**1. Introduction**

282 Pharmacology

Xiang, L. & He, G. (2011). Caloric restriction and antiaging effects. *Ann Nutr Metab* Vol.58,

Yakes, F.M. & Van, H.B. (1997). Mitochondrial DNA damage is more extensive and persists

Yamamoto, H., Schoonjans, K. & Auwerx, J. (2007). Sirtuin functions in health and disease.

Yamamoto, M., Clark, J.D., Pastor, J.V., Gurnani, P., Nandi, A., Kurosu, H., Miyoshi, M.,

Ylikomi, T., Laaksi, I., Lou, Y.R., Martikainen, P., Miettinen, S., Pennanen, P., Purmonen, S.,

Zittermann, A., Schleithoff, S. & Koerfer, R.(2005). Putting cardiovascular disease and

*Natl Acad Sci U S A* Vol.94, No.2, (January 1997), pp. 514-519

*Mol Endocrinol* Vol.21, No.8, (August 2007), pp. 1745-1755

longer than nuclear DNA damage in human cells following oxidative stress. *Proc* 

Ogawa, Y., Castrillon, D.H., Rosenblatt, K.P. & Kuro-o M (2005). Regulation of oxidative stress by the anti-aging hormone klotho. *J Biol Chem* Vol.280, No.45,

Syvala, H., Vienonen, A. & Tuohimaa, P. (2002). Antiproliferative action of vitamin

vitamin D insufficiency into perspective.*Br J Nutr* Vol.94,No.4,(Oct.2005), pp.483-

No.1, (2011), pp. 42-48

492

(November 2005), pp. 38029-38034

D. *Vitam Horm* Vol.64, (2002), pp. 357-406

This chapter will examine pharmacological approaches to neuromodulation in Autism Spectrum Disorders (ASD), pharmacological clinical trials and pharmacological strategies on the horizon.

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.

Children with ASD demonstrate deficits in 1) social interaction, 2) verbal and nonverbal communication, and 3) repetitive behaviors or interests. Many have unusual sensory responses. Symptoms range from mild to severe and present with individual uniqueness and complexity. Some aspects of learning may seem exceptional while others may lag. These children reflect a mix of communication, social, and behavioral patterns that are individual but fit into the overall diagnosis of ASD. Aggression, irritability and/or self-injury in children with autistic spectrum disorders often meet the threshold indicating pharmacological intervention.

Autism Spectrum Disorders have been shown to be related to complex combinations of environmental, neurological, immunological, and genetic factors. In addition to strong genetic links, environmental factors such as infection and drug exposure during pregnancy, perinatal hypoxia, postnatal infections and metabolic disorders have each been implicated in autistic populations. Summarizing an earlier Centers for Disease Control and Prevention Study (CDC) with subsequent major studies on autism prevalence, the CDC estimates 2-6 per 1,000 (from 1 in 500 to 1 in 150) children have an ASD. The risk is 3-4 times higher in males than females (Rice 2006)(CDC 2011).

The pathogenetic components and biological endophenotypes in autism spectrum disorders were described by Sacco and colleagues as: Circadian & Sensory Dysfunction; Immune Dysfunction; Neurodevelopmental Delay; and Stereotypic Behavior (Sacco R, et al 2010).

The heterogeneity of Autism Spectrum Disorders has resulted in many genes being studied that are thought to have an impact on the development of the pathological characteristics

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

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

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

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

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

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.

dysphoric responses, sleep disturbances and appetite supression.

Known stimulant benefits include increased ability to sustain attention, reduced motoric hyperactivity and reduced impulsivity. Adverse effects associated with stimulants include

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

managed by enlisting the parents to be observers utilizing defined measurements.

strengthened by scientific methods and information technology.

continuing ineffective treatments (Gleason MM, et al 2007).

managing risks when substantial benefit is possible.

abnormalities (Groen WB, et al 2011).

associated with Autism Spectrum Disorder (Greer PL, et al 2010). The developmental neurobiology of ASD is incrementally illuminated at the cutting edges of science. The permutations of mutations and epigenetic effects in ASD are both daunting yet increasingly identifiable targets for pharmacologic intervention. Clinical necessity and clincial trials drive discoveries for therapeutic interventions until stem cell or genetic solutions arrive.

Some states or effects seen in ASD may be responsive to developmental interventions while others may not. As we know, prompt thyroid replacement in a hypothyroid infant will generally allow normative intellectual development and prevent developmental disability. An example of variation of developmental impact is a mutation in MECP2, which encodes the epigenetic regulator methyl-CpG-binding protein 2 and is associated with Rett Syndrome. A recent study asked the question whether providing MeCP2 function exclusively during early post-natal life might prevent or mitigate disease in adult animals. Re-expression of MeCP2 in symptomatic mice rescued several features of the disease. The investigators argue "…the temporal association of disease with the postnatal period of development may be unrelated to any 'developmental' or stage restricted function of MeCP2, at least in mouse models." They concluded that "…therapies for RTT, like MeCP2 function must be continuously maintained" (McGraw, et al 2011).

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

associated with Autism Spectrum Disorder (Greer PL, et al 2010). The developmental neurobiology of ASD is incrementally illuminated at the cutting edges of science. The permutations of mutations and epigenetic effects in ASD are both daunting yet increasingly identifiable targets for pharmacologic intervention. Clinical necessity and clincial trials drive

Some states or effects seen in ASD may be responsive to developmental interventions while others may not. As we know, prompt thyroid replacement in a hypothyroid infant will generally allow normative intellectual development and prevent developmental disability. An example of variation of developmental impact is a mutation in MECP2, which encodes the epigenetic regulator methyl-CpG-binding protein 2 and is associated with Rett Syndrome. A recent study asked the question whether providing MeCP2 function exclusively during early post-natal life might prevent or mitigate disease in adult animals. Re-expression of MeCP2 in symptomatic mice rescued several features of the disease. The investigators argue "…the temporal association of disease with the postnatal period of development may be unrelated to any 'developmental' or stage restricted function of MeCP2, at least in mouse models." They concluded that "…therapies for RTT, like MeCP2

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

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

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

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

discoveries for therapeutic interventions until stem cell or genetic solutions arrive.

function must be continuously maintained" (McGraw, et al 2011).

developmentally vulnerable neurodevelopment (Duke, B. , 2008).

preserved and altered emotional processing in ASD (Caria A, et al 2011).

(Ashwood et al, 2006 ) (Careaga M et al, 2010 ).

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

Pharmacological Neuromodulation in Autism Spectrum Disorders 287

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

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

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

"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

"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

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

to mediate symptoms, and are therefore more difficult to treat." (Stahl, 2010, p. 274)

many disorders.

in Autism Spectrum Disorders.

considerations in mind.

and tolerability" (Schwartz & Stahl, 2011 ).

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.

#### **2. 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

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

Physicians and clinician- scientists are humbled distinguishing among nosological categories in the context of the diverse and complex treatment circumstances presented by

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

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

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

**2. Conceptualization of clinical hypotheses, treatment strategies and** 

development of pathological and pathogenic endophenotypes.

those significantly impaired within the spectrum of autism disorders.

**measurement of treatment response** 

response and dynamically test clinical hypotheses.

symptoms in many patients." (Stahl, 2010)

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

Pharmacological Neuromodulation in Autism Spectrum Disorders 289

Drug Classes Used In Autism Spectrum Disorder Clinical Trials

Antidepressant Stimulant Anticonvulsant Antipsychotic

NMDA Antagonists And Glutamatergic

Antibacterial Anti-Infective

Hormone Or Enzyme Factors

Immunomodulator Hyperbaric Oxygen

Anti-Hypertensive

Opioid Antagonist Anti-Oxidants

Trichuris Suis Ova Antidote Heavy Metal Ampa Receptor Modulator

Hypoglycemic Agents

GABA B Recepter Agonist

Table 2. Drug Classes Used in Autism Spectrum Disorder July 2011 NIH

Fig. 1. Spectrum of Drug Classes in Autism Spectrum Disorders

Adrenergic

Diruretic

Supplements

Anxioytic

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.
