**3. 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 1. ASD Study Types- NIH Registrations of Record July 2011

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

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

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

**3. Registered clinical trials (NIH- USA) in autism spectrum disorders** 

reviewing clinical trials that have been conducted and those that are current.

Table 1. ASD Study Types- NIH Registrations of Record July 2011

We can learn a great deal from the current foci of pharmacological interventions in ASD by

Drug Studies 151 53.5 Behavioral Studies 43 15.2 Dietary Studies 18 6.4 Device or Procedure Studies 5 1.8 Obervational and Other Studies 65 23.0 Total 282 100.0

Frequency Percent

glutamatergic and other developmentally critical signaling processes.

by clinical experience and science.

Psychopharmacolgy Institute.


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

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

Pharmacological Neuromodulation in Autism Spectrum Disorders 291

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

(anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis.

Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-

Methylphenidate transdermal system: Methylphenidate HCl is a central nervous system

Donepezil: Current theories on the pathogenesis attribute some symptoms to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its

Acamprosate is a derivative of the amino acid taurine and, like alcohol, reduces excitatory

Memantine: a weak NMDA antagonist. Persistent activation of central nervous system Nmethyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been

Dextromethorphan and quinidine sulfate (Nuedexta): NMDA antagonist; Sigma 1 agonist;

Oxytocin: A nonapeptide hormone released from the neurohypophysis (pituitary gland,

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

Mecobalamin: a study (PMID: 20406575 ) demonstrated a progressive decrease of sciatic nerve IGF-1 mRNA and peptide contents, and peripheral nerve dysfunction in the saline-

Table 3. Sampling of Drugs in ASD Clinical Trials and Their Generally Proposed Actions

treated diabetics over 12 weeks in contrast to the normal control non-diabetics.

Riluzole: A glutamate antagonist (receptors, glutamate) used as an anticonvulsant

threo enantiomer is more pharmacologically active than the l-threo enantiomer.

increasing gamma-aminobutyric acid levels in the brain.

Lamotrigine,Sodium Valproate, or Carbamazepine: Anticonvulsants

Methylphenidate HCl is a central nervous system (CNS) stimulant.

therapeutic effect by inhibiting AChe boosting the availability of ACh.

Drugs with Glutaminergic Effects, AMPA Modulators and NMDA Antagonists

glutamate neurotransmission and enhances inhibitory GABA neurotransmission

hypothesized to contribute to the symptomatology of Alzheimer's disease.

posterior). it differs from vasopressin by two amino acids at residues 3 and 8.

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.

Anticonvulsant Drugs

Stimulant Drugs

(CNS) stimulant.

Hormones

Vasopressin

Choline and Cholinesterase Inhibitors Choline: Precursor to Acetylcholine

binds to SERT; proposed neuromodulator.

Anti-infective-Anti-bacterial-Immunomodulators

Fig. 2. NLM Clinical Trial Reviews 2006 to 2011

Table 3 displays a sampling of drugs in clinical trials and their generally proposed actions.

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

290 Pharmacology

Table 3 displays a sampling of drugs in clinical trials and their generally proposed actions.

Risperidone is a selective blocker of dopamine d2 receptors and serotonin 5-ht2 receptors

postsynaptic D2 receptor antagonistic activity; use associated with hyperglycemia. It can

Aripiprazole has both presynaptic dopamine autoreceptor agonistic activity and

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.

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

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

Fig. 2. NLM Clinical Trial Reviews 2006 to 2011

that acts as an atypical antipsychotic agent.

also be described as a Dopamine Partial Agonist.

Fluoxetine: serotonin specific uptake inhibitor

Atomoxetine: norepinephrine selective reuptake inhibitor.

Antipsychotic Drugs

Antidepressant Drugs

PCP-induced cognitive deficits

dyskinesia

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.

Table 3. Sampling of Drugs in ASD Clinical Trials and Their Generally Proposed Actions

Pharmacological Neuromodulation in Autism Spectrum Disorders 293

Phase II Phase III

Table 4. Antipsychotic Clinical Trials, Trial Phase and Outcome Measures (Continued on

Phase III Aberrant Behavior Checklist (ABC) Irritability Subscale; Clinical Global Impression (CGI) Scale; ABC Subscales; Vineland Maladaptive Behavior Subscales; A modified version of the Compulsion Subscale of the Children's Yale-

Brown Obsessive Compulsive Scale.

