Posted by Autism Treatment Network Medical Director Dan Coury, MD
Considerable community and scientific interest has been raised by recent reports that the beta-blocker propranolol improved word use in adolescents and adults with autism spectrum disorder (ASD). It is important to emphasize that this small study does not provide sufficient evidence of effectiveness or safety to support this use of the drug, which is FDA approved to treat high blood pressure. Although we share excitement in seeing medicines evaluated in bona fide clinical studies, families should be strongly cautioned against over-interpreting media reports as endorsement to pursue this treatment for their loved ones–until larger studies show it is safe and effective.
First and foremost, treatment of autism spectrum disorders (ASDs) should include a combination of behavioral and educational interventions. Many children, adolescents, and adults with ASDs also need treatment of associated medical or psychiatric conditions such as gastrointestinal disorders, asthma, anxiety, and symptoms of attention deficit and hyperactivity disorder (ADHD).
While we have strong evidence that our behavioral treatments provide benefit, we need more research on identifying medicines that can help relieve the core symptoms of ASDs and associated behavior challenges. Interest in propranolol began over 20 years ago, with a small study (involving eight adults with autism) that suggested the drug could reduce problematic aggression. In addition, the researchers noted subtle improvements in language and social behavior. They wondered whether this might be related to the known ability of beta-blockers to reduce the symptoms of so-called overarousal. For instance, some musicians and public speakers will take a beta-blocker immediately before a performance to reduce shakiness from stage anxiety.
The authors of that first study called for further research. And the gauntlet was picked up by David Beversdorf, MD, and his associates at the University of Missouri, one of Autism Speaks Autism Treatment Network (ATN) sites. Their latest report enrolled 14 high functioning teens and adults with autism, all of whom used spoken language. They found that, when taking the medicine, some of the individuals used more words over a given period of time. That is, they had greater “word fluency.” On average, the participants showed 25 percent greater word fluency. However, some of the participants spoke fewer words while taking the medication.
What does this mean? These early studies are too small and too limited in their evidence of benefit for us to recommend that adolescents and adults with ASD begin taking this medicine. We know even less about the safety and effectiveness of beta-blocker medications in younger children. As the authors state, further study is needed to confirm both safety and benefits among a wide range of persons with ASD. And if these benefits are confirmed, we need to find ways to identify which people will respond positively to the medication and which will not. Certainly this is not a medication we want to be administering to everyone on the autism spectrum.
These early studies encourage us to pursue further research with propranolol, as we are doing with an increasing number of other medicines that could potentially help relieve the core symptoms of autism–including repetitive behaviors and impaired communication and social behavior. This exciting and encouraging research includes our study of the biological effects and behavioral benefits of both already approved medications and newly developed compounds.
Meanwhile, we have two FDA-approved medications for treating autism-related irritability that includes aggressive behavior and tantrums. They are risperidone and aripiprazole, both of which influence brain levels of the biochemical serotonin. Newer studies are looking at alternative medicines that affect other brain pathways. Early animal research with these compounds has been promising, and studies are now underway in people.
Bottom line: Studies such as Dr. Beversdorf’s are helping us better understand brain function in persons with ASD. This and related studies will ultimately lead us to new treatments and better outcomes. Until then, please stay tuned.
As researchers and parents, we’ve long known that autism often travels with attention deficit and hyperactivity disorder (ADHD). What we haven’t known before is why that is. Also, few studies have examined how ADHD affects the quality of life of those with autism.
In the past month, two studies have come together to help connect our understanding of autism with behavioral issues such as hyperactivity and attention deficit. The first study looked at gene changes in ADHD and autism. The second looked at how frequently parents see the symptoms of ADHD in their children and how seriously these symptoms affect their children’s daily functioning and quality of life.
The upshot of the first study is that the genetic changes seen in children with ADHD often involve the same genes that are associated with autism. This finding helps explain why children with autism often have ADHD symptoms. In other words, if these disorders share a genetic risk factor, it’s logical that they often occur in the same individuals. Genetic insights, in turn, can help scientists understand underlying causes and, so, may improve how we diagnose and treat these issues.
The second study, described in our science news section, helps clarify both how commonly children on the autism spectrum are affected by ADHD symptoms and documents how this affects their daily function and quality of life. Perhaps the most notable observation was that, even though over half of the children in the study had ADHD symptoms that worsened both daily function and quality of life, only about 1 in 10 was receiving medication to relieve such symptoms.
Clearly, we need more research on whether standard ADHD medications benefit children struggling with both autism and hyperactivity and attention deficits. However, studies have long shown that these medications improve the quality of life of many children with ADHD alone. Autism specialists such as Dan Coury, M.D., medical director of Autism Speaks Autism Treatment Network (ATN), recommend that parents discuss with their child’s physician whether a trial of such medications could be of benefit. (Dr. Coury co-authored the second study.)
