Pharmacological Neuromodulation in Autism Spectrum Disorders

Drugs used in autism target neuromodulation at different neuronal sites. Those utilizing anticonvulsant, neurolepic, anti-depressant, stimulant, cholinesterase inhibitors, anxiolytics, mood stabilizers and other pharmacological interventions in autism do so for a variety of purposes. Each of these classes of drugs will be examined relative to their proposed neuromodulatory actions as they relate to the Autism Spectrum Disorder population.

Genetic-environment interactions in ASD that continue to be investigated include: parental age; maternal genotype; maternal-fetal immunoreactivity; in vitro fertilization; maternal ingestion of drugs; toxic chemicals in the environment during pregnancy; and maternal illnesses during pregnancy such as maternal diabetes or infections (Hallmayer J, 2011) . Recent studies are consistent with a fetal programming hypothesis of ASD that considers environmental risk factors that affect the fetal environment and interact with genetic variants (Szatmari 2011). The pathogenic potential of dysregulated states may further stress developmentally vulnerable neurodevelopment (Duke, B. , 2008).
As these genes and interacting effects become better characterized therapeutic strategies can be developed (Buxbaum 2009) (Levy et al, 2011) (Sanders et al, 2011) (Gilman et al, 2011). These genes include those involved in the patterning of the central nervous system; those that govern biochemical pathways; those responsible for the development of dendrites and synapses; and, genes associated with the immune system and autoimmune disorders (Ashwood et al, 2006 ) (Careaga M et al, 2010 ).
Neuroimaging studies further enlighten our theoretical models and techniques such as diffusion tensor imaging (DTI) have gained prominence as a means of assessing brain development (Isaacson & Provenzale, 2011). Studies of emotional perception demonstrated that while listening to either happy or sad music, individuals with ASD activated cortical and subcortical brain regions known to be involved in emotion processing and reward. The investigators, using functional magnetic resonance imaging compared ASD participants with neurotypical individuals and found ASD individuals had decreased brain activity in the premotor area and in the left anterior insula, especially in response to happy music excerpts. Their findings illuminate our understanding of the neurobiological correlates of preserved and altered emotional processing in ASD (Caria A, et al 2011).
Other imaging studies have found: diminished gray matter within the hypothalamus in autism disorder and suggest this is a potential link to hormonal effects (Kurth F, et al 2011); elevated repetitive and stereotyped behavior (RSB) associated with decreased volumes in www.intechopen.com Pharmacological Neuromodulation in Autism Spectrum Disorders 285 several brain regions: left thalamus, right globus pallidus, left and right putamen, right striatum and a trend for left globus pallidus and left striatum within the ASD group (Estes A, et al 2011 ); alterations in frontal lobe tracts and corpus callosum in young children with autism spectrum disorder (Kumar A, et al 2010); and, revealed pervasive microstructural abnormalities (Groen WB, et al 2011).
As our theoretical constructs are tested and enriched clinical scientists are poised to learn exponentially as treatment response databases and measurement methods and systems are further developed. We are ready to experience an evolution and fusion of medical arts strengthened by scientific methods and information technology.
Psychopharmacological treatment guidelines for very young children suggest that children with persistent moderate to severe symptoms and impairment, despite psychotherapeutic interventions, may be better served by carefully monitored medication trials than by continuing ineffective treatments (Gleason MM, et al 2007).
The treatment of children with ASD has challenges that are also present in the treatment of many mood disorders and in schizophrenia. In Stephen Stahl's text, Essential Psychopharmacology (Stahl 2010), he deconstructs the syndrome of schizophrenia into five symptom dimensions: Positive and Negative symptoms, aggression, affect and cognition. These symptom dimensions are also relevant to children with ASD and many children with mood disorders. Individual presentations and variability of treatment response can be managed by enlisting the parents to be observers utilizing defined measurements.
Multiple medications have utility in ASD treatment and are sometimes used in combination. Thoughtful utilization and management of medications can offer children with autism spectrum disorders significiant reductions of impairment. Each of the medications used, as true with any medication, has varying degrees and potential related to benefits, risk and limitations. Although the antipsychotic risperidone has been demonstrated as effective in reducing serious behavioral problems, it shares adverse neurological and metabolic risks with other typical and atypical antipsychotic agents. Nevertheless, risperidone has demonstrated efficacy at relatively low doses and treatment monitoring can assist in managing risks when substantial benefit is possible.
