First, it’s important to note that medicines for treating autism are most effective when used in conjunction with behavioral therapies. Ideally, medicines are a complement to other treatment strategies.
Medicines for treating autism’s three core symptoms—communication difficulties, social challenges and repetitive behavior—have long represented a huge area of unmet need. Unfortunately, few drugs on the market today effectively relieve these symptoms and none of the options most often prescribed by practitioners work well for every individual.
In fact, while the Food and Drug Administration (FDA) has approved two drugs for treating irritability associated with the autism (risperidone and aripiprazole), it has yet to approve a medicine for treating autism’s three core characteristics. Nonetheless, medicines such as risperidone and aripiprazole can be beneficial in ways that can ease these core symptoms, because relieving irritability often improves sociability while reducing tantrums, aggressive outbursts and self-injurious behaviors.
The good news is that the range of medication options may soon change, thanks to recent advances in our understanding of the biology that produces autism’s core symptoms. This has made it possible for researchers to begin testing compounds that may help normalize crucial brain functions involved in autism. Early experiments suggest that several compounds with different mechanisms of action have great potential for clinical use, and many are now in clinical trials. [This link takes you to the search engine of the NIH clinical trial network, with results under the search term “autism.”]
Although these developments are exciting and hold real promise for bettering the lives of people with autism, we will have to wait at least a few more years before we know if any of these drug studies produce enough information on safety and effectiveness to merit FDA approval for the treatment of core symptoms.
Today, most medicines prescribed to ease autism’s disabling symptoms are used “off label,” meaning that their FDA approval is for other, sometimes-related conditions such as attention deficit hyperactivity disorder (ADHD), sleep disturbances or depression. Such off-label use is common in virtually all areas of medicine and is usually done to relieve significant suffering in the absence of sufficiently large and targeted studies.
An example in autism would be the class of medicines known as selective serotonin re-uptake inhibitors (SSRIs), including fluoxetine. Several of these medicines are FDA-approved for the treatment of anxiety disorders and depression, in children as well as adults. Although large clinical trials have yet to demonstrate their effectiveness, parents and clinicians have found that they can ease social difficulties among some people with autism. However, it has proven to be difficult to predict which medicines in this class may produce the greatest benefit for a given patient with autism. Similarly, determining the best dose can be quite challenging.
Another example would be naltrexone, which is FDA-approved for the treatment of alcohol and opioid addictions. It can ease disabling repetitive and self-injurious behaviors in some children and adults with autism.
These medicines do not work for everyone, and all medicines have side effects. And as noted above, each person may respond differently to medicines. In addition, changes in response to a medicine can occur as time goes on, even when the dose is not changed. Over time, some people develop tolerance (when a drug stops being effective) or sensitization (when side effects worsen).
Because using these medications in children and adolescents can be a difficult decision for parents, you may find it helpful to use our Medication Decision Tool Kit, a guide for actively working with a physician to find the approach that fits best with your values and goals. You can download it free here.
These are exciting times in the development of new medicines for relieving autism’s most disabling symptoms, and Autism Speaks is increasing its funding and focus in this promising area, while placing great emphasis on ensuring the safety of promising new medicines. Please stay tuned!
Read more science news and perspective on the Science Page.
This week on Parenthood, ‘Do Not Sleep with Your Autistic Nephew’s Therapist,’ Adam and Kristina are dealt a huge blow when Gaby, Max’s behavioral therapist, gives notice that she can no longer work with them. Adam and Kristina are unaware at the time why she is leaving, but she is visibly upset.
Adam and Kristina are stirring and unsure what do. They are trying to pick up where Gaby left off, but Max is full-blown meltdown mode and it seems there is little hope in site.
Have you experienced the departure of a therapist that affected your family? How did you handle it?
Please stay tuned this week for even more Parenthood discussion. Watch the full episode here, so you will be ready to participate!
This Top 10 Research Achievements of 2009 post comes from guest blogger Evdokia Anagnostou, M.D., a Clinician Scientist at Bloorview Research Institute and an Assistant Professor, Department of Pediatrics at the University of Toronto. Dr. Anagnostou leads a program of experimental therapeutics and neuroimaging in autism and is leading a series of clinical trials to study the efficacy of oxytocin, memantine, and other compounds for symptoms associated with autism.
