHD was excluded in autism diagnosis in ICD-10, a path that has now been changed in DSM‑5 and ICD-11.

Treatment of ADHD in patients with ASD should follow the same multimodal algorithms as for ADHD alone and should include psychoeducation [87, 219, 238], parental training [41, 85, 87], school-based measures (such as daily record cards [70, 80, 97], structured task organization, physical activity [39, 158, 302]), and medication [31, 285, 296]. ADHD medication is usually less effective, and SE are more pronounced in ASD patients, especially in those with ID [48, 85, 241, 255]. Cognitive training [56] and neurofeedback [88, 212, 252] are less effective and more complex. Occupational therapy [49] is useful as an adjunct for improving comorbid sensory integration and dysexecutive problems.

Medication for ASD/ADHD targets modulating dopamine and epinephrinergic transmitter systems, thereby increasing dopamine availability in frontal areas and striatum, and downregulating dopamine moderators. Usually, two types of medication are distinguished: stimulants (methylphenidate, amphetamine, lis-dexamphetamine) and nonstimulants (atomoxetine and alpha‑2 agonists).

Stimulants. Effectiveness and compatibility of methylphenidate, the most frequently used ADHD medication, have multiply been proven in patients with ASD and ADHD, with and without ID [11, 255, 282, 298]. In addition to the main ADHD symptoms, executive and nonexecutive memory, reaction time, reaction time variability, response inhibition, social communication, and self-regulation are significantly improved with methylphenidate [51, 149, 298] with somewhat lower effect sizes (around 0.5) in children with ASD and ADHD, compared to normally developing children with ADHD. Because of the short \(t\) \(1/2\) of about 2 hours, stimulants are usually administered in a slow-release formulation, acting for 10–14 hours, depending on the preparation. About 70% of the normally developing children and half of the children with ASD and ID respond by improved behavior, especially with decreased impulsivity, improved cooperation and attention, and less hyperactivity. Behavioral improvement is more pronounced in children presenting with hyperactivity and normal IQ [4]. Careful dosage titration is recommended because of the large variability of efficacy that may be explained genetically [206]. The effect of methylphenidate on growth has been divergently debated with height deficits ranging from 0 to 4.7 cm with consistent use [258]. In children with severe side effects or decreased responsiveness to methylphenidate, amphetamine [284], or lisdexamphetamine [52, 54, 127, 145], an inactive amphetamine precursor that is activated in the erythrocytes may be recommended because of their larger effect sizes. Amphetamines, and especially lisdexamphetamine, also improve mood while acting.

Emotional dysregulation (irritability) is a common problem in children with ADHD and with ASD, with rates around 78% for both disorders [179]. Stimulants and atomoxetine act effectively but may also increase emotional dysregulation, although at a much lower prevalence of about 17% [104]. In addition, effects on sleep (longer sleep latency, decreased sleep efficiency, and shorter sleep duration) were observed with stimulant medication [167].

Atomoxetine. The norepinephrine reuptake inhibitor and NMDA receptor antagonist possesses good effectiveness [123, 124] and (compared to methylphenidate) a considerably longer \(t\) \(1/2\) of 35 hours and 99% plasma albumin binding. Because of its nearly continuous action, atomoxetine is a recommendable alternative to methylphenidate, although with a smaller effect size [5, 236, 244], especially in children who respond with pronounced SE to stimulants or are very difficult to handle in the morning and evening hours, when methylphenidate does not act. It may also be recommended in children with comorbid depression, tics, or anxiety disorders [3, 5]. Atomoxetine needs a longer dosing period (up to 12 weeks) and may cause initial fatigue, headache, and gastrointestinal SE, wherefore the medication should initially be started in the evening hours. About 15% of the patients may react with increased aggression, requiring discontinuation of atomoxetine and either addition of risperidone [207] or aripiprazole [231] or switching to extended-release guanfacine [269, 270] or lisdexamphetamine [52].

Comparing atomoxetine and amphetamine derivates, higher effect sizes of methyplhenidate slow release preparations have been reported [121]. Small but significant cardiovascular effects have been reported for stimulant and atomoxetine medication [132], mainly small increases of the heart rate and of systolic or diastolic blood pressure [132]. Because significant cardiovascular effects may not be excluded in a small subgroup of patients (e.g., with slow drug metabolism), occasional blood pressure checks are recommended.

Alpha-2-agonists. Clonidine and extended-release guanfacine are less effective medications against ADHD core symptoms with some antitic potential, pronounced tiredness, and gastrointestinal SE, which may lead to discontinuing the medication. Hyperactivity and impulsivity are improved in about 45% of cases [144, 199, 241, 270, 294].

Other treatments for ADHD. Mindfulness-based [1, 259, 268] and neurofeedback therapies [138] have been tried with some success in children with ASD and ADHD.