Antidepressants have been reported as helpful for some with ASD, particularly related to repetitive or obsessive compulsive behaviors, however, studies reviewing off-label uses of anti-depressants have also reported adverse effects of increased agitation, behavioral activation and sleep disturbance. If we consider these findings as evidence suggesting antidepressants, in some, perturb inhibitory-excitatory neuronal balance or, in a broad sense, contribute to central nervous system hyperarousal, it follows that such effects could contribute to pathogenesis rather than decrease the allostatic load. This does not suggest that antidepressant medications can't be helpful. It is recognized that in many cases antidepressants are helpful; however, vigilance for signs of disinhibition or other dysregulation is prudent.
Known stimulant benefits include increased ability to sustain attention, reduced motoric hyperactivity and reduced impulsivity. Adverse effects associated with stimulants include dysphoric responses, sleep disturbances and appetite supression.
Anticonvulsants have demonstrated their place in the treatment regimen of many children with ASD and approximately twenty percent of those with ASD are thought to have a www.intechopen.com Pharmacology 286 seizure disorder (Tuchman & Cuccaro, 2011). Benefits can include seizure control and mood stabilization while adverse effects can include cognitive dulling. When anticonvulsants are useful, cognitive dulling can often be managed by anticonvulsant selection and dosing.
Current pharmacological interventions in autism spectrum disorders are essentially directed at reducing cognitive and behavioral impairments. Treatment studies have demonstrated little observable benefit to core deficits of ASD, however, the argument is made that, in addition to the practical benefits of reducing behavioral and cognitive impairments, symptom reduction is a reflection of more efficient neural processing and development.
Effective impairment reduction often allows children to remain in a family home, function in a school setting, optimize reponsiveness to behavioral and educational methods and, generally, function more normally than would otherwise be possible. Those of us who treat children who will otherwise be excluded from normal environments appreciate the importance and complexity of these interventions. The greater promise of pharmacological interventions is their potential, through early intervention, to inhibit or reduce the development of pathological and pathogenic endophenotypes.

Conceptualization of clinical hypotheses, treatment strategies and measurement of treatment response
Physicians and clinician-scientists are humbled distinguishing among nosological categories in the context of the diverse and complex treatment circumstances presented by those significantly impaired within the spectrum of autism disorders.
Treatment decisions are based on symptom profiles, types and severity of impairment, riskbenefit calculations, potential treatments available and clinical hypotheses related to the nature of the disorder. Unlike elegantly designed experiments with exquisitely defined variables and thoughtful control of confounding variables, those suffering functional and qualitative impairment present with inherent experimental limitations. Despite these limitations, the application of scientific principles related to individual measurement and monitoring of treatment response provides a platform from which to assess treatment response and dynamically test clinical hypotheses.
The deconstruction of psychiatric syndromes into symptoms is described as a way to establish a diagnosis, deconstruct the condition into its symptoms, match the symptoms to a hypothetically malfunctioning circuit and consider the collection of neurotransmitters and neuromodulators known to regulate the circuit. "Next, one can match each symptom to a hypothetically malfunctioning circuit and -with knowledge of the neurotransmitters regulating that circuit and drugs acting on those neurotransmitters -choose a therapeutic agent to reduce that symptom. If such a strategy proves unsuccessful, it is possible that adding or switching to another agent acting on another neurotransmitter in that circuit can be effective. Repeating this strategy for each symptom can result in remission of all symptoms in many patients." (Stahl, 2010) Knowledge gained in the study of abnormal circuitry in mood disorders, schizophrenia and other neuropsychiatric and neurological conditions provide models by which treatment responses and clinical hypotheses can be tested. Whether the symptoms are hyperkinetic movement disorders or hyperactive mesolimbic systems, pharmacological strategies can inform and interact with the rapidly developing basic and translational sciences. Dysregulation of neuronal inhibition and excitability appears as a common theme among many disorders.
