This guest post is by Nancy Jones, Ph.D, the Program Director for the Autism Treatment Network and Autism Clinical Trials Network at Autism Speaks.
Developing novel and more effective treatments that improve quality of life for individuals with autism is a great need but also a substantial challenge. The challenge is not only to discover treatments but also to support their efficacy with evidence from rigorous treatment trials.
There is a large body of research showing that a wide range of behavioral interventions are safe and effective for improving cognitive and language abilities and adaptive behavior in children with ASD. Many people with ASD can receive additional benefit from the use of medicines, but the medications that are currently available, tend only to address symptoms associated with ASD, such as irritability and hyperactivity. While important, there is a great need to develop medications that can help reduce the core symptoms of ASD, including difficulties in social interaction and communication and repetitive behaviors. To accelerate progress in this area, this year, Autism Speaks launched a Translational Medicine Research Initiative. Its overarching goal is to increase the number of safe and effective medical treatments available for individuals with ASD.
One may wonder why the development of new treatments is such a challenging task. One challenge is getting all of the different stakeholders needed to accomplish this goal together and working collaboratively by sharing resources and ideas. This means bringing together the academic scientists who are making basic discoveries about autism, the clinicians treating children and conducting the clinical trials, private and public funders who provide research grants, the companies that develop pharmaceutical and nutritional treatments and the families and individuals with ASD. To achieve this, one of the first endeavors of Autism Speaks’ Translational Research Initiative was to host two meetings bringing together these key stakeholders. These meetings launched the initiative and set the stage for further directions and activities.
One barrier to the development of effective treatments has been the tremendous individual differences found across individuals with ASD in terms of their symptoms and needs. This raises two important questions: 1) How do we best identify the individuals who will be most responsive to specific treatment, and 2) What is the best way to measure that a treatment has actually had an effect? These questions are concerned with “outcome measures” – the assessments that are used to determine whether a treatment has been effective. Outcome measures were the focus of the first meeting, Outcome Measures for Clinical Trials with Individuals with ASD: Challenges and Opportunities, co-sponsored by Autism Speaks and Pfizer, Inc., held in Washington DC on Jan. 11-12, 2011. The meeting hosted clinicians, academic experts in the field of outcome measurement, representatives from eight pharmaceutical companies, funding agencies, and community stakeholders. The meeting’s goals were: 1) to discuss strategies for promoting more effective clinical trials of medications to address autism core and associated symptoms and 2)to develop consensus regarding the best clinical assessments to determine whether a treatment has been effective in clinical trials.
The group discussed the following key points to be addressed in future initiatives:
- Since there are currently a number of very good outcome measures that are appropriate for clinical trials,developing consensus on a group of standard measures is a key next step. FDA approval of a medication requires consensus outcome measures. Among the questions that were discussed in regards to standard measures were: 1) what are the most sensitive outcome measures, 2) what is the best setting to measure outcome, and 3) from whom should the outcome data be collected (parents, teachers, clinicians)?
- There are opportunities to develop new outcome measures based on promising technologies that provide measures of biological change. Experts in new technologies that can make use of devices such as the iPhone to collect outcome data in real time and in real world settings also offered several promising ideas.
- Long-term success of those conducting clinical trials with people with ASD requires closer collaboration between parents, clinicians, and the basic scientists who are developing treatment targets.
The second meeting was focused on the basic science that is aimed at developing new treatment targets. Translational Medicine Research in ASD: Challenges and Opportunities, was held January 25-27, 2011 in Santa Monica, CA. The goal of this meeting was to identify ways to accelerate the basic science needed to discover and develop new medicines. The meeting included a cross-section of leaders from research funding agencies and the pharmaceutical industry, as well as experts in the fields of molecular biology, neuroscience, animal models, metabolism, and clinical research. Topics ranged from single gene disorders to medical conditions such as GI problems, epilepsy, and mitochondrial disorder, to assays for screening medications, such as induced pluripotent stem cells.
The discussion and presentations addressed three key issues: 1) What have we learned from drug discovery in other disorders that can help us develop novel autism treatments? 2) What does autism biology tell us about promising systems and pathways that might be amenable to treatment? 3) What is needed to take promising ideas from the lab and speed their development into effective treatments?
A number of key points were highlighted, including:
- Private and public partnerships involving non-profit organizations, NIH, and industry will be critical for providing the supportive environment to move discovery forward. Partnerships with industry, in particular, are crucial since these companies are responsible for bringing medications to market. These partnerships are necessary not just for funding opportunities, but also for the creation of research collaborations and shared resources, such as biorepositories and databases.
