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.

Autistic Anxiety: Hidden Triggers

A few days ago, I received a call from a parent of one consumer who lives in our residential program. She was concerned about the antecedent of her son’s last mild self-injurious behavior with anxiety-like symptoms. When our team reviewed the case, we did not find a clear and contingent antecedent of this challenging behavior.

In Dr. Kanner’s 1943 report on autism – one of the first ever studies to be published - he accentuated the role of anxiety in autistic children. I think that autistic anxiety should be understood as an emotional response evoked when an autistic individual perceives an external situation as threatening or fearful even in the presence or absence of the direct stressors. The autistic anxiety may be caused by a chronic or acute “fight or flight” response to feeling trapped by “exposure” to some aversive external stimuli or social situations. Possibly, this situation will result in involuntary avoidance, diversion, fear, depression, retaliation responses and defensive strategies which involve compulsive responses to the overt counter tactics of others and confusion that may result from being unable to "make sense" of the world in a routine way. Based on this definition of autistic anxiety, I have the hypothesis that autistic individuals occasionally respond to a variety of environmental stressors with prolonged latency than the normal population [hidden triggers]. In addition, autistic individuals show “a lack of fear in response to real dangers, and excessive fearfulness in response to harmless situations” (APA, 1994).

Several studies emphasize that common events (e.g. closeness of others, staffing change, over-prompting, special demands, etc) may become a stressor evoking fear or threatening events. Since the autistic individual wants to escape or avoid this situation and has not learned the adaptive coping mechanism to respond to this situation, he or she may behave in a maladaptive manner (e.g. self-injurious behaviors, destruction of property or aggression). In my experience, the identification of the external stimuli that trigger the maladaptive behavior has been very difficult for staff because occasionally the challenging behaviors are apparently dissociated from the original stimuli. However, the contingency relationship between the antecedent stimuli and behavioral response may still be associated.

Recent studies suggest that anxiety is a common feature in autism spectrum disorder (ASD). Morris et al. reviewed the comorbility of autism and anxiety symptoms and they found that 84.1% of the individuals studied met the criteria for anxiety disorder (Weisbrot et. al. 2005). Several studies have provided evidence from brain imaging (fMRI) that the hippocampus and the amygdala by be responsible for the emotional dysregulation in autistic individuals (Gray, & McNaughton, 1982, 2000; Davidson et. al. 1999; Kalin et. al. 2004.)

There are several multi-modal approaches to address the autistic anxiety such as medication, applied behavioral analysis, cognitive behavioral therapy, play therapy, self calming and relaxation techniques, counseling. However, the specific therapy approach depends on the particular case (Chalfant, et. al. 2006). Normally, we can combine medication with another alternative therapy approach (Miller, et. al. 1995). Learning what are the hidden triggers and stressors, and strategies to improve consumer attitudes and behaviors would help to reduce the incidence of anxiety symptoms that would result in maladaptive behaviors.

WORLD AUTISM DAY

Wednesday 2nd April has been designated World Autism Awareness Day by the United Nations General Assembly in New York. The April 2 events will take place on three continents and in venues ranging from the floor of the New York Stock Exchange to local bookstores and the worldwide web, and are expected to generate significant national and international media coverage.

World Autism Day hopes to break the “barrier of shame” of people suffering from autism and raise international awareness of the importance of early diagnosis and treatment of the brain disorder, which was estimated to affect 35 million people worldwide.

QSAC will be participating in A Day to Believe: Autism Awareness Day at Shea to also help raise awareness of autism.

Benefits of Physical Activity for Autistics: A Multi-Modal Approach to Manage Problem Behaviors

A few weeks ago we had the opportunity to observe the operations of the Princeton Child Developmental Institute (PCDI). It was in this institute that the communication system so-called “Teaching Conversation to Children with Autism” and the “Activity Schedules for Children with Autism” were developed. During the tour through the facility we were attentive to understand how they were addressing some challenging behaviors with the low functioning autistic individuals [e.g. physical aggression, property destruction and self-injurious behaviors]. We learned that they reduced these types of behaviors by combining the Applied Behavioral Analysis (ABA) and activity schedules with physical activities.

When I review the literature, I found an extensive and significant body of research documents about autism and physical activities. Physical activities in conjunction with Applied Behavioral Analysis or other modalities such as TEACCH plays an important role in the healthy lifestyle of autistic individuals as well as in developing communication abilities, social skills, and reducing maladaptive behaviors (Muller, et. al. 2008; Tood & Reid 2006; Schultheis, et. al. 2000).

According to the National Research Council (2001), motor functioning of individuals with autism spectrum disorder (ASD) has been a neglected area despite the fact that participation in physical activity has been shown to have multiple benefits, including reduction of stereotypic behavior (Todd and Reid, 2006).

Several studies have documented an association between clumsiness, gross and fine motor apraxia, with autism (Ghaziuddin 1998; Minshew & Golstein, 1997). In addition, a few studies reported abnormal postural balance in individuals with autism. Minshwe in 2004 found that autistic subjects had reduced postural stability. Data from several motor system studies suggests that more general involvement of neural circuitry beyond the neural systems for social behavior, communication, and reasoning, will promote better sensory integration. Increased physical activities may improve proprioception and maintain balance, posture, and the body's orientation in space controlled by the vestibular system. In addition, it may also reduce aggression, self-injurious behaviors and / or repetitive behaviors for some individuals with Autism Spectrum Disorder (Celiberti, et.al.1997; Rosenthal-Malek & Mitchell, 1997).

Tood & Reid 2006 demonstrated that an instructional strategy that included self-monitoring, verbal cuing and edible reinforcers was associated with increased sustained participation in a physical exercises program. In addition, by engaging individual with autism in physical activities we can improve their cardiovascular system. Cardiovascular exercises not only improve autistic’s heart, lungs, and circulatory system, but are likely to decrease inappropriate behaviors and promote appropriate behaviors (Watters & Watters, 1980; Kern, Koegel & Dunlap, 1984).

At Qsac Day Habilitation and Residential Programs we emphasize the important role of the motor system and physical activity in promoting a healthy lifestyle, contributing to improve abnormalities in neural connectivity [neuroplasticity] and reducing challenging behaviors in autistic individuals.

Comorbidity of Autism and Seizure Disorders

At a QSAC meeting, there arose the question of what could be the underlying causes or triggers of impulsive behaviors and cognitive impairment for individuals affected by autism and epilepsy. Is the seizure disorder worsening the autistic symptoms? How could we effectively treat the co-occurrence of these problems? These are interesting questions that I would like to invite those who read this Blog to think about.

Epilepsy is quite common in autism spectrum disorders, and it is increasingly recognized as an additional clinical problem. We evaluated the coexistence of autism and seizure disorder among the adult consumers at QSAC and found there to be a prevalence of about 30%, which correlates with studies that have reported a prevalence of 5% to 38.3% of comorbidity. These values are higher than in the normal population of children and adolescents (0.5%) (Tuchman & Rapin 2002; Clarke, et. al. 2005; Blumenfeld and Taylor, 2003).

The high prevalence of seizure disorders within autistic populations supports the notion that autism is a neurobiological disorder where the dysfunction of the nervous system is caused by genetic, metabolic, or other biological factors. Complex partial seizures and infantile spasms are probably the most common seizure types in autism and in some occasions, tuberous sclerosis. To return to the original questions, I believe that the seizure disorder is one of the risk factors that increase the cognitive impairment, adaptive and behavioral problems in individuals with autism. When autism is associated with chronic epilepsy or uncontrolled seizures this may lead to loss of neurons in the region of the hippocampus [e.g. hippocampal sclerosis]. The seizure disorder in individuals with autism may complicate the impaired cognition such as memory deficits, language impairment, visuospatial changes, decreased executive function, wandering, pacing, agitation, disruptive vocalizations, and exacerbation of repetitive behaviors. We would like to hypothesize that the comorbidity of autism and epileptic symptoms may lead to a deterioration and regression of the cognitive functions (Tharp, 2004).

Paradoxically, the impaired cognition of affected individuals could be secondary to adverse effects of antiepileptic drugs, to an underlying biological abnormality, or to the abnormal release of the cytokine protein by neurons in the hippocampus, cortex and amygdala [cytokine mediate and regulate immunity, inflammation, and hematopoiesis] (Lorenz, 2001, Jankowsky & Patterson, 1999).