Consideration of the pathological developmental aspects of autism spectrum disorders provokes the possibility that altering disease progression may rescue or support improved functional neurodevelopmental outcomes. In a broad statement regarding psychiatric disorders that supports that potential, Stephen Stahl remarks, "It may also be possible to prevent disease recurrence and progression to treatment resistance by treating not only symptoms but also inefficient brain circuits that are asymptomatic. Failing to do so may allow 'diabolical learning' where circuits run amok, become more efficient in learning how to mediate symptoms, and are therefore more difficult to treat." (Stahl, 2010, p. 274) The lessons and theoretical models related to pharmacological interventions in other neurological and psychiatric syndromes can be applied to treatment conceptualizations with the autistic spectrum disordered as well. For example, constructs investigated with antiepileptic drugs (AED) can also be considered within the neural circuitry issues involved in Autism Spectrum Disorders.
"Several pathophysiological mechanisms inducing a neuronal excitability seems to be involved in an imbalance of both GABAergic and glutamatergic neurotransmissions and therefore could be similar in epilepsy and hyperkinetic movement disorders. The main targets for the action of the AEDs include enhancement of GABAergic inhibition, decreased glutamatergic excitation, modulation of voltage-gated sodium and calcium channels, and effects on intracellular signaling pathways. All of these mechanisms are of importance in controlling neuronal excitability in different ways." (Siniscalchi, Gallelli & De Sarro, 2010) When pharmacological interventions are applied, secondary to their clinical intent, they serve as probes of endophenotypic neural functioning and circuitry states revealing response to particular pharmacodynamic and pharmacokinetic profiles. The classes of antipsychotic drugs considered to be atypical are described by Schwartz with such considerations in mind.
"The second generation antipsychotics are clearly delineated in the treatment of psychosis and mania and share similar mechanisms of action to achieve these results: dopamine-2 receptor antagonism for efficacy and serotonin-2a receptor antagonism for EPS tolerability. From here, each agent has a unique pharmacodynamic and pharmacokinetic profile where some agents carry more, or less antidepressant, anxiolytic, or hypnotic profiles. Choosing an agent and dosing it in low, middle, or high ranges may result in differential effectiveness and tolerability" (Schwartz & Stahl, 2011 ).
We are further humbled by the incomplete pharmacodynamic and pharmacokinetic profiles of the drugs we employ. Many of the drugs and compounds used have poorly understood neuromodulary effects in addition to known receptor specific actions. Nevertheless, contributions to our knowledge continue to further characterize and define drugs as well as continue to discover relationships of enviromental effects and immunological response. Researchers, for example, have recently shown the inhibitory effects of some antidepressants as well as some typical/atypical antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, which the investigators state have been discovered to cause synaptic pathology, a decrease in neurogenesis, and white matter abnormalities found in the brains of patients with psychiatric disorders. (Monji A, 2011). We operate with limited visibility that is increased by clinical experience and science.
Despite the complexity and challenges of ASD, potential for early interventions are supported by animal research. An example is the recent demonstration that autism risk genes differentially impact cortical development (Eagleson K, et al 2011). The demonstrations of these risk genes and their interaction with various states, illustrate animal models that may further elucidate pathogenic developmental processes. The role of glutamate (Hamberger A, et al 1992 ), serotonin (Levitt P, 2011) and sigma 1 ligands (Yagasaki Y, et al 2006) have each demonstrated potential importance in modulating glutamatergic and other developmentally critical signaling processes.
In autism spectrum disorders as well as in other neurological and neurodegenerative disorders, discoveries in developmental neurobiology and genetics will continue to provide increasingly sophisticated models in which interventions of developmentally specific neuropathogenic processes can be assessed and clinical hypotheses considered and tested. Coinciding are increasingly sophisticated objective measures that will allow greater definition of treatment response characteristics and endophenotypic response profiles. Applications related to treatment response measurement and management utilizing on-line observational and other measurements related to eye, facial, voice, reaction time consistency, sleep and activity are currently being studied and developed at the Child Psychopharmacolgy Institute.

Registered clinical trials (NIH-USA) in autism spectrum disorders
We can learn a great deal from the current foci of pharmacological interventions in ASD by reviewing clinical trials that have been conducted and those that are current.  Table 3 displays a sampling of drugs in clinical trials and their generally proposed actions.

