Medications Used in the Treatment of Children with Autism Spectrum Disorders

Abstract

Objectives: The identification of children with autism spectrum disorder (ASD) is occurring with increasing frequency. ASD is commonly associated with other comorbid conditions. Medications are used to treat problems associated with these conditions. Currently, the studies of medication use in children with ASD are limited. Selected studies are reviewed. Symptom-specific treatment plans are discussed. Medication use and potential side effects are highlighted.
Conclusion: Despite limited studies of medications used in the treatment of ASD, trials of medication to target specific symptoms can be beneficial. Ongoing medical follow-up appointments allow careful monitoring and dose titration. Practitioners are encouraged to collect and share data on the efficacy of medication trials in the symptomatic treatment of ASD.

Keywords: autism , autism spectrum disorders , pharmacotherapy

INTRODUCTION

Autism spectrum disorders (ASD) are characterized by deficits in the three core areas of communication, reciprocal social interaction and the presence of stereotyped and repetitive behaviors¹. Autism is a spectrum disorder with varying degrees of severity and often occurs in combination with other developmental differences. Published practice parameters have aided practitioners in establishing a systematic plan for diagnostic assessment and follow up². These parameters have helped to standardize the tools necessary to comprehensively assess children who present with concerns in the areas of the featured core deficits as noted above. The Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview (ADI) are now recognized as the "gold standard" assessment tools to evaluate communication and social interaction skills in the workup for ASD. In combination, these tools provide very thorough and comprehensive information about the child's past history and current status, and aid in proper diagnosis of this disorder.

Signs of autism include poor eye contact, repetitive or difficult behavior, sensory difficulties, expressive and/or receptive language delay, limited use of communicative gestures, use of atypical ways to communicate, atypical social interaction and may include a history of regression of language skills. Absolute indications for referral of children for suspected ASD include the following: no babbling by 12 months, no gesturing by 12 months, no single words by 16 months, no two-word spontaneous phrases by 24 months and ANY loss of ANY language or social skills at ANY age. Assessment by a multidisciplinary team with experience in evaluating children with autism is preferred. This team may include developmental pediatrics, neurology, psychiatry, psychology, speech and language pathology and occupational therapy¹.

DIAGNOSTIC ASSESSMENT FOR AUTISM

The diagnostic workup for children with suspected ASD needs to include a detailed family, birth, medical and developmental history. A physical examination is performed to assess for any other possible medical problems and should include a thorough review of any abnormal skin findings. Since there is no specific genetic marker for autism, laboratory evaluations are not conclusive but are obtained to rule out any other possible genetic syndromes or problems. Laboratory evaluations may include chromosomal analysis and probe for fragile X syndrome, which causes developmental delay. Girls with delayed development and accompanying significant cognitive deficits and regression of skills should be screened for Rett syndrome, a genetic syndrome related to abnormalities with the X chromosome. The pattern of regression in Rett syndrome is very different than regression seen in autism and may be progressive. Electroencephalogram (EEG) studies are recommended if there is a history of language regression or suspicion of seizure activity. However, a recent study of patients with ASD with the diagnosis based on DSM-IV criteria³, found that regression, alone, was not predictive of EEG abnormalities. Differences between rates of epileptiform activity in those patients with regression (60.9%) and those without regression (59.9%) were not significant. Patients with abnormal epileptiform EEGs were offered treatment with Valproate. Improvement, either clinically or in the EEG pattern, was noted in 63% of the patients who were treated with Valproate. Early screening EEG studies and ongoing medical follow up were recommended by the study authors⁴.

MEDICATION USE IN THE TREATMENT OF AUTISM

The use of medication in children with autism is evolving, with new studies aiding practitioners in ongoing medical management. There is no one "autism-specific" medication. The decision to trial a medication is sometimes difficult and is considered when behavioral interventions have failed to address a specific problem. Medication should never be the first line of treatment. Medications are used to target specific symptoms associated with ASD and are always considered "adjuvant" treatment in combination with other treatments and interventions. Information on which to base medication decisions is very limited because there have been so few randomized, placebo-controlled trials of medication in ASD, and in general, studies of children with ASD receiving medications are limited. Off label use of medication is frequently necessary, because few medications that target specific symptoms associated with ASD have been approved for use in children. Side-effect profiles of selected medications are considered carefully and reviewed with care providers. The potential benefits and costs or side effects are examined. Ultimately, the care provider, in collaboration with the health care practitioner, decide whether a medication trial is warranted and/or desired. Once a decision is made to use medication, a trial period should be initiated. Care providers or family members are asked to record data as to the child's status before and during the medication trial. During this trial, the child is carefully monitored for signs of improvement or side effects. Dose titration often follows a "start low and go slow" approach so as to lessen initial side effects and to enhance the possibility for a successful trial. The goal during a medication trial should be to lessen the severity of a symptom that is interfering with the child's ability to make progress. If medications are discontinued, tapering or weaning the drug may lessen withdrawal effects. Care providers are encouraged to contact the health care provider as needed with any concerns or for guidance.

The selection of a medication is determined after careful consideration of the specific symptom or symptoms. Care providers are encouraged to think about what areas are most troublesome and warrant priority in treatment. When medications are discussed, care providers should be instructed as to what can reasonably be expected as a result of the treatment. Prescribing medication is presented as only one facet of treatment for various problems and never replaces other needed interventions. For example, behavioral intervention is just as important, if not more so, in the treatment of behavioral difficulties. Medication can be characterized as "just one tool in the tool box" in the management of problems.

Health care providers may be assisted in medication management by obtaining and reviewing serum pharmacogenetic testing results. This newly available testing provides information as to the rate of metabolism of select medications based on certain genetic variants of metabolizing enzymes. For example, if it is determined that a child is a poor metabolizer for a considered medication, dosing is more cautious and conservative in order to avoid side effects. Conversely, if a child is an ultrarapid metabolizer for a considered medication, dosing may proceed less conservatively and approach standard dosing for the child's age and weight. In our clinic, a recent review of our pharmacogenetic testing results of 56 children revealed that 66% were extensive metabolizers and 18-23% were intermediate metabolizers. A smaller number, 2-7%, were slow metabolizers and 3.5 % were ultrarapid metabolizers. These findings are similar to those found in studies of the general population⁵. This information is most helpful when considering the use of medications that do not have serum therapeutic levels established. As the field of pharmacogenetic medicine expands, this additional clinical information may assist in more comprehensive medication management.

In deciding upon a medication plan, care providers may require assistance in determining the best way to administer the drug. If an individual has significant oral sensory aversions, the taste or texture of the medication may influence compliance with the medication regimen. The selection of a liquid or tablet form of the medication will determine how it is administered. How to mix the medication for the best palatability and with the least difficulty should be reviewed as the medication trial is explained. If one form of the medication is not tolerated, another may be substituted. Some children experience apprehension or are determined to avoid taking a medication. The importance of the medication must be weighed with the stress that it may provoke in the child and family. If the potential benefit of the medication outweighs the difficulty in administering, creative problem solving is necessary in order to find a way that the child can successfully take the medication.

CORMORBID MEDICAL PROBLEMS IN AUTISM

As medication management is based on an individual's symptomatology, it is helpful to review comorbid medical problems seen in children with ASD to better understand what medications to consider. The following review is not intended to be comprehensive but is inclusive of the authors' clinical experience and scope of practice in developmental pediatrics.

Epilepsy and antiepileptic medication

Epilepsy in children with autism has been well described. The prevalence of seizures in children with autism is estimated to be 7%-42% ⁶. Electroencephalogram (EEG) studies provide diagnostic information about the occurrence or risk for seizures⁷. Prolonged EEG telemetry studies are recommended for those children with a history of language regression or suspicion of seizure activity ². Localization of the EEG abnormalities has frequently been seen in the temporal regions of the brain⁷. In children with abnormal EEG studies or a clinical history of seizures, antiepileptic medications may be indicated. Various antiepileptic medications have been described in the treatment of children with autism. Valproate (Depakote, Depakene) has been reported to be an effective treatment with subjective reports of improvement in eye contact, receptive speech and hyperactivity, as well as improved EEG patterns, even in the absence of clinical seizures ⁸. Other antiepileptic medications in use include Oxcarbazepine (Trileptal), Gabapentin (Neurontin), Topiramate (Topamax), Lamotrigine (Lamictal) and others. Side effects of these medications may vary from person to person. In general, antiepileptic medications may cause drowsiness and dizziness when introduced or when doses are adjusted. Valproate is metabolized by the liver, so monitoring liver function is important. Platelet levels can be lowered by Valproate, so excessive bruising needs to be reported by families to their providers and investigated by clinical exam and complete blood and platelet counts. Lamotrigine (Lamictal) has a possible adverse effect of severe skin rash and Stevens Johnson syndrome, which requires immediate evaluation. Lamotrigine in combination with Valproate may increase the risk for this serious adverse effect. Other antiepileptic medications can also cause skin rash, which may indicate allergic sensitivity and the need to discontinue. Oxcarbazepine (Trileptal) has caused instability of electrolytes in some patients^{9, 10}.

