News The latest developments in autism research.
Profiles Portraits of scientists who are making a mark on autism research.
Toolbox Emerging tools and techniques that may advance autism research.
Spotted A roundup of autism papers and media mentions you may have missed.
Opinion Conversations on the science of autism research.
Viewpoint Expert opinions on trends and controversies in autism research.
Columnists Dispatches from experts on various facets of autism.
Crosstalk Debates and conversations about timely topics in autism.
Reviews Exploring the intersection of autism and the arts.
Q&A Conversations with experts about noteworthy topics in autism.
Deep Dive In-depth analysis of important topics in autism.
Special Reports Curated collections of articles on special topics in autism.
Webinars Presentations by leading experts on their latest research.
Opinion / Viewpoint

How to evaluate new medications for autism

by  /  10 June 2014
The Expert:

Jeremy Veenstra-VanderWeele

Julia Yellow Long quest: In finding treatments for autism, scientists must grapple with autism’s enormous diversity.

There are just two medicines, risperidone and aripiprazole, approved for treating children with autism. Both are intended for treating irritability and agitation in children with the disorder, and their approval was based on data from randomized, placebo-controlled studies of children and adolescents1, 2.

So far, however, no medications have been approved for treating the core symptoms of autism. But there are many studies underway.

This is, therefore, a good time to examine the approaches we need to develop and test potential treatments.

We must take into account what has been learned about autism risk factors over the past few years. Relatively rare genetic syndromes3, copy number variants, which duplicate or delete stretches of DNA4, 5, and spontaneous single-nucleotide mutations6, 7 have provided the most traction for understanding the neurobiology of autism. These rare genetic risk factors appear to contribute to risk in upwards of 15 percent of children with autism.

Common environmental risk factors, such as extremely low birth weight and maternal diabetes, have also emerged8, but these have yielded insights more amenable to prevention rather than to treatment. Our clearest ideas about the underlying neurobiology of autism risk are therefore based on small subgroups of individuals.

Testing treatments:

There are two main approaches that researchers are pursuing to identify treatments that may benefit children with autism. The first and most common approach is to evaluate a treatment in the entire group of people affected by autism, usually excluding a small number of people who have a known genetic syndrome.

The second approach is almost the exact opposite: to study a medication for autism-related symptoms in a single defined genetic syndrome that confers substantial risk of autism, but which constitutes less than 2 percent of individuals with the disorder.

Down the line, we can hope for a third approach that is somewhere in the middle: researchers evaluating a treatment in a large subgroup of individuals with autism who share a common biological marker of the disorder.

Most of the evidence that we have for existing medications is derived from the first approach, based on studies that include a broad group of children who may have different underlying risk factors or causes for their autism9.

Successful treatments identified using this approachexclusively target symptoms that extend beyond the core autism diagnosis, such as methylphenidate for hyperactivity10 in children or fluoxetine for compulsive behaviors in adults11. These medications harness knowledge of fundamental brain circuitry and signaling that does not depend upon an understanding of autism risk factors.

Notably, many more studies have found no benefit for medications posited to have some relationship to autism’s causes. In another example, secretin, a hormone that affects gut and brain function, was thought to be effective for autism because a small group of children showed improvement in their language and autism symptoms.But several randomized, placebo-controlled trials of secretin all yielded negative results12.

These trials taught us that the placebo effect is substantial in autism, with parents or clinicians typically rating about 30 to 45 percent of children in the control group as improved.

A few large studies of medications in the overall group of children with autism are underway or were completed in the past few years. Some studies are evaluating response to manipulations of the oxytocin or vasopressin systems, two peptide hormones that modulate social function across species. There is little evidence suggesting that deficits in either of these hormone pathways confersrisk of autism, but their roles in social function make them logical targets for a disorder that includes social impairment.

Two ongoing studies — presented at scientific meetings, but not yet published — are using medications that might normalize a possible imbalance between excitatory and inhibitory brain signaling. This theory of a signaling imbalance in the brains of people with autism has become popular based on data in certain animal models and the increased rate of epilepsy in autism13.

The largest treatment study ever conducted in autism used what is called a randomized withdrawal design. All children initially took memantine, an Alzheimer’s drug that dampens one form of excitatory signaling. If they showed significant benefit, they were assigned randomly either to a group that continued taking memantine or a group that got a placebo.

The majority of children in both groups worsened, with no significant difference between them14. This suggests that the expectation of being switched off of memantine led to worsening in many study participants, regardless of whether they were actually switched to placebo or not. It’s possible that a subgroup of people with autism benefit from memantine, but researchers don’t know which subgroup that might be.

