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Testing a new approach for easing self-harm and dangerous outbursts

Autism Speaks Postdoctoral Fellow Alan Lewis provides a peek inside early research into a potential new pharmaceutical approach

By Alan Lewis, recipient of a 2015 Autism Speaks Meixner Post-doctoral Fellowship in Translational Research. Dr. Lewis is pursuing his fellowship project at Yale University as part of his residency training in psychiatry.

Editor’s note: The following information concerns early research on a potential therapy that must undergo testing for safety and effectiveness before it is used outside of a carefully monitored research setting.

Autism complicated by aggression warrants treatment by a qualified healthcare professional. For help finding resources in your area, please call or email the Autism Speaks Autism Response Team: (888) 288-4762; (888) 772-9050 en Español; familyservices@autismspeaks.org.

I was only a few months into my psychiatry residency when I began working with a boy who had autism and persistent challenging behaviors. These behaviors included self-harm as well as physical aggression toward family members.

Of course, aggression is not the norm among people who have autism. When it does occur, it often reflects an inability to communicate pain and/or frustration.

Unfortunately, this young man’s challenging behaviors persisted despite behavioral therapy and FDA-approved medications.

Eventually, the often-asked question “what’s next?” went unanswered.

The great need for safe and effective medicines
Even today, my memories of this terrible – but common – predicament remain strong. Solutions are so important because dangerous behaviors can present a great barrier to interactions with peers, family and community.

Thankfully, behavioral treatments help the majority of children and adults who have autism complicated by aggressive behaviors. When it’s not enough, we also have two FDA-approved medicines for treating irritability in children who have autism.

However, current medications for aggression aren’t universally effective. And sometimes they lose effectiveness over time. For many individuals, these medicines also come with serious side effects such as excessive weight gain and metabolic abnormalities.

For all of these reasons, we need improved treatment options for people who have autism complicated by dangerous behaviors.

Exploring the pharmaceutical effects of purified nicotine
During my residency, I was excited to learn of research showing that purified nicotine reduced aggression in in a broad variety of lab animals. A handful of studies with people likewise suggested that nicotine could ease problematic aggression in people.

As you may know, nicotine is the addictive component in cigarettes. Research shows that it acts on the brain’s reward pathway. However, research also shows that nicotine’s effects depend on a number of things. These include dose, how it is given and the duration of treatment. For example, research suggests that nicotine patches don’t produce addiction – probably because they release the chemical slowly.

What’s more, nicotine’s actions on the brain are complex. It acts on a broad class of receptors on the surface of brain cells. We call them nicotinic acetylcholine receptors.

Our early research
Intrigued by this previous research, I and my colleagues in the lab of neurobiologist Marina Picciotto conducted studies with mice. We found that nicotine’s anti-aggressive, or serenic effect, is activated by a specific nicotinic receptor in the brain. It’s called the alpha-7 receptor.

Returning to the library, we found previous studies that linked problems with this brain cell receptor to 15q13.3 deletion syndrome. This rare syndrome involves deletion of the gene coding for the alpha-7 receptor. Many people with this condition have severe aggression as well as autism, epilepsy and attention deficits.

Though 15q13.3 deletion syndrome is a rare cause of autism, more subtle changes in alpha-7 and other nicotinic receptors have been found in many people with autism. We also find them in mice bred to display autism-like behaviors.

My colleagues and I reasoned that activation of the alpha-7 receptor – and possibly other nicotinic receptors – might help ease the type of aggression seen in some people with autism.

In addition, several studies had already explored using nicotine to relieve symptoms of Alzheimer’s disease and other cognitive problems in non-smoking seniors. These studies suggest that nicotine patch treatment is safe, effective and non-addictive.

However, the effect on someone who has autism may be different. This is why we knew it was so important that we and other researchers evaluate nicotine’s safety and effectiveness in carefully controlled and monitored studies before it’s used in the wider autism community.

From basic research to clinical trial
Like all Autism Speaks translational fellowships, my project involves translating the findings of basic research (in this case, in mice) into clinical trials involving people who have autism. I will be conducting the clinical trial under the leadership of my second fellowship mentor, psychologist Denis Sukhodolsky.

Now underway, the trial is the first to test the nicotine patch as a treatment for severe irritability and aggression in people with autism. We hope to enroll 16 adults with autism who have problems with aggression. The trial will last three weeks. During this time, participants will wear either a nicotine patch or a placebo patch.

The placebo patches look just like nicotine patches. But they don’t contain biologically active chemicals. Neither the participants, their caregivers nor the researchers will know who is wearing which type of patch, until the trial is done.

During the study, we’ll ask the participants and their caregivers to report instances of irritability or aggression. At the end of the study, we hope to have a clearer understanding of whether nicotine can be used to safely and effectively ease this challenging behavior.

Meanwhile, we have published a recent case study describing how we safely and successfully used the nicotine patch to ease severe aggression in a teenager with autism who had failed to respond to behavioral therapy and medicines. You can learn more about this study here.

I am grateful that Autism Speaks is not just standing by when people in the autism community have no answers to “what do we do next?” By funding our research – and studies like it – Autism Speaks is advancing us to the day when we can deliver safe and effective solutions to this question.

I look forward to partnering with our study participants and their families in our shared mission. I sincerely encourage you to contact our research team with any comments, questions or suggestions. You can reach me at alan.lewis@yale.edu.

Meet more of our research fellows - and learn about their groundbreaking research in our Science@Work column here.

 

The Autism Speaks blog features opinions from people throughout the autism community. Each blog represents the point of view of the author and does not necessarily reflect Autism Speaks' beliefs or point of view.