Anxiety and obsessive-compulsive difficulties

Behavioral problems in children with ASD can often be found to be provoked or triggered by anxious and/or obsessive-compulsive qualities. Selective serotonin reuptake inhibitors (SSRIs) have been studied in children with ASD to address these features. Fluoxetine (Prozac) has been found to effect improvement in language function in one study, although the mechanism for this improvement is unknown¹¹. Citalopram (Celexa) has also been studied in children with ASD. One retrospective chart review of 15 children with ASD reported reduced symptoms with a low incidence of adverse events when treated with Citalopram at a median dose of 17 mg/day¹². Potential side effects of SSRIs include restlessness, agitation, changes in sleep patterns, hyperactivity, weight gain and libido changes. Side effects may be avoided by careful titration, starting "low" with doses and gradually increasing to the target dose. The benefit of Fluoxetine may take longer to appreciate secondary to the longer half-life of this medication. Careful and slow titration with ongoing clinical follow up is recommended for Fluoxetine and all SSRI medications. Care providers should be informed of recent concerns about suicidal ideation and suicidal acts by adolescents in treatment for depression who are receiving SSRIs. These recent reports help to illustrate the need for ongoing monitoring and follow up during medication trials. The association of suicidal ideation in children with ASDs treated with SSRIs is unknown and has not been reported.

Other medications used for the treatment of anxiety in children with ASD include benzodiazepines. Benzodiazepines are useful agents for administration during particularly stressful encounters or situations on an as needed basis. A "trial run" of benzodiazepines should be done before the planned stressful encounter to determine whether the child will have an idiosyncratic response. Care providers should be advised about possible side effects, including the development of tolerance, if benzodiazepines are administered on a regular schedule. Buspirone (Buspar), an anxiolytic, has also been used to relieve anxiety in children with ASD¹³. Buspar may be administered on a regular schedule or is sometimes used as needed during stressful encounters. Buspar may cause drowsiness, or, adversely, enhance agitation.

Distractibility, hyperactivity and attention difficulties

Children with ASD and hyperactivity and attention problems may benefit from treatment with medication. Stimulants have been used to target these difficulties. Side effects of stimulants include appetite suppression and possible interference with growth. Sleep changes may occur if stimulants are given later in the day or evening. Increased emotional behaviors may occur if withdrawal effect or "rebound" is experienced. Short-acting stimulants may be trialed before longer-acting products are introduced. Recent reports of sudden death of children being treated with stimulants should be reviewed with caregivers, and careful clinical follow up is recommended¹⁴.

Other agents that may help in the treatment of the symptoms of hyperactivity in ASD include Atomoxetine (Strattera), a norepinephrine reuptake inhibitor. Atomoxetine, by report, may cause less appetite suppression. Initially, Atomoxetine may cause drowsiness. The late onset of action and long half-life of Atomoxetine require careful titration and monitoring for signs of improvement. Alpha 2 adrenergic agonistic agents may also be helpful to target hyperactivity. Catapres (Clonidine) and Guanfacine (Tenex) have been helpful in reducing activity levels and in improving sleep. Side effects of Clonidine and Tenex include drowsiness and potential lowering of blood pressure. Caregivers should be instructed to slowly titrate dosing both initially and when withdrawing in order to avoid fluctuation of blood pressure and causing ill effects. Catapres is available as a transdermal skin patch, which may aid administration and decrease unwanted sedation. However, ingestion of the skin patch is very dangerous. Caregivers should be cautioned regarding the possibility of ingestion and tips to keep the patch in place should be reviewed.

Agitation, aggression and self-injurious behaviors

Agitated, aggressive and self-injurious behaviors can be quite problematic for many families of children with ASD. Medication is considered in the treatment for these problems only after a very thorough review of antecedents, possible provoking factors, ongoing medical concerns and the presence of a consistent behavioral plan. If, despite our best efforts to address these variables, no decrease is seen in aggressive behavior, a medication trial may be indicated. Atypical antipsychotic medications are among the best-studied medications in children with ASD. A multicenter, double-blind, placebo-controlled study of 101 children with ASD showed that Risperidone (Risperdal) was effective and tolerated with minimal side effects in the treatment of tantrums, aggression or self-injurious behaviors¹⁵. This well-designed study provided very strong evidence of efficacy in treating aggression in children with ASD. A continuation of the original study of Risperidone showed continued efficacy with reduced behavioral problems. When Risperidone was discontinued, behavior rapidly deteriorated and self-injurious events returned. The study authors recommended gradual weaning of Risperidone only after a stable period of functioning and with appropriate psychosocial supports in place¹⁶. A very common side effect of Risperidone is increased appetite and resultant weight gain. Weight gain can be quite dramatic and requires education of caregivers about monitoring food intake, portion size, limiting the use of food as a reinforcer, increasing the amount of physical activity and monitoring the child's access to food. Because of the concern for development of metabolic syndrome and/or diabetes, some suggested laboratory monitoring includes fasting lipid and glucose levels, serum insulin level and liver function test.

Other antitypical antipsychotics used with children with ASD include Aripiprazole (Abilify), Quetiapine (Seroquel) and Ziprasidone (Geodon). The side-effect profiles for these medications are similar. Anecdotally, however, less weight gain has been reported. These agents may be considered for trial if the side effects of Risperidone are of concern. All atypical antipsychotics have the potential to cause tardive dyskinesia and/or a dystonic reaction. Caregivers need education about how to recognize these side effects and how to manage them if they occur. Benadryl may be indicated in the treatment of a dystonic reaction and should be reported to the prescribing health care provider. Akathisia is a frequent adverse effect of atypical antipsychotic medications and should be reported to the prescribing clinician.

Olanzapine (Zyprexa) is a thienobenzodiazepine that has been used for calming children who are aggressive or agitated. The authors' use of Zyprexa is very rare and limited to those who have failed other agents.

Self-injurious behaviors have also been treated with Naltrexone, an opiate antagonist. A review article of the studies of Naltrexone noted that available literature is lacking in establishing efficacy of this intervention, and the studies fail to separate the impact of other concurrent interventions on outcome¹⁷.

Propanalol, a beta-adrenergic blocker, has been used for many years in the treatment of individuals with developmental and cognitive deficits. The authors' use of Propanolol (Inderal) is limited due to concern about potential side effects, including bradycardia and hypotension. Neuroleptics are being used less commonly secondary to potential side effects as well. Tricyclic agents have limited use in children secondary to the potential side effect of cardiac arrhythmia. Newer agents in use include the tetracylcics and antidepressants, such as Desyrel (Trazodone) and Mirtazapine (Remeron), which are helpful sleep agents and can be used in treating aggression.

Sleep disturbances

Difficulties with sleep are a common problem in children with ASD. These problems can range from delayed sleep onset to interrupted sleep and abnormally shortened sleep cycles. When sleep problems are a concern, clinicians should review the importance of a consistent nighttime routine and the use of behavioral strategies when responding to nighttime wakefulness. Melatonin, a naturally occurring pineal gland hormone sold over the counter as a dietary supplement, is a helpful agent in the treatment of delayed sleep onset. Melatonin may help a child ease into sleep. Melatonin has a short duration of action and may cause some changes in sleep patterns, including increased dreams or nightmares. With chronic unsustained sleep, another agent may be helpful. Because of their sedative side effects, antihistamines have been used for some children. Alpha 2 adrenergic agonist agents, Catapres or Guanfacine, may improve sleep duration. Risperidone has also been used to improve nighttime sleep. Desyrel (Trazodone), an antidepressant, may be helpful in prolonging sleep through the night. Priapism is a potential side effect of Trazodone, and caregivers should be cautioned about this potential complication. Sedative hypnotics are not recommended due to the concern about tolerance and dependence.

Mood instability

Frequent mood fluctuations or mood instability may respond to mood stabilizer medication.Antiepileptic drugs used to treat mood instability include Valproate (Depakote, Depakene), Oxcarbazepine (Trileptal) and Lamotrigine (Lamictal).Potential side effects should be reviewed with caregivers givers. Lithium (Lithobid), an antimanic drug, has limited use in children and requires close monitoring of serum levels and regular follow-up visits.

Gastrointestinal problems

Ongoing gastrointestinal problems may be a concern to some families. Chronic constipation may adversely affect behavior and other aspects of day-to-day functioning. Stool softeners, such as Lactulose and Miralax, are helpful in facilitating stool cleanout and easing fecal elimination. Education about diet may also be helpful. Digestive enzymes are recommended by some practitioners, but studies have yet to determine efficacy of this intervention. Secretin is a gastrointestinal hormone with potential central nervous system effects. Both synthetic and porcine preparations have been studied extensively but have not been found to show efficacy in the treatment of ASD or the core symptoms of ASD.

Dietary interventions have been tried over the years for children in the autism spectrum, with varying anecdotal results. Gluten and casein-free diets are recommended by some practitioners. Evidence-based studies are not yet available on the efficacy of this intervention. Small but preliminary empiric data indicate no effect¹⁸.

Vitamin and mineral supplementation have been reported, anecdotally, to be beneficial. Interest in vitamin supplementation may be heightened if ingestion of a balanced daily diet is difficult. Caregivers should be cautioned about giving megadoses of vitamins, especially oil-soluble vitamins. No well-designed studies are available, to date, regarding this intervention. Dietary supplements, such as dimethylglycine (DMG), have also been described but are not supported by clinical studies at this time.

Immune abnormalities

Researchers have speculated about the occurrence of immune abnormalities in children with ASD ¹⁹. Family studies have shown an increased incidence of autoimmune disorders in family members of children with autism. Intravenous immunoglobulin has been studied, but limited benefit was reported in a small sample size ²⁰. Steroids (prednisone) have been recommended in some cases to stimulate language or to lessen symptomatology. Careful review of potential side effects of these interventions and the lack of evidence to support them should be shared with care providers.

Heavy metal exposure

A current alternative intervention that is being trialed in several parts of the U.S. is heavy metal chelation. This treatment involves administering chelating agents orally, intravenously or transdermally to aid in the elimination of heavy metals theoretically being stored in the body. This exposure to heavy metal is theorized to have occurred in the form of thiomersol, a component of ethyl mercury and a preservative used in multiple-dose immunization vials. Many concerns about safety have been raised about this treatment regimen, and no evidence-based studies have proven that heavy metal exposure has caused autism or that heavy metal chelation treatments result in improvement or cure. Our center is not participating in any chelation studies or treatment protocols and does not recommend this treatment modality.

SUMMARY

ASD is a multifaceted condition with many comorbid concerns and difficulties. Medication trials attempt to target specific problems that interfere with progress in therapeutic interventions. Regular medical follow-up visits are important during medication trials in order to monitor progress and possible side effects. Slow tapering of medication is recommended for children with ASD, as this may result in fewer failed trials and fewer initial and withdrawal side effects. Frequent follow up provides caregivers with the opportunity to ask questions about treatment plans and share their concerns about response to treatment. Prescribing medication for problems should never be the only approach recommended. Medication is only one "tool in the toolbox" in managing difficulties. Psychosocial supports are very important in managing the challenges of difficult behavior seen in children with developmental disabilities. Caregivers should look for patterns and triggers for problems, and antecedents and responses to difficulties should be examined. Behavioral approaches should be consistent in all settings, and care should be taken not to reinforce negative behavior. A consistent, structured behavioral plan should be in place and followed by all caregivers in all settings.

Because studies are limited in the use of medication in children with ASD, practitioners are encouraged to share their clinical experiences in the use of these medications. Controlled study trials are needed to examine effects of medications and to measure outcomes. Outcome measures need further refinement in order to provide accurate appraisals of these treatments. As more of these outcomes are shared, protocols can be devised to guide clinicians in the treatment process. As we build the knowledge base of autism treatment, the hope is that we expand treatment options and improve quality of life for the children. Each step in the understanding of treatment may lead to more successful outcomes. We hope to shorten a child's journey to a happy outcome, but this will require dedicated and mutual efforts to achieve. We look forward to ongoing critical appraisal and sharing of data in order to continue our work on this journey.