Phase I Clinical Global Impression Improvement (CGI-

Involuntary Movement Scale (AIMS)

Behavior Checklist; Clinical Global

Phase II Children's Psychiatric Rating Scale; Clinical Global Impressions; Abberant Behavior Checklist; Treatment Emergent Symptoms Scale; Olanzapine Untoward Effects Checklist; Abnormal Involuntary Movement Scale;

Phase III The IrritabIrritibility subscale of the Aberrant

Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment;

Caregiver, Investigator); Primary Purpose:

Aberrant Behavior Checklist (ABC) and other ABC subscales at end of treatment compared with baseline; Change from baseline to end of treatment in Nisonger Child Behavior Rating Form (N-CBRF), Visual Analogue Scale

Masking: Double Blind (Subject,

Phase III Change in the Irritability Subscale of the

Behavior Checklist (ABC) will be used as the caregiver-rated primary outcome measure. The Clinical Global Impression- Improvement(CGI-I) will be included as a primary outcome

Neurological Rating Scale

Neurological Rating Scale

Phase IV Allocation: Randomized; Endpoint

measure

Treatment

AD); Aberrant Behavior Checklist; Abnormal

Children's Psychiatric Rating Scale; Aberrant

Impressions; Treatment Emergent Symptoms Scale; Olanzapine Untoward Effects Checklist; Abnormal Involuntary Movement Scale;

Evaluating the Effectiveness of Aripiprazole and D-Cycloserine to Treat Symptoms Associated

Efficacy of Aripiprazole Versus Placebo in the Reduction of Aggressive and Aberrant Behavior in Autistic Children

Long-Term Olanzapine Treatment in Children With

A Controlled Study of Olanzapine in Children With

Study of Paliperidone ER in Adolescents and Young Adults

A Study of the Effectiveness and

Risperidone in the Treatment of Children and Adolescents With

A Study of the Effectiveness and Safety of Risperidone Versus Placebo in the Treatment of Children With Autistic Disorder

Developmental Disorders (PDD)

Safety of Two Doses of

Autistic Disorder

and Other Pervasive

With Autism

Autism

table 5)

Autism

With Autism


Phase II The Clinical Global impression (CGI)

Phase II The Clinical Global impression(CGI)

Phase III Number of Participants With Serious Adverse

Phase II Clinical Global Impressions; Children's Psychiatric Rating Scale

Phase II Clinical Global Impressions-Improvement; Aberrant Behavior Checklist-Irritability

Phase IV RBS-R (Repetitive Behavior Scale - Revised);

Phase IV Time from randomization to relapse; Mean change from end of Phase 1 to Week 16 endpoint (LOCF) on the Aberrant Behavior Checklist - Irritability Subscale; Mean Clinical Global Impression - Improvement scale score

at Week 16 endpoint (LOCF)

Phase III Mean Change (Week 8 - Baseline) in the

Phase III Mean Change (Week 8 - Baseline) in the

CY-BOCS (Children's Yale-Brown Obsessive

Autistic Behavior Checklist (ABC) Irritability

Impressions Improvement Scale (CGI-I) Score; Number of Participants With Response at Week 8; Mean Change (Week 8 - Baseline)

Autistic Behavior Checklist (ABC) Irritability

Impressions Improvement Scale (CGI-I) Score; Number of Participants With Response at Week 8; Mean Change (Week 8 - Baseline)

Subscale Score; Mean Clinical Global

Subscale Score; Mean Clinical Global

Compulsive Scale)

subscale

Compulsive Scale)

Improvement Scale.; The Irritability subscale of the Aberrant Behavior Checklist (ABC); The Clinical Global Impression Severity Scale.

Improvement Scale.; The Irritability subscale of the Aberrant Behavior Checklist (ABC); The Clinical Global Impression Severity Scale.;CY-BOCS (Children's Yale-Brown Obsessive

Events (SAEs), Treatment-Emergent Adverse Events (AEs), Deaths, AEs Leading to Discontinuation, Extra Pyramidal Syndrome (EPS)-Related AEs; Mean Change From Baseline in Total Simpson-Angus Scale (SAS)

Study of Aripiprazole to Treat Children and Adolescents With

A Study of Aripiprazole in Children and Adolescents With Aspergers and Pervasive Developmental Disorder.