This clinical treatment of affected individuals with autism and epilepsy is very complex because the efficacy of antiepileptic drugs and psychotropic medications is limited to the treatment of respectively the seizures or the specific problematic behaviors such as irritability, impulsivity, hyperactivity, repetitive behaviors, or aggression. Anticonvulsant medications could also potentially tamper with mood and behavioral disturbances frequently observed in Autism Spectrum Disorder (ASD).

The antiepileptic medications should always be adjusted against the frequency seizures episodes. Some studies argue that some individuals with autism and seizure episodes should not receive any anti-seizure medications. In some cases the management of seizure episodes has led to the minimizing of the core symptom domains of autism. In addition, some studies indicate that seizures may be part of the underlying pathophysiology of autism (Gillberg, 1991; Tuchman & Rapin 2002).

Therefore, the treatment of individuals with a comorbidity of epilepsy and autism is still obscure and clinicians should carefully evaluate the maladaptive behaviors, psychiatric symptoms, and seizure episodes, to determine the appropriate combination of medication and dosage for each affected individual (Gillberg, 1991; Tuchman, 2004; Hrdlicka, et. al., 2004).

For your viewing pleasure, I have attached below an interesting, yet - to warn you - quite long video lecture on the subject of “Seizures in children with Autism disorder” by Barry Tharp, M.D. as part of the M.I.N.D. Institute Lecture Series on Neurodevelopmental Disorders.

Accelerated Head Growth Can Help Predict Autism

Two new studies out of the University of Washington's Autism Center say accelerated head growth can help pediatricians predict autism before behavioral symptoms start. According to the research, children later diagnosed with autism have normal-size heads at birth, but show accelerated head growth between six and nine months of age. The center says that this period precedes the onset of many behaviors that enable physicians to diagnose the developmental disorder. The study also indicates that this aberrant growth is present in children who have the early onset form of autism as well as those later diagnosed with the regressive type of the disorder, suggesting that an atypical biological process was in place before the regression occurred.

It is important to keep in mind that accelerated head growth doesn't lead to a higher risk for autism. However, accelerated head growth in an infant sibling of a child with autism, who is at higher risk for the disorder, should be monitored closely.

NEURO-BEHAVIORAL MODEL: Autism, Brain Plasticity and Behavioral Reinforcement System

Autism is a neuro-biological developmental disorder that's associated with a range of developmental problems, mainly with social interaction impairment, speech and language deficits and restricted and repetitive pattern of behaviors. I have been intrigued by the miraculous, resilient capability of the brain to develop new connections and functions. We call this ability brain plasticity.

An increasing number of studies detail how the brain can reorganize its neural circuits to develop such activities as language, reading and social tasks. Several neuroscience studies are pointing out that social interaction impairment, one of the symptom domains in autism, may be a result of a dysfunctional frontostriatal limbic system. Frontostriatal circuits are neural pathways that connect frontal lobe regions with the basal ganglia that mediate motor, cognitive, behavioral and emotional processes within the brain (Alexander et al., 1986, 1990). Imaging studies sustain that the anatomy of the frontostriatal limbic system is abnormal in individuals with autism spectrum disorder (Courchesne and Pierce, 2005).

Findings using fMRI support the hypothesis that stimulation of the frontostriatal and frontolimbic reward system induced by behavioral reinforcement may make changes in cerebral function that lead to improvement in social interaction.

It would be interesting to further study the correlation of the behavioral reinforcement during cognitive tasks achievement and social interaction tasks and brain activation. One new experiment successfully shows how individuals with Asperger’s disorders can improve their social interaction behavior deficits by activation of areas in the brain responsible for attention and arousal by behavioral reinforcement (Schmitz, et. al., 2008).

Based on brain plasticity, there are emerging therapeutic options that integrate applied behavioral analysis and cerebral stimulation for the treatment of individuals with autism.For example, some studies have shown that behavioral intervention and neuro-stimulation (e.g. Neurofeedback, brain gym and auditory integration training) especially during the pre-school period could impact neural systems related to several symptom domains such as verbal behavior and hyperactivity ( Bock & Goode, 2003).

Below is an illustration of a case of brain plasticity.