Another large study examined arbaclofen, a drug expected to boost one form of inhibitory signaling. The researchers saw no difference between arbaclofen and placebo on the primary outcome measure, an index of social withdrawal and lethargy. However, clinicians rating autism severity saw a substantial improvement in a subgroup of participants15. This pattern of response in a subgroup may be consistent with a treatment that lies nearer to one cause of autism, but for which researchers have not yet identified a biomarker.

Syndrome clues:

The second approach to treatment development focuses on specific genetic syndromes for which we have better knowledge of the underlying neurobiology than we do for autism. Mouse models of fragile X syndrome point to several opportunities for intervention, including drugs that block the activity of a signaling receptor called mGlu516. Studies of these drugs in people with fragile X syndrome have so far yielded mixed results17.

Research on three other autism-related syndromes is following close on the heels of this work. A clinical trial is underway to test the effectsof insulin-like growth factor 1 (IGF-1) in people with Rett syndrome18, 19. A conference presentation at the 2014 International Meeting for Autism Researchdescribed encouraging findings from a randomized, crossover study of IGF-1 in nine children with Phelan-McDermid syndrome20. Likewise, work is ongoing to move research on mTOR inhibitors from mouse models of tuberous sclerosis complex into human trials21.

Each of these syndromes accounts for less than 2 percent of individuals with autism, but they are logical places to start because we have an understanding of their underlying cause. Ideally, we would take medications that work in these narrow populations and test them in a larger subgroup of people with autism who share a common biomarker — the as-yet largely theoretical third approach to treatment development.

Building on the observation that mTOR inhibitors normalize the increased brain size in some mouse models of tuberous sclerosis complex and related syndromes, one could imagine testing mTOR inhibitors in a subgroup of children with autism who show brain overgrowth22.

Before using drugs such as these, which have significant side effects, however, one would really want to see evidence of increased mTOR activity in the blood cells of these children — or another marker of a shared risk factor. Other biomarkers, such as elevated blood levels of the chemical messenger serotonin, may also have potential for identifying subgroups of individuals that may respond to a common treatment23.

With increasing knowledge of both neurobiology and autism risk, helpful medications are likely to emerge from both the first and second approach. Neither tactic is likely to yield a medication that benefits every child with autism, however.

I would guess that the medications that most closely target the cause of autism for a particular subset of children are the most likely to be transformative, but they will probably help the smallest numbers of children. By contrast, those treatments that target core brain circuitry — but have little to do with the root causes of autism — seem likely to help a larger percentage of children, but to a smaller degree.

Jeremy Veenstra-VanderWeele is associate professor of psychiatry at Vanderbilt University in Nashville, Tennessee. He has consulted with Roche Pharmaceuticals and Novartis on medication development in fragile X syndrome and has received research funding from Roche, Novartis, Seaside Therapeutics, Forest, Sunovion and SynapDx.


1: McCracken J.T. et al. N. Engl. J. Med. 347, 314-321 (2002) PubMed

2: Owen R. et. al. Pediatrics124, 1533-1540 (2009) PubMed

3: Betancur C. Brain Res. 1380, 42-77 (2011) PubMed

4: Sebat J. et al. Science. 316, 445-449 (2007) PubMed

5: Sanders S.J. et al. Neuron 70, 863-885 (2011) PubMed

6: Neale B.M. et al. Nature 485, 242-245 (2012) PubMed

7: Sanders S.J. et al. Nature 485, 237-241 (2012) PubMed

8: Gardener H. et al. Br. J. Psychiatry 195, 7-14 (2009) PubMed

9: Warren Z. et al. (2011). Therapies for children with autism spectrum disorders. Rockville, MD: Agency for Healthcare Research and Quality.

10: Research Units on Pediatric Psychopharmacology Autism Network Arch. Gen. Psychiatry 62, 1266-1274 (2005) PubMed

11: Hollander E. et al. Am. J. Psychiatry 169, 292-299 (2012) PubMed

12: Krishnaswami S. et al. Pediatrics. 127, e1322-1325 (2011) PubMed

13: Rubenstein J.L. and M.M. Merzenich Genes Brain Behav.2, 255-267 (2003) PubMed

14: Hardan A.Y. (2014, May 5). Efficacy and safety of memantine in a global, double-blind, placebo controlled, randomized withdrawal study in children with autism spectrum disorder. Paper presented at the American Psychiatric Association Annual Meeting, New York, NY.

15: Veenstra-VanderWeele J. et al. (2013, May 2). Randomized, controlled, phase 2 trial of STX209 (arbaclofen) for social function in ASD. Paper presented at the International Meeting for Autism Research, San Sebastian, Spain.

16: Michalon A. et al. Neuron. 74, 49-56 (2012) PubMed

17: Jacquemont S. et al. Sci. Transl. Med. 3, 64ra61 (2011) PubMed

18: Tropea D. et al. Proc. Natl. Acad. Sci. USA 106, 2029-2034  PubMed

19: Khwaja O.S. et al. Proc. Natl. Acad. Sci. USA 111, 4596-4601 (2014) PubMed

20: Buxbaum J.D. (2014, May 14). Paper presented at the International Meeting for Autism Research Press Conference, Atlanta, GA.

21: Ehninger D. et al. Nat. Med. 14, 843-848 (2008) PubMed

22: Chawarska K. et al. Arch. Gen. Psychiatry 68, 1021-1031 (2011) PubMed

23: Mulder E.J. et al. J. Am. Acad. Child Adolesc. Psychiatry 43, 491-499 (2004) PubMed

  • Claire Boekraad

    I like the illustration of Julia Yellow very much……! gr., CB.

  • Katie Wright

    I believe most researchers are looking at autism too broadly. Autism is not like diabetes. It is highly unlikely that any one drug will help even a majority of people with autism. For example, my son’s primary issue is autoimmune dysfunction. This is a common problem for 25% of people on the spectrum. Monthly IVIG treatments have tremendously improved the quality of his life and saved his health. A majority of people with ASD have gastrointestinal issues, TSO is often very helpful for some of these sufferers. Sometimes a sudden and severe onset of OCD can be attributed to untreated Strep or PANDAS. This is also treatable if identified early. We need to look at treating autism below the neck and as the whole body disease it is for so many.

    Risperdal addresses behavior only and the side effects are horrendous. We need to spend more time looking at the biological causes of behavior. Pain, for example, is often the cause of self-injurious behavior- whether it be an impacted tooth or inflammatory bowel disease( common in the ASD population).

  • N. Bishop
  • Katie

    Yes, TSO is the same for kids or adults. I know TSO sounds insane but it has tremendously helped so many children like my own. Rather than spending decades and tens of millions researching rare genetic variants I fail to understand why treatment research not more practical / here and now focused. Seaside failed because FX research does not automatically translate to the other 97% of ASD people without Fragile X. I feel that this area of research has long over promised and under delivered.

    We need to focus on urgent matters at hand- especially those involving acute pain.

  • autism mom

    My son has responded to Lutimax (luteolin) an anti-inflammtory, enzymes and probiotic. I agree with Katie targetting the underlying immune dysfunction is key- I feel that our childrens immune system has gone haywire resulting in neuroinflammation in the brain and GI. Our kids behavior is a symptom of a and neuroimmune dysfunction. Researchers found that microglia in the autistic brain appear “angry” in children with autism- that is a red flag that the brains microglia are damaged and therefore not working right. Target those areas (GI and brain inflammation) for treatment.

  • Walt Brooks

    I find this article to be heavily biased. The unfortunate difficulty of the autism spectrum is its complexity. As a grandparent to a 7 year old who is currently being well treated in the Seattle, WA school district from his early diagnosis at 2 years to present time I see continuous improvement. Whether he will ever be a very social person or not I am sure he will be able to support himself as an adult. Your article does not mention some of the latest discoveries but in time I am sure that a medication will be found that significantly reduces autism’s symptoms. Your foundation should make every effort to encourage research to find effective medications. I am sure that each individual will require some sort of specialized medical regimen to minimize Autism’s symptoms. In terms of finding out what are the root causes of this disease I would suggest that your foundation help fund large scale genetic studies to identify why some individual who have genetic traits that would be indicative of expecting autistic symptom but show no such symptoms. I refer you to Sci Am. Mind’s recent article about this approach and it advantages and difficulties.

  • No one

    The problem is that no matter what they find there’s always a “safety concern” or “more research needed” or “we aren’t yet convinced”. There’ll always be denial. Or the drug gets banned or whatever . And nothing is ever good enough. These genetic studies on mice do nothing to help patients and their families. It’s a load of crap. No one is holding their breath anymore.


Log in to your Spectrum Wiki account

Email Address:



Request your Spectrum Wiki account

Spectrum Wiki is a community of researchers affiliated with an academic or research institutions. To be considered for participation, please fill out this form and a member of our team will respond to your request.


Email Address:

Title and Lab:

Area of Expertise: