Can medication management smooth the journey for families of autistic children?

Caring for a child with autism is a long haul for families but not often a smooth ride.  Medications can contribute to child functioning and family quality of life but the evidence and symptoms that may benefit require our careful consideration.  

Although I am discussing medication treatment here, the best evidence-based treatments for autism symptoms in improving social communication and Repetitive Restricted Behaviors (RRB) symptoms are behavioral (e.g. Applied Behavior Analysis), CBT (Cognitive Behavior Therapy) and parent training. These modalities also augment the effectiveness of medications in many cases. Educational adjustments and specific therapies, when indicated, such as speech-language, occupational and physical therapy are also beneficial. 

Autism symptoms change with age from early regression; later RRB; then depression, and are complicated by co-existing conditions. Not surprisingly then, studying the effectiveness and side effects of medications is complicated and guidance in flux as reliable data emerges. The ideal study of medication effectiveness is a randomized double-blind placebo-controlled trial with adequate subjects from unbiased selection and balancing adverse effects but this is not commonly done. 

With a shortage of specialists and increasing prevalence of autism, as primary care providers we need to be prepared to manage, monitor and sometimes start medications for our autistic patients. With great individual differences, and the hopes and fears of distressed parents making them desperate for help and susceptible to placebo effects, we need to be as evidence-based as possible to avoid serious side effects or delaying effective behavioral or medicinal treatments. 

As there is no cure for autism at this time, our help is mainly in addressing the many co-occurring symptoms: 37-85% ADHD, 50% anxiety, 7.3% bipolar disorder, and 54.1% depression (by age 30). Many autistic children have problematic irritability, explosive episodes, interfering repetitive or rigid routines, difficulty with social engagement, or trouble sleeping.  We need to be clear with families about the evidence and, whenever possible, use our own time limited trials with placebos and objective measures that include target symptoms and goals for improvement, complicated by that fact that the child may have trouble communicating about how they feel, have hypo- or hypersensitivity to feelings, as well as confounding co-existing conditions.

For irritability, the FDA has approved the atypical antipsychotics risperidone (ages 5–16) and aripiprazole (ages 6-17) both superior to placebo in reducing symptoms of irritability by 25-50% such as agitation, anger outbursts, and self-injurious behavior, stereotypy, and hyperactivity within 8 weeks. Aberrant Behavior Checklist can be used for monitoring. These benefits are largest with behavior therapy and at doses of 1.25-1.75 mg/day (risperidone) or 2-15 mg (aripiprazole). Unfortunately, side effects of these medications we need to disclose and monitor include somnolence, increased appetite and weight gain (average of 5.1 kg), abnormal blood lipids and glucose, dyskinesia, and elevated prolactin (sometimes galactorrhea). Aripiprazole was equivalent to risperidone for irritability, had decreased prolactin, less metabolic effects, but sometimes extrapyramidal symptoms. Other second generation atypical antipsychotics had less evidence but may have fewer side effects. With careful monitoring these medications can make a major difference in child behavior.  

ADHD symptoms often respond to methylphenidate within 4 weeks but at lower dose and with more side effects of irritability, social withdrawal, and emotional outbursts than for children with ADHD without ASD. Formulations such as liquid short or long acting or dermal patch may facilitate the important small dose adjustments and slow ramp up we should use with checklist monitoring e.g. Vanderbilt. Atomoxetine also reduces hyperactivity, especially along with parent training, but has associated nausea, anorexia, early awakening and rare unpredictable liver failure. Mixed salts of amphetamine has not been studied. Clonidine (po or patch) and guanfacine extended release have also shown some effectiveness for hyperarousal, social interaction and sleep although they can cause drowsiness/hypotension. 

Sleep issues can improve with melatonin, especially combined with CBT,  including sleep onset, duration and disruptions even sometimes helping anxiety, rigidity and communication. Using a certified brand and avoiding accidental ingestion of gummy forms are important precautions. Note that Obstructive Sleep Apnea is significantly more common in children with ASD and should be evaluated if there are signs. Childhood Sleep Questionnaire can be used to monitor.

Depression and anxiety in children with ASD do not have data for responding to selective serotonin reuptake inhibitors (SSRI) but can respond to CBT. Buspirone improved RRB (at 2.5 mg BID) but did not help mood. Mood stabilizing anti-epileptics have had mixed results (valproate reducing irritability but serious side effects), no benefits (lamotrigine,  levetiracetam), or no trials (lithium, oxcarbazepine, topiramate). In spite of this, a Cochrane report recommends antidepressants “on a case by case basis” for children with ASD, keeping in mind the higher risks of behavioral activation (consider comorbid bipolar), irritability, akathisia, and sleep disturbance. We can monitor with Short Moods and Feelings Questionnaire and Problem Behavior Checklist (U. Washington). 

NMDA and GABA receptors are implicated in the genesis of ASD. Bumetanide, a GABA modulator, at 1 mg BID, improved social communication and restricted interests, but had dose-related hypokalemia, increased urination, dehydration, loss of appetite, and asthenia.  Donepezil (cholinesterase inhibitor) in small studies improved autism scores and expressive/receptive language.  N-acetylcysteine (NAC), D-cycloserine, and Arbaclofen did not show efficacy.

Currently 64% of children with ASD are prescribed one psychotropic medication, 35% >=2 classes, and 15% >=3.  While we may look askance at polypharmacy, several medications not effective as monotherapy for children with ASD, in combination with risperidone have significant effects; notably memantine, riluzole, NAC,  amantadine, topiramate and buspirone compared with placebo.  Memantine alone has shown benefits in 60% on social, language and self stimulatory behaviors at 2.5-30 mg, enough that 80% chose continuation.

As families often use complementary or alternative medicine (CAM) we need to ask as CAM medications may interact or complicate determining the source of side effects or benefits. Oxytocin has promising but inconclusive data for improving social cognition but only for 3-8 year olds. Omega-3 fatty acid had benefits for young child stereotypy and lethargy but only by parent report. Vitamin B12, folinic acid, vitamin D3, and digestive enzymes may help but lack  data. It is important that families not replace evidence-based treatments with CAM when there are significant symptoms needing care.

Being a person with autism, beyond the stress of rigid routines and social difficulties, may include being a target of physical or sexual abuse or bullying, all risks for suicide. Suicide is 8-fold greater in autism, especially high functioning, thus we need to include in our routine suicide screening for all children those with ASD.

DR. HOWARD is Assistant Professor of Pediatrics at The Johns Hopkins University School of Medicine, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard's contribution to this publication was as a paid expert to Elsevier.  Email her at pdnews@elsevier.com.

References: 
Ritu Goel, Ji Su Hong, Robert L. Findling & Na Young Ji (2018) An update on pharmacotherapy of autism spectrum disorder in children and adolescents, International Review of Psychiatry, 30:1, 78-95, DOI: 10.1080/09540261.2018.1458706

Ekaterina Stepanova, Susannah Dowling, Molly Phelps & Robert L. Findling (2017) Pharmacotherapy of emotional and behavioral symptoms associated with autism spectrum disorder in children and adolescents, Dialogues in Clinical Neuroscience, 19:4, 395-402, DOI: 10.31887/DCNS.2017.19.4/rfindling