Home > Science > What is the value of combination therapies in autism?

What is the value of combination therapies in autism?

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]

  1. Katie Wright
    April 26, 2010 at 7:45 pm

    Yes, parents RARELY have success utilizing one intervention alone. As the author said ASD children and their symptoms are so heterogenous, much trial and error goes on in homes. It is a difficult, exhausting and pain staking process- with your child’s entire future in the balance.

    I must disagree w/ the author regarding “great progress” w/in mainstream autism science over the past 10 yrs. Since 2000 autism has exponetially increased- by any measure the problem is worse than ever and more children are suffering. The failure to produce solid causation science or innovative treatment interventions is terrible.

    As a result of this failure many parents have undertaken massive research endeavors in order to understand their child’s disorder and also treat it. Studies by Jepson, Ashwood, Hewitt, Bradstreet, Usman, McGinnis, MacFabe, just to name a few, have made great progress outside the mainstream because they are willing to follow any leads. These are courageous scientists willing to risk their careers in pursuit of real causation factors and treatment breakthroughs. Many of them are parents of ASD children.

    The Defeat Autism Now community is where the best translational research cane be found. Yes, it needs much more intensive study- but that will not be possible until a larger org has the courage to fund such work.

  2. Kate
    April 26, 2010 at 10:52 pm


    Thank you for speaking the TRUTH. As a patient, I’ve had to do the same thing. Foruntately, scientists at the Cold Spring Harbor Labs in New York have made a number general discoveries on the brain lately. We will eventually see results. It’s disheartening when I can only find a few institutions in this country that are going beyond the current borders of autism. USC Davis & UPenn are two others I can think of. Austrailia has the best knowledge. It’s time the world get on one page.

    I was so sick, I had no choice but to tear the internet apart. With a little help from a neurologist who specializes in Multiple Sclerosis and some research, I managed to reverse most of the symptoms. I’m pretty dismayed that I did this in 3 years, when scientists have yet to produce any pharmacological results. Sadly, not everyone can even afford ABA, so many children go left untreated. I’ve worked countless hours to find alternative treatments that parents can utilize at an affordable rate. Keep in mind, I’ve only had 1 month of therapy yet my functioning level less than a year ago was at elementary school level. Today, my therapist observes me as having graduate level vocabulary.

    There will be a day that comes where I will be calling Autism Speaks to inform them of my treatment.

  3. deb
    April 27, 2010 at 2:11 am

    My son is now 18. After reading this; I really don’t know quite what to say. My son became autistic following his 1 year immunizations. At that time; there were 1 in 3,000 children diagnosed with autism. Now it is 1 in 150. I agree with the 1st post following this blog in that we (meaning the USA) need to gather data from Australia and any other country that has done clinical trials in both traditional and non-traditional treatments. This problem is too large for one country to address. It’s senseless to me that we don’t collectively join efforts. If we really care about these children and not just about money or making a name for ourselves, then we will do what is best for all of them.

    My son is currently on one of the anti-psychotic meds mentioned and it horrifies me. While it definitely suppressed the temper tantrums that he was having in school; it has also increased his OCD symptoms 10 fold. He has also gained 25 to 30 pounds within a one year to 15 month time frame that he has been on the medicine. His blood sugar has to be monitored. The other side effect that is incredibly prevalent is RESTLESSNESS. It is very different than hyperactivity. He simply cannot enjoy being still, for a moment. So, a sedative was added to counteract this side effect. By the way, this side effect has not and will not go away. The sedatives make him appear so foggy and not present that I discontinued using them. Another thing that has occurred is that his breath smells like urine. Based on my understanding; this could be symptomatic of poor kidney or liver function. Is this being caused by the medication?
    While there will always be a need for pharmaceuticals; I still feel that in the treatment of autism, that they are only band-aids. They aren’t repairing or fixing anything. They only help the symptoms.

    We have spent a fortune on both traditional and non-traditional therapies, pharmaceuticals, neutraceuticals, etc., over the years. The anti-psychotic med is the only pharmaceutical he is taking now. I sincerely believe that everything that we have done without pharmaceuticals has been so much more effective long-term. He has made astounding progress since his diagnosis. I do not contribute these gains to any medicine that he was given. I attribute it more to the following:

    1) dietary changes – for several years, eliminating all wheat/gluten, dairy and dyes.
    2) healing the gut with probiotics, proteolytic enzymes and by eliminating the foods that were assaulting his gut.
    3) Giving him pharmaceutical grade supplements under an MD’s care, such as DMAE, EFA’s, DHA, anti-oxidants, etc., etc., etc.
    4) Acupuncture and Accupressure, NAET Treatments to help with eliminating food allergies/sensitivities.
    5) Spect Brain Studies
    6) Occupational Therapy
    7) Speech Therapy

    There are no magic bullets. I have searched for a very long time for one, but through a multi-disciplinary approach; these children can reach their highest potential.

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