Antipsychotic Drugs
Risperidone is a selective blocker of dopamine d2 receptors and serotonin 5-ht2 receptors that acts as an atypical antipsychotic agent. Aripiprazole has both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity; use associated with hyperglycemia. It can also be described as a Dopamine Partial Agonist. Ziprasidone -antipsychotic-A benzisothiazoylpiperazine derivative; has combined dopamine and serotonin receptor antagonist activity; structurally related to tiospirone. Zyprexa (olanzapine) has combined dopamine and serotonin receptor antagonist activity. Antidepressant Drugs Fluoxetine: serotonin specific uptake inhibitor Citalopram serotonin specific uptake inhibitor. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia The SSRI fluvoxamine is not only an inhibitor of SERT, but also acts at sigma receptors, perhaps as a sigma-1 agonist, with some preclinical evidence that fluvoxamine can improve PCP-induced cognitive deficits Atomoxetine: norepinephrine selective reuptake inhibitor.

Anticonvulsant Drugs
Divalproex sodium: A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain. Riluzole: A glutamate antagonist (receptors, glutamate) used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. Lamotrigine,Sodium Valproate, or Carbamazepine: Anticonvulsants Stimulant Drugs Methylphenidate is a racemic mixture comprised of the d-and l-threo enantiomers. The dthreo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate HCl is a central nervous system (CNS) stimulant.
Methylphenidate transdermal system: Methylphenidate HCl is a central nervous system (CNS) stimulant. Choline and Cholinesterase Inhibitors Choline: Precursor to Acetylcholine Donepezil: Current theories on the pathogenesis attribute some symptoms to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its therapeutic effect by inhibiting AChe boosting the availability of ACh. Drugs with Glutaminergic Effects, AMPA Modulators and NMDA Antagonists Acamprosate is a derivative of the amino acid taurine and, like alcohol, reduces excitatory glutamate neurotransmission and enhances inhibitory GABA neurotransmission Memantine: a weak NMDA antagonist. Persistent activation of central nervous system Nmethyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Dextromethorphan and quinidine sulfate (Nuedexta): NMDA antagonist; Sigma 1 agonist; binds to SERT; proposed neuromodulator. Hormones Oxytocin: A nonapeptide hormone released from the neurohypophysis (pituitary gland, posterior). it differs from vasopressin by two amino acids at residues 3 and 8. Vasopressin Anti-infective-Anti-bacterial-Immunomodulators N Acetylcysteine N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen. Cycloserine Antibiotic substance produced by Streptomyces garyphalus. Sapropterin: reduces blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin-(BH4-) responsive Phenylketonuria (PKU). Proposed Neuroprotective and neurotransmitter effects. Mecobalamin: a study (PMID: 20406575 ) demonstrated a progressive decrease of sciatic nerve IGF-1 mRNA and peptide contents, and peripheral nerve dysfunction in the salinetreated diabetics over 12 weeks in contrast to the normal control non-diabetics. To comparZ-scores for height, age at current Tanner stage, and prolactin-related adverse events between patients exposed to risperidone and patients exposed to other atypical antipsychotic drugs.; Assess the prolactin value and risk of hyperprolactine

Pharmacological strategies in autism spectrum disorders
Treatment monitoring and treatment response measurement provide methods by which treatment strategies may be assessed, tested and dynamically applied to the treatment process. Two examples are presented. The first illustrates the longitudinal measurement of risperidone response and the second illustrates a treatment review and re-conceptualization of treatment strategy.
The first case is an actigraphic, psychometric and observational study of risperidone response in a six year old autism spectrum disordered child with Kabuki Syndrome. It provides an illustration of circadian and behavioral disturbances in a child, and the utility of single subject repeated actigraphic, psychometric and observational measurements of treatment response (Duke, 2010).
Actigraphic measurements, such as those used in the following case, are not necessary to obtain meaningful treatment response data, although additional measurements, such as actigraphic data, are helpful.
The non-invasive nature of watch-like actigraphy devices (Rispironics Actiwatch) is particularly attractive for use in pediatric populations. Meaningful treatment response measurements are obtained when actigraphic data is combined with psychometric and observational repeated measurements.
This case study includes baseline and repeated psychological, observational and actigraphic measurements that were initiated prior to treatment with risperidone and repeated throughout the treatment process.
Actigraphic measurements provide a basis by which to measure sleep and sleep onset latency as well as periods of mobility and immobility. In this case the actigraphic device was programmed to record activity every thirty seconds.
Actigraphic measurements were made utilizing a watch-like actigraphic device with an 11 day baseline actigraphic measurement period and continued measurements that included the initiation of a pharmacological intervention for 6 days, followed by a planned adjustment to b.i.d. dosing that was measured for an additional 4 days. This initial actigraphic study resulted in over 65,000 measurements of activity. Repeated observations continued throughout the treatment period and actigraphic studies were repeated after 23 months of risperidone treatment.
The measurement methods included the Personality Inventory for Children (PIC) an objective multidimensional measurement of affect, behavior, ability and family function.
The PIC was administered prior to treatment with risperidone and repeated after 23 months of treatment. The PIC serves as both an actuarial pre-treatment diagnostic tool as well as a post-treatment repeated measurement indicating treatment and developmentally associated change (Duke, B., 1991).
Observational methods were employed throughout the treatment process. A primary observer (The Child's Mother) was trained to report symptom percentages present since previous observations utilizing the operationally defined and observer defined items of the Systematic Observation Scale™ (Duke, B., 1990) throughout the treatment process. The Systematic Observation Scale™ utilizes single-subject repeated measurements. Symptoms and issues of interest are defined and a variety of frequency and sampling methods can be applied. The Systematic Observation Scale was designed so Primary Observers (parents, guardians, self observers or others) can make pre-treatment and subsequent observations to track, document and evaluate symptom variation over the course of an illness. The measurement utilized is the percentage of time the symptom is observed by the primary observer since the previous observation. Fig. 3. The child's parents kindly consented to the use of this photograph.
The actigraphic study was designed to select a child anticipating a psychopharmacological intervention.
The study was reviewed and approved by the Child Psychopharmacology Institute Institutional Review Board and was registered with the National Institutes of Health Protocol Registration System (NCT00723580) as a non-randomized, single subject, case study clinical trial. The child's impulsivity and inability to sleep represented a significant symptom and risk factors. She frequently moved about restlessly until 5:00 AM and would often sleep (or partially sleep) with her eyes open. She had frequent infections and had been previously stimulated by diphenylhydramine, over-sedated on clonidine and had mood destabilization when tried on mirtazapine. The child's diagnosis of Kabuki Syndrome had been previously established by a geneticist at the Mayo Clinic. The child presented with severe impulsivity, psychomotor acceleration, severe insomnia and obsessive compulsive behaviors that included touching objects to the whites of her eyes (these behaviors occurred multiple times an hour). An MLL2 mutation has been verified in this child. It has recently been reported that Kabuki Syndrome is caused by mutations in MLL2, a gene that encodes a Trithoraxgroup histone methyltransferase, a protein important in the epigenetic control of active chromatin states (Hannibal et, al, 2011).
Dr. Niikawa and Dr. Kuroki described Kabuki Syndrome in 1981. The term was used because of the affected children's facial resemblance to the famous Kabuki actors that perform in traditional Japanese theater.
Kabuki Syndrome is rare and diagnosis is complicated by the diverse spectrum of characteristics. Arched eyebrows, thick eyelashes, eversion of the lateral lower lid and long palpebral fissures contribute to the resemblance. Skeletal and dermatological abnormalities are common along with short stature, behavioral and pervasive developmental disorders and mild to moderate intellectual disability. Congenital heart defects and hearing impairment are often associated with the syndrome. The proportion of male to female occurrence is equal and no correlation with birth order has been found (Adam & Hudgins, 2005).
The assessment and treatment plan included a baseline biopsychosocial history, a baseline cognitive and personality assessment and the initiation of actigraphy measurements. The initial 21 day study of actigraphic measurements included an eleven day baseline prior to pharmacological interventions. The pharmacological Intervention following the medication free baseline utilized risperidone .25 mg q.h.s. initiated for seven days and then increased to twice daily dosing. Subsequent actigraphic measurements reflected the subsequent risperdal dose of .5 mg three times daily. Systematic observations continued throughout the treatment period and the personality assessment was repeated at the study end point. The established treatment goals were to: improve sleep; reduce general impairment; reduce hyperactivity; reduce impulsivity; reduce irritability and improve social functioning. H2: Sleep quality will be reflected by reduced standard deviations of activity during sleep periods.