Due to the fact that antidepressant medication is of questionable effect in children and adolescents with ASD, their use may generally not be recommended. There is no clear-cut evidence that this recommendation is also valid for patients with severe depression, and the widespread use of antidepressant medication reflects this challenge, especially in the light that the prevalence of comorbid depression in autistic patients is fourfold compared to the nonautistic population [318]. Combining antidepressants with (low-dose) antipsychotic medication may generally be recommended for augmenting antidepressant effects in therapy resistant depressive patients and–although with low evidence [78]–in suicidal patients. This relates to the long period needed for antidepressant drug effects to become evident and to the effect of antipsychotics to reduce initially present internal drive and suicidality. Psychotherapy adds to antidepressant therapy for light to medium severe depression in the short term but better in the long term. For severe depression, combining psycho and pharmacotherapy is recommended in normotypic children [40, 65].

Suicidality has been reported in 21.3% (7–47%) of patients with ASD [142, 324]. Suicidal ideation is very common in adolescents with ASD, especially in Asperger’s autists, and is largely related to their increased vulnerability to stress, anxiety, and depression, their inflexibility, and their proneness to become bullied or sexually abused [142].

Bipolar disorders are detected in 6–21% of adult ASD patients [307], and 30% of bipolar I patients meet the criteria for ASD [161]. Data for children and adolescents are still lacking. Therapeutic options include SGA, valproic acid, AD medication if severe depressive symptoms are present, and lithium. Lithium medication also improves social functioning in animals and adults [190]. Its use may be especially limited in children because of the narrow therapeutic range, its effect on thyroid function, the resulting need of a highly compliant and supportive environment, and the considerable and poorly tolerated emotional indifference created by the drug [208, 277].

About 40% of children with ASD present with various anxiety disorders, phobias including social phobia, general, and separation anxiety disorder, and OCD [323]. They also often react with symptoms of anxiety or even panic in reaction to changes in their environment. An early study [292] reported beneficial effects with low-dose AD medication against anxieties. Stachnik et al [290] reviewed the beneficial effect of neuroleptics for anxiety disorders in children with ASD. High doses of antidepressants may reduce OCD symptoms in normotypic children. Unfortunately, their effectiveness is not confirmed in children with ASD [169, 222, 253], possibly because of the background similarities of ASD and OCD [271].

In general, the treatment methods of choice for fears and OCD are parent training, play therapy, and cognitive behavioral therapy (CBT) [6, 60]. Antidepressants in higher dosages may be tried in individual patients as an adjunct to cognitive therapies. Because of the poor flexibility of patients with ASD, CBT may be very laborious in autistic children and adolescents.

Medication may be helpful in inducing and improving disturbed sleep but should be provided with caution: melatonin will improve sleep rhythm in 85% of the children with ASD even in those without disturbed melatonin circadian rhythm at a daily dosage of 1–6 mg given 30 minutes before bedtime [108, 267]. Advancing sleep onset will require a smaller dose of 0.2–0.5 mg given 3–5 h prior to the desired sleep time [32, 175]⁹.

Other sleep stimulating agents, like valerian, passion flower, and hops provide placebo support; benzodiazepines, zolpidem, and zaleplon act on GABA receptors, helping in inducing sleep but usually have a long \(t\) \(1/2\), decrease REM sleep phases, but lead to habituation, to losing sleep induction effects during prolonged use, and to promoting anxiety [234]. Sleep-inducing antidepressants like trazodone are commonly used. For contraindications (tricyclics, mirtazapine), see Sect. 3.2.

Restless legs syndrome [59, 280]¹⁰, another syndrome disturbing sleep and quality of life based on a genetic predisposition, dysregulation of iron metabolism, and the dopaminergic system, suggest considering iron deficiency as a cause of sleep disturbance [308].

Other sleep-stimulating agents, like valerian, passion flower, and hops, provide placebo support; benzodiazepines, zolpidem, and zaleplon act on GABA receptors, helping in inducing sleep but usually have a long \(t\) \(1/2\), decrease REM sleep phases, lead to habituation, may lose sleep induction effects and promote anxiety during prolonged use [234]. Sleep-inducing antidepressants like trazodone¹¹ are commonly used. For contraindications (tricyclics, mirtazapine), see Sect. 3.2.

Benzodiazepines, especially those targeting \(\text{GABA}_{A}\) receptor subtypes, may attenuate ASD symptoms [216]. The clinical significance of this effect is not known at present¹².

Epilepsy (more than one convulsion) occurs in about 5–46% of children with ASD, (compared to 1–2% in children not on the spectrum), depending on the clinical sample and the severity of ID [287]. Comorbid epilepsy adds to the impact of ASD on quality of life [303] because of a number of additional problems, such as cognitive, speech developmental, sleep, affective, medical, social, and behavioral issues [90, 118]. Phenotypes and causes are still insufficiently researched.