Study of Aripiprazole in the Treatment of Serious Behavioral Problems in Children and Adolescents With Autistic

Aripiprazole in Children With

Autism: A Pilot Study

An Open-Label Trial of Aripiprazole in Autism Spectrum Disorders

Pilot Study of the Effect of Aripiprazole Treatment in Autism Spectrum Disorders on Functional Magnetic Resonance Imaging (fMRI) Activation Patterns and Symptoms

OPT - Phase IV Long Term Maintenance Study of

Autistic Disorder

Disorder (AD)

Disorder (AD)

Aripiprazole for the Treatment of Irritability Associated With

Study of Aripiprazole in the Treatment of Children and Adolescents With Autistic

Study of Aripiprazole in the Treatment of Children and Adolescents With Autistic

Disorder (AD)

Autism


Table 4. Antipsychotic Clinical Trials, Trial Phase and Outcome Measures (Continued on table 5)


Pharmacological Neuromodulation in Autism Spectrum Disorders 295

Scale

Study of Fluoxetine in Autism Phase III The percentage change from baseline to the

Phase I

PhaseI

Phase II Clinical Global Improvement; Safety

Aberrant Behavior Checklist;

PhaseI Functional Magnetic Resonance Imaging; Clinicians Global Improvement Scale;

Phase III Safety Outcomes: Laboratory determinations,

Phase II Subscores of Autism Diagnostic Interview (ADI-R)at each visit of the protocol

Phase III Feasibility and safety of conducting placebo

Phase III The severity of the autistic child's behaviour or

Phase III Pediatric Anxiety Rating Scale (PARS); Clinical

Global Impressions (CGI)

Severity (CGI-S AD)

The indirect effect.

out evaluation

studies

Table 6. Antidepressant Clinical Trials, Trial Phase and Outcome Measures

Monitoring Uniform Research Form (SMURF); Children's Yale-Brown Obsessive-Compulsive Scale (CYBOCS); Repetitive Behavior Scale-Revised (RBS-R); Parent Chief Complaint;

Childrens Yale- Brown Obsessive Compulsive

Urine drugs of abuse tests,Vital Signs,Physical Examinations, Adverse Events/Serious Adverse Events, Clinical Global Impression of

(LECOUTER et RUTTER, 1989); Sides effect scale (FSEC); Aberrant Behavior Checklist (Aman et al., 1985); Clinical Global

Impressions (CGI) severity and improvement.

endpoint visit for the CYBOCS-PDD score; The time and dose related course of therapeutic effects; The inter-relationship between these effects in the context of global clinical changes;

control trial of fluoxetine; Side effect and drop

condition (assessed by parents); Weight and vital signs; Blood count and liver function

Citalopram for Children With Autism and Repetitive Behavior

Functional MRI Evaluation of the Effect of Citalopram in Autism Spectrum Disorders

Randomized Study of Fluoxetine in Children and Adolescents

Study of Fluoxetine in Adults With Autistic Disorder

Extended Management and Measurement of Autism

Fluoxetine Essay in Children

(STAART Study 1)

With Autism

With Autism

Effectiveness of Early

and/or Mood?

Intervention With Fluoxetine in Enhancing Developmental Processes in Children With Autism (STAART Study 2)

Fluvoxamine and Sertraline in Childhood Autism - Does SSRI Therapy Improve Behaviour

Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders


Table 5. Antipsychotic Clinical Trials, Trial Phase and Outcome Measures (Continued)

ABC and CGI; ABC

Phase I Quantify tVariability of clearance and volume

metabolite concentrations.

Home Situations Questionnaire; Vineland

Impressions-Improvement

Phase II Clinical Global Impressions; Children's Psychiatric Rating Scale

To comparZ-scores for height, age at current

events between patients exposed to risperidone and patients exposed to other atypical antipsychotic drugs.; Assess the prolactin value and risk of hyperprolactine

Tanner stage, and prolactin-related adverse

Phase II Aberrant Behavior Checklist

(CGI-I)

Table 5. Antipsychotic Clinical Trials, Trial Phase and Outcome Measures (Continued)

Daily Living Skills Scale; Irritability subscale-Aberrant Behavioral Checklist; Clinical Global

of distribution among AE rating, weight gain and ABC responder status; Exploratory analysis will be performed to examine the relationship of other factors to risperidone and

Phase II Phase III

Phase III

Phase I

Pharmacogenomics in Autism

Treatment of Autism in Children

Risperidone Pharmacokinetics in

Children With Pervasive Developmental Disorder (PDD)

Pharmacogenetics of

Comparison of Applied Behavioral Analysis (ABA) Versus ABA and Risperidone

RUPP PI PDD: Drug and

Risperidone Treatment In Children With Autism Spectrum Disorder And High Levels Of

Ziprasidone in Children With

Compared With Other Atypical Antipsychotic Drugs on the Growth and Sexual Maturation

An Observational Study to Evaluate the Safety and the Effects of Risperidone

Repetitive Behavior

Autism: A Pilot Study

in Children

Behavioral Therapy for Children With Pervasive Developmental

Disorder (PDD)

Disorders

Risperidone in Children With Pervasive Developmental

Treatment

and Adolescents


Table 6. Antidepressant Clinical Trials, Trial Phase and Outcome Measures

Pharmacological Neuromodulation in Autism Spectrum Disorders 297

questionnaire

Drug Treatment for Autism Phase II Cognitive Assessment

Table 9. AcetylCholine Esterase Inhibitors Clinical Trials, Trial Phase and Outcome

Checklist

Version

Table 10. Immunomodulator Clinical Trials, Trial Phase and Outcome Measures

Phase IV Core autistic symptoms (ATEC); Side effects

Phase II The primary outcome measure of this protocol

outcome, including cognitive.

Phase III Autism Diagnostic Observation Schedule-

(hyperactivity/irritability sections).

Phase II Irritability subscale of the Aberrant Behavior

Phase II Adverse events; Irritability Subscale of the

Aberrant Behavior Checklist, Community

Phase II Aberrant Behavior Checklist-Social Withdrawal Subscale

is to determine if donepezil can increase the percentage of time that subjects with autism spend in REM sleep.; A secondary aim of this protocol is to examine changes in functional

Generic (ADOS-G)- Change from Baseline to Final Visit; Clinical Global Impression

Improvement (CGI)- Change from Baseline to Final Visit; Aberrant Behavior Checklist (ABC)

and adverse events questionnaire; Linguistic performance (CELF-4); Adaptive functioning (Vineland-II); Co-morbid behaviors (CSI-4 questionnaire); Executive functions (BRIEF)

Treatment With Acetyl-Choline Esterase Inhibitors in Children

The Effect of Donepezil on REM Sleep in Children With Autism

Galantamine Versus Placebo in

An Open Label Extension Study of STX209 in Subjects With Autism Spectrum Disorders

Study of Arbaclofen for the Treatment of Social Withdrawal

Open-Label Study of the Safety and Tolerability of STX209 in Subjects With Autism Spectrum

in Subjects With Autism Spectrum Disorders

Childhood Autism

Measures

Disorders

With Autism Spectrum

Disorders


Table 7. Stimulant Clinical Trials, Trial Phase and Outcome Measures


Table 8. Anticonvulsant Clinical Trials, Trial Phase and Outcome Measures

Table 7. Stimulant Clinical Trials, Trial Phase and Outcome Measures

Phase IV

Phase III

Table 8. Anticonvulsant Clinical Trials, Trial Phase and Outcome Measures

behavior

Phase III Conners' Teacher Rating Scale-Revised (CTRS-R); Continuous Performance Test (CPT); Matching Familiar Figures Test (MFFT); Speeded Classification Task (SCT); Delay of Gratification Task (DOG); Conners' Parent

Rating Scale (CPRS)-Short Form;

tolerated by children with Autism co-morbid for ADHD; Determine if Daytrana is effective

Phase III Determine if Daytrana is safe and well-

in both school and home

Phase II Clinical Global Impression-Improvement;

Aberrant Behavior Checklist Clinical Global Impression-Improvement; Aberrant Behavior

Checklist; Clinical Global Impression-Improvement; Aberrant Behavior Checklist

Phase II epileptiform EEG discharges; Improvement in

1 Vineland Adaptive Behavior Scales; Aberrant Behavior Checklist; Clinical Global Impression Improvement Scale; Autism

Diagnostic Observation Schedule

Phase II Reduction of 30% or more in Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and Repetitive Behavior Scale;

> Much/Very much improved on Clinical Global Impressions - Improvement score (CGI-I)

Methylphenidate for Attention Deficit Hyperactivity Disorder and Autism in Children