The last decade has been fairly productive when it comes to research in psychopharmacology. Large scale multicenter studies have been conducted and more than one medication has shown benefit for the treatment of symptoms associated with autism. Still, our approach to pharmacology research has been relatively limited. We have examined the similarities between symptoms associated with autism and symptoms in other disorders, assumed that similar symptoms across disorders have similar neurobiology, and “borrowed” medications from other disorders with “overlapping “ symptoms to test in autism. The approach has been somewhat successful. We now have evidence from large multisite studies to support the efficacy of some atypical antipsychotics for irritability and aggression (risperidone (1) and aripiprazole (2)), and stimulants for the treatment of ADHD-like symptoms (3). This approach also has its limitations. An example may be the failure of large multisite studies to show effectiveness for the treatment of repetitive behaviors for serotonin re-uptake inhibitors (SSRIs). Although much remains to be explored and many questions still remain, one cannot help but wonder whether it is time for a paradigm shift in the way we approach pharmacology research. There are plenty of approaches that still remain to be tested in this population. Firstly, we have not yet done truly translational work. In other words we have not yet used the findings from genetics/ animal models/ pathology to develop treatments based on the neurobiology of autism itself, as it is revealing itself to us over the past few years. Secondly, we have not addressed what we really do in real life which is combine medications with psychosocial interventions. In fact, we have no data to date that any of the medications we use actually treat autism. Medications do not teach skills. It is the psychosocial interventions that treat autism. What we attempt to do with medications for the most part, is to enhance learning from such interventions either indirectly by reducing behaviors that interfere with learning ( e.g. irritability, aggression, hyperactivity, repetitive behaviors) or by directly facilitating learning processes (potential examples in trials: memantine, oxytocin). The question remains whether the combination of medications with psychoeducational treatment is favorable compared to medications alone or the psychoeducational treatment alone. Previous studies in other neurodevelopmental disorders, such as ADHD, (4) have taught us that when the effect of medication is large, it may be hard to show additional benefit from psychosocial interventions. As such both comparisons: combination treatment vs. medication, and combination treatment vs. psychosocial intervention are worth exploring.
Recently, the RUPP group published the first randomized controlled trial that tested the combination of a medication with a parent training curriculum based on ABA principles for the treatment of irritability/aggression (link to Top 10 story on combination therapy) (5). This was a 24 week randomized trial of combination treatment vs. medication only (risperidone/aripiprazole alone). 124 children ages 4-13 with frequent aggression, self injury and tantrums were recruited. The primary outcome measure was a modified for autism version of the Home Situations Questionnaire (HSQ), a 20 item questionnaire aimed to measure non compliance in every day circumstances. Secondary measures included the Aberrant Behavior checklist, the Clinical Global Impressions measure and the Children Yale Brown Obsessive – Compulsive Scale-PDD version. The parent intervention consisted of 11 sessions with a certified therapist, three additional optional sessions and up to 3 booster session for a total of up to 17 sessions, lasting 60-90 min and delivered individually to the families. The curriculum included teaching on visual schedules, positive reinforcement, compliance, functional communication and adaptive skills. The sessions were fairly individualized to the child’s level and needs. The medication was risperidone dosed by weight and was switched to aripiprazole by week 8 if the risperidone was ineffective. The study reported that combination treatment was more effective than medication alone as measured by the HSQ, irritability hyperactivity and stereotyped speech as measured by the ABC. They also reported that the mean dose of medication required in the combination group was less than that required in the medication alone group (1.98 mg/d vs. 2.26 mg / day respectively).
In summary, combination treatment was more effective at improving everyday outcomes than medication treatment alone. This Top 10 paper provides initial evidence that such trials are feasible and worth exploring. The authors argued that this study aimed at a different outcome (real life situation improvement) than the original risperidone studies, and as such, suggests that integrated trials can be successful when the outcome measure for the medication is somewhat different than that for the psychosocial intervention / combination treatment. In fact, as previously discussed, it makes sense that generalizability of the medication effect is accomplished by parent training given that the medication itself is not likely to teach the child or the family any skills. The question still remains in the blogger’s mind whether the effects of combination treatment should be tested against intensive parent training alone. Although I agree with the authors that the effect size of the risperidone is large, these medications are associated with a relatively unfavorable side effect profile and it would be of great interest to learn how much of the effect size observed with the combination treatment can be achieved by using parent training alone, given that decisions on the using a medication are not solely based on the efficacy profile of medications. Such studies may have implications for systems delivery and the generalization of results may be more difficult given the differential insurance coverage for medications vs. psychosocial interventions, but may have significant impact in the way we treat children with autism
The study is very important as it is the first such trial in autism and highlights the need for integrated medication/psychosocial intervention trials. Future studies will likely focus on integrated treatments targeting both decrease of maladaptive behaviors as well as skills acquisition.
1. Research Units on Pediatric Psychopharmacology Autism Network. Risperidone in children with autism and serious behavior problems. N Engl J Med. 2002;347:314Y321.
2. Owen R, Sikich L, Marcus RN, Corey-Lisle P, Manos G, McQuade RD, Carson WH, Findling RL. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics. 2009 Dec;124(6):1533-40.
3. Research Units on Pediatric Psychopharmacology Autism Network. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry. 2005 Nov;62(11):1266-74.
4. MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-month outcomes of treatment strategies for attention-deficit/hyperactivity disorder. Pediatrics. 2004 Apr;113(4):754-61.
5. Aman MG, McDougle CJ, Scahill L, Handen B, Arnold LE, Johnson C, Stigler KA, Bearss K, Butter E, Swiezy NB, Sukhodolsky DD, Ramadan Y, Pozdol SL, Nikolov R, Lecavalier L, Kohn AE, Koenig K, Hollway JA, Korzekwa P, Gavaletz A, Mulick JA, Hall KL, Dziura J, Ritz L, Trollinger S, Yu S, Vitiello B, Wagner A; the Research Units on Pediatric Psychopharmacology Autism Network. Medication and Parent Training in Children With Pervasive Developmental Disorders and Serious Behavior Problems: Results From a Randomized Clinical Trial. J Am Acad Child Adolesc Psychiatry. 2009 Oct 23. [Epub ahead of print]
5|25: Celebrating Five Years of Autism Science Day 22: Combined Therapies Hold Promise for More Effective Treatments
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our 22nd item, Combined Therapies Hold Promise for More Effective Treatments, is from Autism Speaks’ Top 10 Autism Research Events of 2009..
Just over three years ago the FDA’s landmark approval of risperidone for the treatment of ASD represented a significant breakthrough for the autism community. Since then other large-scale autism studies have sought FDA approval for drugs that target core or associated symptoms for autism, but unfortunately few of these trials have proven successful. In 2009, taking a cue from other disorders such as ADHD where a combined effect of both medication and behavioral therapies has proven fruitful, researchers published the first successful combined randomized controlled trial for ASD. The paper in the Journal of the American Academy of Child and Adolescent Psychiatry demonstrated that combined pharmacological and behavioral treatments was more effective than pharmacological treatment alone for reducing challenging behaviors.
Risperidone is approved for reducing aggression and irritability in children and adolescents with autism. However, its use still presents a number of challenges to clinicians. Like other atypical anti-psychotics it can have adverse side effects including weight gain, potentially leading to increased risk for obesity, and GI symptoms such as diarrhea and constipation, which can already be problematic for children with ASD. Clinicians must therefore balance the benefit of treating the problem behaviors with the potential for creating new health challenges for the child. On the other hand, behavioral therapies have been shown to be one of the most reliably effective treatments for improving problem behaviors with limited side effects. Combination therapies create a synergistic therapeutic environment in which medication allows a child to get more from behavioral therapies and, at the same time, the benefits of behavioral therapy may mean lower doses of medication are required.
A new multi-site study by the Research Units on Pediatric Psychopharmacology Autism Network, the same group that conducted the pivotal studies leading to the approval of risperidone, investigated whether combining risperidone treatments with a simultaneous behavioral intervention would be more effective than medication alone. Their 24-week study of 124 children ages 4-13, compared a treatment regime of risperidone alone with a combined treatment regimen of risperidone and a parent training program that followed the principles of applied behavioral analysis. While both the combined and medication-only treatments reduced the severity of non-compliant behaviors, the combined therapy resulted in a significantly greater reduction while using lower doses of risperidone. The combined therapy was also better at reducing other challenging behaviors, such as irritability and hyperactivity.
This study provides hope for a wider range of available treatments and greater flexibility for clinicians who should be encouraged to use combined approaches in cases where medications or behavioral interventions are not effective on their own. Confirming the effectiveness of coordinated treatments that take full advantage of the benefits of both pharmaceutical and behavioral approaches also demonstrates the continued need to support research establishing the most effective treatments in all realms. Finally, the vast majority of clinical trials conducted to date have only addressed how an individual treatment compares to a placebo. Very few studies have been conducted that make head-to-head comparisons of two or more treatments as was done here, so the success of this trial will also serve to highlight the utility of “comparative effectiveness trials” for determining the best treatments for ASD.
Did you know?: Autism Speaks’ funded Interactive Autism Network (IAN) is a web-based family registry and social network that brings together thousands of families with autism research and provides a forum for families to report information about their experiences. In a recent study on over 5000 children in IAN, 35% of parents reported that their children were taking at least one psychotropic medicine and the use of these drugs increased with age. The incidence of a comorbid condition such as seizures, ADHD or anxiety increased the likelihood of medication use. The IAN authors also reported on correlations between insurance access and use of multiple medications, noting that those children using public insurance plans (such as Medicaid) tended to be on more medications, possibly due to an inability to get coverage for behavioral therapies.