- New findings in the areas of genetics and neuroscience are helping us better understand the biology of ASD and are pointing toward the development of new treatments. Some new treatments are already in the pipeline and others are being studied. Continued investments in understanding the underlying physiology and biology of ASD are crucial for making continued progress in this area.
- The discovery of new therapeutics for ASD can take advantage of what has been learned from related single gene disorders such as Rett Syndrome, Fragile X and Tuberous Sclerosis. Because we know so much more about the biology of these conditions, drugs targets and in some cases, human clinical trials are already developed for these conditions. Will some of these medications also be useful for the larger population of individuals with ASD?
- New technologies exist for understanding the biology of ASD and testing novel therapeutics that were not previously available. The hope is that these technologies will accelerate discovery.
- Individuals with ASD and their families can provide vital information about their experience with treatments and their treatment needs to prioritize future research investments. Progress will depend on families and scientists working closely together.
Many families and individuals with ASD have been awaiting the development of novel treatment options. A clear message from both these meetings is that we are at a place where we have knowledge, promising technologies, and most importantly, the interest and commitment amongst key stakeholders to be successful in this pursuit.
Staff blogger Nancy Jones, Ph.D., Program Director for the Autism Treatment Network and the Autism Clinical Trials Network
Finding evidence-based treatments is one of the greatest challenges for those seeking treatments for autism, particularly for those with complex or severe health issues. While support for behavioral treatments is robust, rigorous evidence for pharmacological and biomedical treatments is still needed. As individuals with ASD have different needs and different levels of symptom severity, it is critical to have a range of treatment options known to be reliably safe and effective. A report by the Cochrane Collaboration, released on Monday, reported on a comparative analysis of randomized controlled clinical trials conducted to date that examined the effectiveness and safety of various SSRIs (selective serotonin reuptake inhibitors) as treatments for core symptoms of autism and other associated symptoms. SSRIs have a long history of use as treatment for disorders such as depression, anxiety and obsessive compulsive disorder, and have been found in small studies and clinical use to be helpful for repetitive and compulsive behaviors in autism. Based on this recent analysis, the authors conclude that there currently is no evidence to support the use of SSRI’s for children with ASD and limited evidence for their use of as a treatment for adults with ASD.
What does this study mean for us now? Does this mean that we know for sure that SSRI’s don’t work at all for individuals with autism? With the evidence that we have to date, it may be premature to say we have definitive evidence to rule out the effectiveness of such treatments for some individuals with autism. It does suggest, as is stated in the report itself, that at this point, for the treating physician, that a decision to use on SSRI would need to be made on an individual basis. There are as of now only a few randomized controlled trials of SSRIs in children, five of which were reported on in the paper, and there have only been two large scale studies to date, the NIH-funded study of citalopram, which was included in the Cochrane review, and the Study of Fluoxetine in Autism, which was not included in the review. The five studies also were focused on different types of outcomes, making a harder to compare across the limited number of studies to determine relative effectiveness for the different outcomes.
The review does highlight some of the key challenges for doing treatment research in autism. One major challenge is dealing with the fact that individuals with ASD may manifest the core symptoms of autism, as well as associated symptoms,to different degrees and may suffer from different levels of symptom severity. In order to address the needs of this diverse population we will need to carefully consider how best to conduct research that will be comparing individuals with autism with the same types of symptom profiles. For example, both of the larger studies of SSRIs observed that children showed improvement over the course of the study, but level of improvement was not any better for the treatment group than the comparison (placebo) group. This means that the treatment may be effective for at least some subgroups of children. A recent presentation at IMFAR of additional analysis of the citalopram study, identified certain factors that may distinguish those who responded to the medication and those that did not. These may be significant in understanding treatment response.
Does this mean that we know for sure that SSRIs will work for everyone? No. But there may not be enough information now to say we have sufficiently determined for whom the SSRIs may work, for what type of autism symptoms and why. Future research needs to focus on identifying which subgroups of people with ASD respond to which medications.
It is important to continually provide families with the best evidence about treatments, so they can make informed decisions and have more treatment choices. Autism Speaks continues to support treatment research but is also launching new initiative to address the challenges faced in doing treatment trials and translating our basic science discoveries into to viable treatments. A major focus of this effort is to identify biomarkers that can help identify subgroups of individuals with ASD for whom specific treatments may be effective.
Williams K, et al “Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders” Cochrane Database of Syst Rev 2010; 8: CD004677.
For more about the Cochrane Collaboration: