Pharmacological Prospects For The Treatment of Autism

I reviewed with a mother of one of our consumers the status of her son’s care, health, and some alternative medication approaches. In brief, the consumer is part of the Residential/Day Programs and is developing challenging behaviors associated with compulsivity, irritability and mood dysregulation disorders. At Qsac we are not solely in favor of psychotropic medication as a treatment for autism or regard it with higher esteem than other alternative medication approaches because we know according to several randomized studies that no drugs are free of side effects, these drugs tend to ameliorate some symptoms within the scope of the core symptom domains in autism, but not cure them. However, some studies have shown that Selective Serotonin Reuptake Inhibitors (SSRI) such as Prozac and Lexapro and atypical antipsychotic drugs such as Risperdal, Seroquel, and Abilify have suggested improvement in some components of social and communication impairments and repetitive patterns of behaviors. For instance, according to a research Units network, Risperdal has been proven to have good results in individuals with autism and irritability, hyperactivity, and stereotypic behavior, but not in social and communication impairments, and appropriate speech (New England Journal of Medicine, 2002, 347:314–321).

Despite this study, we have different modalities of treatments for individuals with autism. Some medications lack comprehensive support with numerous large randomized studies to prove their efficacy. From the pharmacological point of view, in the last decades, we have observed a paradigm shift in the way we think about psychotropic medications and their effects on the brain. In today’s age, we are exploring the function of new neurotransmitters and expanding the use of drugs traditional targeted to other mental disorders, which might be helpful for autism.

For several decades, scientists had paid more attention to dopamine and serotonin neurotransmitters in designing treatment for mental disorders, but on October 2006, Dr. Schoepp and other scientists had focused their attention on the neurotransmitter, glutamate. Now we are fascinated with glutamate. Glutamate is an excitatory neurotransmitter in the brain, which is a critical link in circuits involved directly in cognitive functions such as memory, learning and perception. In addition, glutamate may play a role in brain maturation and alteration in autism. In studies postmortem, autistic brains have reduced glutamate levels affecting among many factors its conversion into another critical neurotransmitter, gamma amino-butyric acid (GABA). The brain depends on a balanced level of glutamate, such that too much glutamate leads to seizures and the neuronal cell death and too little glutamate can cause mental disorder and coma. According to Dr. John Krystal, a scientist at Yale, glutamate is the main pathway of communication in the brain (NY Times, Feb. 2008). In addition, researchers have implicated the gene Neurexin 1 on chromosome 2, and a sequence on chromosome 11 with glutamate synaptic function. Neurexin 1 is specifically believed to be involved in the functioning of presynaptic neurons and the section of chromosome 11 has been linked to proteins that ferry glutamate across synapses. A combination of mutations in any of these genes could contribute to the likelihood of being born with autism, although this is one of a myriad of plausible causes of autism. Individuals with autism may have specific abnormalities in the AMPA-type glutamate receptors and glutamate transporters in the cerebellum (Purcell, et. al. 2001; Jamain, et. al. 2002; Segurado, et. al. 2005; Shinohe, et. al., 2006).

At Rush-Presbyterian St. Luke’s Medical Center and University of California are conducting a trial to evaluate the use of drugs to enhance glutamate transmission. The study will evaluate Ampalex® and Ampakine® compound, and Dr, Schoepp and Lilly Research Laboratories are working to develop a new drug to enhance glutamate for schizophrenia, which may help for autism.

Memantine (Namandia), a drug approved by the FDA for dementia is a noncompetitive NMDA inhibitor that has shown improvement in individuals with autism in the areas of language, attention, motor planning and self-stimulation and relates symptoms such as compulsive and impulsive behaviors. Memantine has been evaluated at Mount Sinai School of Medicine, The Seaver and New York Autism Center of Excellence.

Oxytocin, a drug approved by the FDA for the initiation or improvement of uterine contractions, has showed promise for improved brain function and less repetitive behavior in a small pilot study of patients with autism spectrum disorder. "The animal studies, healthy-control studies, and preliminary data in autistic patients converge to suggest that this may be a very promising compound for the treatment of autism. However, we are still early on in this process. What our data suggest is that it is warranted to design larger studies." (Anagnostou, 6th International Meeting for Autism Research: May 3-5, 2007; Hollander & Anagnostou, 2007.)

Amantadine, normally used for influenza and Parkinson’s disease, has moderate effects on hyperactivity and irritability in a double-blind controlled trial study (King, et. al., 2001).

Dextrometorphan, an antitussive drug, which in a double-blind pilot study demonstrated improvement in attention-deficit hyperactivity disorder and challenging behaviors in individuals with autism (Woodard et. al., 2007).

Mecamylamine (Inversine) is a ganglionic blocker, secondary amine and an oral antihypertensive agent, which prevents stimulation of postsynaptic receptors by acetylcholine released from presynaptic nerve endings. It is a drug used in the 1950's indicated for the management of moderate to severe high blood pressure (hypertension). This agent works by relaxing and dilating blood vessels. Because Mecamylamine is a nicotine antagonist (that is, it blocks the effect of nicotine), it has been researched in smoking cessation. Mecamylamine may block the rewarding effect of nicotine and thus reduce the urge to smoke (Lancaster, 2007 on Cochrane Rev Abstract; Shytle, et. al., 2002; Webster, et. at. 1999). This drug was rarely used due to its side effects (e.g. constipation, drowsiness, and dry month). However, since Mecamylamine may have important therapeutic properties, it is important to fully explore and understand its pharmacology (Papke, et. al. 2001). Recently, Mecamylamine has been used as a treatment for symptoms associated with Tourette's syndrome and Attention Deficit Disorder. Now, it is about to be tested by a team at Ohio State University Medical Center as a treatment for autism symptoms.

Another promising drug is D-Cycloserine (DCS), a drug originally approved by the FDA for the treatment of tuberculosis. DCS has been tested as a treatment for neuro-cognitive deficits in schizophrenia and Alzheimer’s disease. D-Cycloserine in contrast to other drugs that target serotonin receptors, boosts a subtype of glutamate receptors called N-methyl-D-aspartic acid (NMDA) in the amygdala. Recently, it has been used to augment exposure-based behavior therapy for several anxiety disorders (e.g. phobias and Post-Traumatic Stress Disorder [PTSD]).

“Watching a video of what you fear while under the influence of DCS writes new, strong memories to the amygdala that aren’t associated with a traumatic event. Thus, when you see a mouse again, the amygdala doesn’t initiate a fear response.” (Behar, 2008 - on Dr. LeDoux’s research-NYU)

In a double-blind study, D-Cycloserine has improved obsessive-compulsive symptoms and related disorder and social and communication skills in individuals with autism (Posey, et. al., 2004; Wilhelm, et. al. 2008).

I would like to hypothesize that this drug with the aid of visual stimulation might help to form new memories that dissociate a stimulus from the conditioned maladaptive behavior that it evokes. The rational for this hypothesis is that the amygdala associates the image with the memory of the stimulus and signals the hypothalamus to prepare the body for action. For instance, this approach can be used to treat a consumer who engages in aggressive behavior toward others when triggered by staff demands. The consumer can watch a visual representation of staff demands and other neutral images, like swimming in the beach, under the influence of the drug and learn to form a new memory that associates staff demands with the other visual images and appropriate behavior.