On a deeper level, this research raises a question: Why is it, given the same genetic changes, some children develop autism alone, some develop autism and ADHD symptoms, and some develop neither—or something completely different?
I and other geneticists have seen how a given genetic change can alter normal development in various ways—if it does so at all. We have good evidence, for example, that outside influences affect how and whether autism develops in those who are genetically predisposed to it. These influences include a variety of stresses and exposures during critical periods of brain development—particularly in the womb and around the time of birth.
Still, by better understanding how altered genes produce symptoms—be they hyperactivity or social difficulties—we gain important insights into how to develop treatments that can improve the daily function and quality of life of those affected.
Ultimately there’s no substitute for working with your child’s physician and behavioral specialist to address your child’s behavioral challenges and needs within the context of your goals and values. To this end, the specialists at Autism Speaks Autism Treatment Network have developed a medication decision aid—“Should My Child Take Medicine for Challenging Behavior?”—available for free download on our website. Please let us know what you think.
As many parents know, there currently are no available medical treatments for ASD targeting core autism symptoms. Available medications target symptoms associated with ASD, such as hyperactivity, irritability, anxiety, or depression. Although the available medicines have helped many who struggle with the challenge of these symptoms, these drugs do not address the difficulties in the areas of social and communication deficits or repetitive behaviors and restricted interests.
Recently, hope has recently been kindled in a new drug for ASD that developed out of basic research on the neural mechanisms of Fragile X syndrome. Back in 2005 research in Dr. Mark Bear’s lab at Harvard showed the Fragile X mutation affects communication between neurons. Specifically, the mutation results in an excess of an excitatory neurotransmitter called glutamate, which impairs communication between neurons by making them over-stimulated. Seeing the potential to help families, a small company called Seaside Therapeutics was started to see if certain drugs could help reduce the level of excitability of neurons.
The drug, arbaclofen, is the first drug being tested. Arbaclofen works by increasing GABA, an inhibitory transmitter, which counteracts the over-excitability of cells. The preliminary results of a trial conducted with children with Fragile X syndrome looked so promising that Seaside Therapeutics announced the results on this year’s meeting of the International Society for Autism Research (read a review of that meeting’s highlights). More recently, arbaclofen has been tested in children with ASD without Fragile X. The results of this trial have been reported in the news. The trial treated 25 children and adolescents with autism for 8 weeks and the preliminary data revealed that arbaclofen was not only well-tolerated but also increase sociability and eye contact, and reduced tantrums and anxiety.
Of course, the testing of this drug continues and a review of the data by independent scientists is essential for evaluating the true benefit of this new drug, however these preliminary results offer good reason for hope and that news is always worth sharing.
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]
Finding appropriate treatments for autism is a challenge for families and clinicians alike. While behavioral treatments are an effective mainstay of therapeutic approaches, many individuals with autism benefit from the addition of medicinal interventions, particularly for problem behaviors, severe self-injury, and disruptive repetitive behaviors. A major impediment to finding effective treatment regimens is the fact that individual responses to the same medicine can vary greatly due to genetic background. Finding the most effective dose with the fewest side effects means slowly trying various doses, and possibly having to switch medicines. This is not only a challenge for the physician, but is also a confounding factor in large-scale clinical trials that aim to determine the overall effectiveness of a medication.
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.
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 sixth item, FDA Approval of Risperidone, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
In late 2006 the U.S. Food and Drug Administration (FDA) approved the first medication indicated to treat certain symptoms associated with autism, making 2007 the first year an approved drug for autism was available. The drug, risperidone sold under the brand name Risperdal, is manufactured and marketed by Janssen, L.P., a subsidiary of Johnson & Johnson.
First introduced in 1993 as an atypical antipsychotic to treat schizophrenia, Risperdal can now be marketed as a treatment of irritability associated with autistic disorder in children and adolescents aged 5-16 years. This includes symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums and quickly changing moods. Importantly, Risperdal does not treat the core symptoms of autism such as communication problems and trouble with social interactions. However, J&J used two clinical trials to demonstrate the benefits of the drug in treating the associated behavioral disturbances that can interfere with school, learning and family life.
This event not only sets precedence for gaining FDA approval for medications that treat autistic symptoms, it also shows that autism is considered a viable market for the pharmaceutical industry which will hopefully lead to the development of new compounds that will benefit the quality of life for those living with autism.
Update since this story was first run: On November 20, 2009 the FDA approved Abilify (aripiprazole) for the treatment of irritability associated with autism, making it the second medication to receive an autism indication. Specifically, the drug is approved for children 6-17 to help alleviate symptoms of “aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods.” Aripiprazole, which is manufactured and marketed as Abilify by Bristol-Myers Squibb, is an atypical antipsychotic medication used to treat schizophrenia, bipolar disorder and depression. Although an FDA approval for a medication addressing the core symptoms of autism is still lacking, the approval of Abilify will offer additional options for families and clinicians.