H3: Positive treatment response as reflected by reduced percentages of primary symptoms will be associated with decreased activity during activity periods.
H4: Reduced impulsivity will be associated with reduced standard deviations of activity during activity periods.  Study conclusions: Sleep quantity was increased; Sleep quality was improved; Hyperactivity was reduced; Impulsivity was reduced; Significance between treatment conditions, activity and target symptoms was demonstrated.

Outcome
The second case is a ten year old male who had received numerous medications over the past several years. Despite these treatments, and optimal family environment and commitment, the primary symptoms of mood instability and cognitive impairment continued. The child was receiving aripiprazole 5 mg q.a.m. and Concerta 36 mg q.a.m. Prior to the treatment review, the child had become disinhibited and severely impulsive in response to treatment with an SSRI, which was discontinued. He had also demonstrated a dose related worsening when tried on quetiapine. The quetiapine was discontinued due to associated insomnia and worsened mood and behavioral states.
At the time of the review the child presented with neurological immaturity, delayed fine motor integration, jerky saccadic eye movements and possible symptoms of partial complex seizures. The child's episodic emotional dyscontrol, attention and cognitive functioning did not appear to be, pharmacologically, optimally addressed.

Pharmacological protection and prevention strategies on the horizon: Glutamatergic modulation and neuroprotection
Although pharmacological interventions utilized in Autistic Spectrum Disorders are generally associated with targeting behavioral or emotional impairments, little attention has been given to the important potential of glutamatergic regulation and neuroprotection in this vulnerable population.
While a single drug has not triumphed in the treatment of autism spectrum disorders, many drugs have proven helpful to varying degrees and for various purposes. The dearth of children's pharmacological studies stand in stark contrast to wide use of pharmacological interventions in ASD children.

Fig. 7. Symptom Percentage Observation Scale Averages
Alternative pathways of ASD pathology being explored include the study of tetrahydrobiopterin (BH 4 ) as a novel therapeutic intervention and point to ASD children as having low levels of BH 4 . Early studies suggest low BH 4 levels during development have devastating consequences on the central nervous system leading to or potentiating the neuropathology of ASD (Frye, et al, 2010). These studies are promising and may suggest a role for BH 4 treatment or treatment augmentation in the ASD population.
It is proposed that pharmacological approaches with neuroprotective characteristics have potential to reduce the dynamic pathogenic states that are likely occurring in highly symptomatic young children who are in developmentally critical stages of neural patterning and maturation. In a manner similar to the example provided regarding atypical antipsychotics, drugs will increasingly be chosen based on their particular characteristics or used together for separate or synergistic effects.
Arriving at a full understanding of these approaches will take further studies that consider the potential for unwanted effects. The Frye study, for example, noted that based on seven studies in which 451 patients with autism were treated with sapropterin (synthetic BH 4 ) that ninety-seven (21.5%) experienced adverse effects for which a causal relationship with the study drug could not be ruled out. The most frequently reported adverse effects were sleep disorders, excitement, hyperkinesia, enuresis and diarrhea. It will be important to learn if sapropterin's benefits are primarily from developmentally critical neuroprotective effects and/or effects on neurotransmitters. It will also be important to determine if indiscriminate neurotransmitter potentiation in dysregulated neurons and circuits are being reflected in the adverse effect profile that some demonstrate.
Synaptic molecules are important targets for protective treatments, to slow disease progression and preserve cognitive and functional abilities by preserving synaptic structure and function. Glutamate receptors and post synaptic density proteins play a central role in excitatory synaptic plasticity. Synaptic dysregulation may contribute to brain disorders present in those with Autism Spectrum Disorders by preventing appropriate synaptic signaling and plasticity.
The NMDA receptor is fundamental to excitatory synaptic plasticity and neurological diseases. Synaptic loss is a pathologic correlate of cognitive decline. Synaptic dysfunction is evident long before synapses and neurons are lost. The synapse constitutes an important target for treatments to slow progression and preserve cognitive and functional abilities in these diseases. (van Spronsen & Hoogenraad, 2010 )

Excitotoxity and glutamatergic activity
Current hypotheses propose excessive glutamate activity can lead to excitotoxicity interfering with normal neurodevelopment in schizophrenia. Similarly, these effects may be involved in the neurodevelopment in ASD. The excitotoxicity is hypothesized to continue and is linked to disease progression in schizophrenia ultimately resulting in pathologically functioning NMDA glutamate receptors. These hypotheses are consistent with those that identify the final common pathway of many neuropsychiatric diseases as synaptic pathology.
While the future promises biomarkers, RNAi strategies, stem cell transplantation and other genetic treatments, arresting and/or reducing developmental pathogenic potential by discovering and developing methods of effecting glutamatergic regulation by NMDA antagonism or other methods is a worthy, if not urgent, treatment goal for Autism Spectrum Disordered children. Blocking or moderating excessive glutamate neurotransmission with NMDA antagonists may prevent or mitigate damage, maladaptive neurodevelopment or neurodegenerative processes.
Some NMDA antagonists appear to be neuromodulators that reduce the excitotoxicity effects of dysregulated circuits and support dendritic health, long term potentiation and neural plasticity. Such treatments may one day provide preventative pharmacological interventions as well as those that can reduce impairment and improve functioning.
Two NMDA antagonists are particuilarly interesting candidates for therapeutic potential in the ASD population, memantine and dextromethorphan/quinidine (Duke & Kaye, 2010).
Memantine, as an augmenting agent, demonstrated significant improvements in open-label use for language function, social behavior, and self-stimulatory behaviors, although selfstimulatory behaviors comparatively improved to a lesser degree. Chronic use so far appears to have no serious side effects (Chez MG, et al 2007).
Dextromethorphan/quinidine (DM/Q) shares the attributes of being an uncompetitive NMDA antagonist with memantine, however, importantly; DM/Q is a sigma 1 agonist and binds to SERT. Binding data comparing memantine with DM/Q demonstrate the presence of Sigma 1 and SERT binding in DM/Q but not in memantine (Werling, et al 2007).
One of the characteristics that suggests DM/Q might have therapeutic potential in ASD is its efficacy in pseudobulbar affect (PBA). The efficacy and safety of dextromethorphan and quinidine was demonstrated in clinical trials of late stage neurological conditions (amyotrophic lateral Sclerosis and Multiple Sclerosis) demonstrating reductions of emotional lability and improvements in sleep. These findings suggest that the pharmacological characteristics of DM/Q may, at some level rescue synaptic signaling and may have the potential to affect neurodevelopmental trajectory in dysregulated developing nervous systems such as those with Autism Spectrum Disorders.
AVP-923 was approved by the FDA in 2010 as Nuedexta™ the first and only treatment for Pseudobulbar Affect (PBA). This is an important therapeutic for those suffering the debilitating effects of pseudobulbar affect. The efficacy in reducing dysregulated and involuntary congruent and incongruent emotional expressions is a significant achievement. Why is DM/Q (Nuedexta) effective in PBA? That, of course, is unknown, but PBA is often considered the result of connectivity and neural circuitry failures and ASD is known to have signaling and connectivity pathologies. Emotional lability is often associated with behavioral dyscontrol, irritibility, assaultive and raging behaviors that prompt pharmacological intervention in children with ASD.
NMDA antagonists may offer a therapeutic pathway through modulation or regulation of dysregulated glutamatergic processes. The potential of DM/Q (Nuedexta) in ASD, particularly in the early developmental stages of the illness, to rescue and support synaptic function is worthy of further study.
Although the mechanism of action of DM/Q is not fully characterized, its unique properties as an NMDA receptor antagonist and as a Sigma 1 receptor agonist appear to convey effects of both neuroprotection and neuromodulation. Future studies will help us determine if these unique characteristics will lead to improved outcomes for those with autism spectrum disorders.

Conclusion
The distress, irritability and emotional lability often seen in Autism Spectrum Disorders may be a reflection of pathological glutamatergic functioning or otherwise dysregulated circuits relative to inhibitory-excitatory balance. When sustained, these symptoms demonstrate potential for pathological development of abnormal neural circuits capable of dysregulation through neural synchronicity and state dependent effects on genetic expression. Within the framework of this hypothesis the neural plasticity and critical periods, present in developing brains, place them at particular risk.