Mitochondrial respiratory chain defects have been detected as an important link between epilepsy and ASD [315]. In addition, three ASD associated syndromes with known genetic cause, tuberous sclerosis, Rett’s syndrome, and fragile X syndrome, are associated with epilepsy. Another group of disorders, epileptic encephalopathies, have been described in the context of brain dysfunction and increasing autistic symptomatology [74], affecting about 40% of children with convulsions in early childhood. These include early myoclonic encephalopathies, West, Dravet, Lennox Gastaud, and Landau–Kleffner syndromes, myoclonus epilepsy in nonprogressive encephalopathies, and continuous spike waves in slow-wave sleep (CSWS) [303]. Risk factors include epilepsies with known structural defects, bilateral frontal EEG changes, and persistent hypsarrhythmia [303].

Gastrointestinal distress related to constitutional, behavioral, and inflammatory causes is frequently observed in children with ASD and may be related to altered ASD severity [140]. Alterations of the intestinal microbiota, permeability, and functioning may, for example, alter intestinal serotonin metabolism and cause hyperserotoninemia, alter immune responses, and even brain functioning and behavior via the gut–brain axis [12, 193]. Attempts to influence these disturbances by diets (such as a gluten-free diet), probiotics, antibiotic or other “treatments” such as detoxification, would need careful prospective randomized clinical trials, precise diagnostics, and well-established clinical algorithms. At present, this clinical evidence is not available [240]

Impulsive aggression and related disruptive behavior, as well as self-injuring behavior are frequently observed in ASD/ADHD and are the leading cause for school suspension, clinical referrals, and ward admissions [182]. Positive parenting [71], early intensive psychosocial and behavioral interventions [60, 76], specific multisystemic programs, such as multisystemic therapy [131] or the Fast Track program [25, 55], and psychosocial interventions such as T‑MAY [279] or TRAAY [276], and group sessions for social competence [101] lead to significant improvements of adaptive behavior. Recommendations for medical treatment include stimulants (in the case of comorbid ADHD) and nonstimulant medication, SGAs (cf. Sect. 3.1), antidepressant and mood stabilizing agents [48, 68, 75, 91, 116, 159]. In addition to pharmacotherapy, behavioral and social competence training, and parental counselling are strongly recommended.

Independently of their intellectual capacity, up to \(2/3\) of children with ASD suffer from sleep problems: delayed sleep onset, frequent night awakenings, reduced total sleep time, dys and parasomnias [26, 57, 63, 157, 175, 189, 197, 205, 256, 308, 317]. These problems often persist into adulthood. The causes range from poor sleep hygiene and inconsistent parental behavior [317], (self) regulatory problems and central excitatory/inhibitory imbalance, delayed sleep pattern maturation, a disturbed hypothalamic-pituitary-adrenal axis, and decreased and dysrhythmic melatonin secretion to decreased binding of melatonin to its transporter protein and melatonin receptor dysfunction [57, 141, 202]. Recently, slow-release melatonin¹³ was approved by the European Medicines Agency for the treatment of sleep disorders in children with ASD from the age of 2. In addition, anxiety [305], ADHD/ASD associated sleep and sensory integration problems [126] leading to increased external stimulation (or decreased stimulus filtering), and cerebral convulsions may disturb sleep and quality of life of affected children and, consequently, of the whole family. Therefore, sleep diagnostics and treatment are important for both children with ASD and their families [174, 308].

Restless legs syndrome [59, 280], another syndrome disturbing sleep and quality of life based on a genetic predisposition, dysregulation of iron metabolism, and the dopaminergic system, suggest considering iron deficiency as a cause of sleep disturbance [308].

Behavioral measures [30, 283, 314] like fixed bedtime routine, providing sleeping cues and a low stimulation evening routine, supporting self-soothing behavior, light therapy¹⁴ [84], avoiding daytime sleeping, etc., and sensory integration therapy [325] have proven to be helpful, although with little evidence [30].

Chronic tic disorders and motor stereotypies are common comorbid movement disorders in children and adolescents with ASD [249]. The prevalence of chronic tic disorder is about 6.5% [281], about 10 times higher than in normally developing children. It is characterized by involuntary movements or utterings that vary in onset and frequency, depending on daytime and seasonal variations and stress exposure. Treatment is necessary if severity and frequency exceed subjective or environmental tolerance. Effective treatment options [249] (besides relaxation, stress reduction, and bio or neurofeedback) include antipsychotics such as risperidone, aripiprazole, or pimozide, eventually with added pentoxyfylline, and the anticonvulsant topiramate are effective, whereas haloperidole, levetiracetam, guanfacine, and atomoxetine, as well as metoclopramide and odansetron, have not proven effective [249, 262].