A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD)

Divalproex Sodium ER vs

Childhood/Adolescent Autism valproex Sodium vs. Placebo in Childhood/Adolescent Autism

Divalproex Sodium ER in Adult

A Study of Divalproex Sodium in Children With ASD and

Oxcarbazepine Versus Placebo

Riluzole to Treat Child and Adolescent Obsessive-

Valproate Response in

Compulsive Disorder With or Without Autism Spectrum

Aggressive Autistic Adolescents

Symptoms

Placebo in

Autism

Disorders

Epileptiform EEG

in Childhood Autism


Table 9. AcetylCholine Esterase Inhibitors Clinical Trials, Trial Phase and Outcome Measures


Table 10. Immunomodulator Clinical Trials, Trial Phase and Outcome Measures

Pharmacological Neuromodulation in Autism Spectrum Disorders 299

Phase III

Phase I Phase II

Symptoms of Attention Deficit Disorder With Hyperactivity

Efficiency of Bumetanide in Autistic Children

A Trial of CM-AT in Children With Autism

Mercury Chelation to Treat Autism

(ADHD) in Children and Adolescents With Autism Spectrum Disorder Atomoxetine, Placebo and Parent Management Training in Autism

Table 11. Hormone or Related Clinical Trials, Trial Phase and Outcome Measures

A Study of Atomoxetine for Attention Deficit and Hyperactive/Impulsive Behaviour

Atomoxetine and Parent Management Training in Treating Children With Autism and

Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents

Atomoxetine Versus Placebo for Symptoms of Attention-Deficit/Hyperactivity Disorder

Dimercaptosuccinic Acid (DMSA) Treatment of Children With Autism and Heavy Metal

Trial of Low-Dose Naltrexone for Children With Pervasive Developmental Disorder (PDD)

Treatment of Sleep Problems in Children With Autism Spectrum Disorder With Melatonin

Early Pharmacotherapy Aimed at Neuroplasticity in Autism : Safety and Efficacy

Buspirone in the Treatment of 2-6 Year Old Children With Autistic Disorder A Trial of CM-AT in Children With Autism- Open Label Extension Study

Effects of CX516 on Functioning in Fragile X Syndrome and Autism

A Pilot Trial of Mecamylamine for the Treatment of Autism

Phase II Clinical Global Impression -- Improvement

(CGI-I) Scale; Preschool Language Scale (PLS); Vineland Adaptive Behavior Scale-II; Children's Yale Brown Obsessive Compulsive Scale (C-YBOCS); Connor's Preschool ADHD

questionnaire; Adverse Events Scale

Phase I Empathic accuracy performance; fmri BOLD response during empathic accuracy task

Behavioral Changes

Sapropterin as a Treatment for

Secretin for the Treatment of

The Effects of Oxytocin on Complex Social Cognition in Autism Spectrum Disorders

Characterization and Treatment

Problems in Children With ASD

Cholesterol in ASD:

With Autism

Toxicity

Autistic Disorder

Autism


Clinical Global Impressions Scale; Vineland Adaptive Behavior Scale; Clinical Global Impression: Severity; Children's Yale Brown Obsessive Compulsive Scale; Parental Global Assessment; Preschool Language Scale; Connor's Preschool ADHD question

Diagnostic Analysis of Nonverbal Accuracy (DANVA2); Change from Baseline to week 12

Diagnostic Analysis of Nonverbal Accuracy, Adult Paralanguage Test (DANVA2-AP); Repetitive Behavior Scale (RBS); Event Contingent Reporting; Yale-Brown Obsessive-

on the Social Responsivity Scale (SRS); Change from Baseline to week 12 on the Clinical Global Impressions Scale -

Phase II Change from Baseline to week 12 on the

Phase II Clinical Global Impressions Scale (CGI);

Phase II Tolerability of Oxytocin Nasal Spray;

Phase I Changes in brain activations; Performance

Phase I Improvement in both developmental skills and behavior with either glutathione or

and laboratory safety parameters.

Oxytocin Nasal Spray

Compulsive Scale (YBOCS); Social

Biomarkers; Feasibility; Acceptability of

scores and reaction time on behavioral tasks.

glutathione, Vitamin C and N-acetylcysteine therapy as compared to placebo therapy. Subjects will also be monitored using clinical

Improvement

Responsiveness.

Phase II Phase III

Phase I

Phase III

Phase III

Open-Label Extension Study of

Intranasal Oxytocin for the Treatment of Autism Spectrum

Intranasal Oxytocin in the Treatment of Autism

An fMRI Study of the Effect of Intravenous Oxytocin vs. Placebo on Response Inhibition and Face Processing in Autism

A Study of Oxytocin in Children and Adolescents With Autistic

Brain Imaging Study of Adults

Study of Glutathione, Vitamin C and Cysteine in Children With Autism and Severe Behavior

Synthetic Human Secretin in Children With Autism

Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction

With Autism Spectrum

Kuvan for Autism

Disorders

Disorder

Disorders

Problems


Table 11. Hormone or Related Clinical Trials, Trial Phase and Outcome Measures

A Study of Atomoxetine for Attention Deficit and Hyperactive/Impulsive Behaviour Problems in Children With ASD

Atomoxetine and Parent Management Training in Treating Children With Autism and Symptoms of Attention Deficit Disorder With Hyperactivity

Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism

Atomoxetine Versus Placebo for Symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) in Children and Adolescents With Autism Spectrum Disorder

Atomoxetine, Placebo and Parent Management Training in Autism

Efficiency of Bumetanide in Autistic Children

Early Pharmacotherapy Aimed at Neuroplasticity in Autism : Safety and Efficacy

Buspirone in the Treatment of 2-6 Year Old Children With Autistic Disorder

A Trial of CM-AT in Children With Autism- Open Label Extension Study

A Trial of CM-AT in Children With Autism

Effects of CX516 on Functioning in Fragile X Syndrome and Autism

Mercury Chelation to Treat Autism

Dimercaptosuccinic Acid (DMSA) Treatment of Children With Autism and Heavy Metal Toxicity

Trial of Low-Dose Naltrexone for Children With Pervasive Developmental Disorder (PDD)

A Pilot Trial of Mecamylamine for the Treatment of Autism

Treatment of Sleep Problems in Children With Autism Spectrum Disorder With Melatonin

Pharmacological Neuromodulation in Autism Spectrum Disorders 301

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

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

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

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

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

months of risperidone treatment.

observer since the previous observation.

change (Duke, B., 1991).

intervention.

study clinical trial.

An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.

Efficacy Study of Subcutaneous Methyl-B12 in Children With Autism

Methylphenidate in Children and Adolescents With Pervasive Developmental Disorders

Omega-3 Fatty Acids Monotherapy in Children and Adolescents With Autism Spectrum Disorders

Evaluation and Treatment of Copper/Zinc Imbalance in Children With Autism

Dose Finding Study of Pioglitazone in Children With Autism Spectrum Disorders (ASD)

Transcranial Magnetic Stimulation (TMS) Measures of Plasticity and Excitatory/Inhibitory Ratio as Biomarkers: R-baclofen Effects in Normal Volunteers

Melatonin for Sleep in Children With Autism

Trichuris Suis Ova Adult Autism Symptom Domains

Multidimensional Measurement of Psychopharmacological Treatment Response \* CPI

Table 12. Other Clinical Trials

#### **4. 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.

An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic

Methylphenidate in Children and Adolescents With Pervasive Developmental Disorders Omega-3 Fatty Acids Monotherapy in Children and Adolescents With Autism Spectrum

Dose Finding Study of Pioglitazone in Children With Autism Spectrum Disorders (ASD) Transcranial Magnetic Stimulation (TMS) Measures of Plasticity and Excitatory/Inhibitory

Multidimensional Measurement of Psychopharmacological Treatment Response \* CPI

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

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

Actigraphic measurements, such as those used in the following case, are not necessary to obtain meaningful treatment response data, although additional measurements, such as

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

This case study includes baseline and repeated psychological, observational and actigraphic measurements that were initiated prior to treatment with risperidone and repeated

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

Evaluation and Treatment of Copper/Zinc Imbalance in Children With Autism

Efficacy Study of Subcutaneous Methyl-B12 in Children With Autism

Ratio as Biomarkers: R-baclofen Effects in Normal Volunteers

**4. Pharmacological strategies in autism spectrum disorders** 

Melatonin for Sleep in Children With Autism

Table 12. Other Clinical Trials

of treatment strategy.

treatment response (Duke, 2010).

observational repeated measurements.

programmed to record activity every thirty seconds.

throughout the treatment process.

actigraphic data, are helpful.

Trichuris Suis Ova Adult Autism Symptom Domains

Medications.

Disorders

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.

Pharmacological Neuromodulation in Autism Spectrum Disorders 303

H1: Reduced percentages of primary symptoms will be associated with increased sleep during sleep periods (activity and sleep measurements). Actiwatch Communication and

H2: Sleep quality will be reflected by reduced standard deviations of activity during sleep

H3: Positive treatment response as reflected by reduced percentages of primary symptoms

H4: Reduced impulsivity will be associated with reduced standard deviations of activity

b. Baseline May 12, 2008 and two additional 21 day periods between May 12, 2008 to July

d. Personality Inventory for Children-Revised: pre-test May 2008 and post-test April 2010

c. Systematic Observation ScaleTM Measurements: May 7, 2008 to July 14th, 2010

Fig. 4. Target Symptoms by Treatment Condition (BL- .25 mg - .5 mg t.i.d)

**Hypotheses and Outcome Measures:** 

periods.

during activity periods.

**Outcome Measures** 

14, 2010

Sleep Analysis Instruction Manual (Respironics).

will be associated with decreased activity during activity periods.

a. Actigraphic Measurement of Treatment Conditions:

The Study Investigator's DSM-IV diagnoses were:


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.

## **Hypotheses and Outcome Measures:**

H1: Reduced percentages of primary symptoms will be associated with increased sleep during sleep periods (activity and sleep measurements). Actiwatch Communication and Sleep Analysis Instruction Manual (Respironics).

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.

#### **Outcome Measures**

302 Pharmacology

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

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

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

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.

The Study Investigator's DSM-IV diagnoses were:



chromatin states (Hannibal et, al, 2011).

perform in traditional Japanese theater.

(Adam & Hudgins, 2005).








Fig. 4. Target Symptoms by Treatment Condition (BL- .25 mg - .5 mg t.i.d)

Pharmacological Neuromodulation in Autism Spectrum Disorders 305

Activity Between Groups 4.476E8 3 1.492E8 1057.569 .000

Poor Sleep Between Groups 16583.631 4 4145.908 10.542 .002

Impulsive Between Groups 13278.274 4 3319.568 15.707 .000

Within Groups 2.698E10 191235 141065.613

Within Groups 3539.583 9 393.287

Within Groups 1902.083 9 211.343

Within Groups 2258.333 9 250.926

Within Groups 420.833 9 46.759

Within Groups 7564.583 9 840.509

Following the treatment review the initial strategy was to add carbamazepine 200 mg ER q.p.m. x 7 days then b.i.d. Subsequent to improved emotional stability and broadly reduced symptoms the contribution of aripiprazole was assessed by a dose reduction to 2.5 mg q.a.m. for four days and subsequently replaced with risperidone .5 mg b.i.d. Plans were made to subsequently assess his stimulant treatment response as the monitoring continued. Figure 7 displays symptom percentage averages over the treatment

Printable observation forms and item defintions are available and free for non-commercial use on the Child Psychopharmacology Institute website (www.

Irritable Between Groups 838.095 4 209.524 4.481 .029

**Squares df Mean** 

Between Groups 11034.524 4 2758.631 10.994 .002

Between Groups 14721.131 4 3680.283 4.379 .031

**Square F Sig.** 

**Sum of**

Total 2.742E10 191238

Total 20123.214 13

Total 15180.357 13

Total 13292.857 13

Total 1258.929 13

Total 22285.714 13

Fig. 6. Treatment Response: Analysis of Variance

ChildPsychopharmacologyInstitute.org).

Hyperactivit

y

Easily Distracted

transition.

Fig. 5. Personality Inventory Pre-Test and Post-Test

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.

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.

DSM IV Diagnoses: Axis I:

299.80 Pervasive Developmental Disorder NOS

296.90 Mood Disorder NOS

314.01 Attention Deficit/Hyperactivity Disorder, Combined Type

307.7 Encopresis

Study conclusions: Sleep quantity was increased; Sleep quality was improved; Hyperactivity was reduced; Impulsivity was reduced; Significance between treatment conditions, activity

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

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

Fig. 5. Personality Inventory Pre-Test and Post-Test

associated insomnia and worsened mood and behavioral states.

314.01 Attention Deficit/Hyperactivity Disorder, Combined Type

not appear to be, pharmacologically, optimally addressed.

299.80 Pervasive Developmental Disorder NOS

and target symptoms was demonstrated.

DSM IV Diagnoses: Axis I:

296.90 Mood Disorder NOS

307.7 Encopresis


Fig. 6. Treatment Response: Analysis of Variance

Following the treatment review the initial strategy was to add carbamazepine 200 mg ER q.p.m. x 7 days then b.i.d. Subsequent to improved emotional stability and broadly reduced symptoms the contribution of aripiprazole was assessed by a dose reduction to 2.5 mg q.a.m. for four days and subsequently replaced with risperidone .5 mg b.i.d. Plans were made to subsequently assess his stimulant treatment response as the monitoring continued. Figure 7 displays symptom percentage averages over the treatment transition.

Printable observation forms and item defintions are available and free for non-commercial use on the Child Psychopharmacology Institute website (www. ChildPsychopharmacologyInstitute.org).

Pharmacological Neuromodulation in Autism Spectrum Disorders 307

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

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 BH4) 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

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

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

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

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

used together for separate or synergistic effects.

adverse effect profile that some demonstrate.

these diseases. (van Spronsen & Hoogenraad, 2010 )

**5.1 Excitotoxity and glutamatergic activity** 

signaling and plasticity.

pathology.

neurodegenerative processes.

## **5. 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 (BH4) as a novel therapeutic intervention and point to ASD children as having low levels of BH4. Early studies suggest low BH4 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 BH4 treatment or treatment augmentation in the ASD population.

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

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

Alternative pathways of ASD pathology being explored include the study of tetrahydrobiopterin (BH4) as a novel therapeutic intervention and point to ASD children as having low levels of BH4. Early studies suggest low BH4 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

**5. Pharmacological protection and prevention strategies on the horizon:** 

**Glutamatergic modulation and neuroprotection** 

Fig. 7. Symptom Percentage Observation Scale Averages

role for BH4 treatment or treatment augmentation in the ASD population.

this vulnerable population.

interventions in ASD children.

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 BH4) 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 )

#### **5.1 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.

Pharmacological Neuromodulation in Autism Spectrum Disorders 309

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

We currently have drugs and compounds that have the ability to reduce impairment and improve functioning in many with ASD when used, monitored and managed thoughtfully. Early pharmacological intervention related to severe emotional lability, irritability and dysregulated circuits may also reduce the pathogenic potential and reduce or prevent the

As a faculty member of the Child Psychopharmacology Institute and as a consultant for Avanir Pharmaceuticals I wish to express my gratitude to my colleagues Randall Kaye, M.D., MPH, R. Dennis Staton, Ph.D., M.D. and Scott Siegert, Pharm.D. for their collegial

Adam, MP & Hudgins, L. "Kabuki Syndrome: A Review." Clin Genet, 2005: Mar;67(3):209-

Ashwood, P., Wills S., and Van de Water, J. "The immune response in autism: a new frontier for autism research." *Journal of Leukocyte Biology*, 2006 : Volume 80, July. Buxbaum, JD. "Multiple rare variants in the etiology of autism spectrum disorders."

Careaga M, Van de Water J, Ashwood P. "Immune dysfunction in autism: a pathway to

Caria A, Venuti P, & de Falco S. "Functional and Dysfunctional Brain Circuits

Chez MG, Burton Q, Dowling T, Chang M, Khanna P, Kramer C. "Memantine as adjunctive

Duke, B. & Kaye, R. "Breaking Pharmacological Barriers to Innovation: The Case for

Underlying Emotional Processing of Music in Autism Spectrum Disorders." *Cereb Cortex*, 2011: May 6. CDC. *Autism Spectrum Disorders.* August 1, 2011. http://www.cdc.gov/ncbddd/autism/research.html (accessed August 1,

therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability." *J Child Neurol.* , 2007:

Assessing Dextromethorphan/Quinidine in Autistic Spectrum Disorders." *Journal* 

periods, present in developing brains, place them at particular risk.

development or maintenance of pathological processes.

*Dialogues Clin Neurosci.*, 2009: 11(1)35-43.

treatment." *Neurotherapeutics*, 2010 : Jul;7(3) 283-92.

**6. Conclusion** 

**7. Acknowledgement** 

support and expertise.

**8. References** 

19.

2011).

May;22(5):574-9.

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.
