Developing Treatment, Treatment Validation and Treatment Scope in the Setting of an Autism Clinical Trial

Growing evidence supports oxidative stress may contribute to autism. Docosa Hexanoic
Acid(DHA)is a normal substance that is present in large amounts in the brain and can be used
by the body to produce natural antioxidants. Our hope is that supplementing DHA in
individuals with autism may improve some aspects of their functioning. Specifically our aims
are:

Aim 1. To assess the effect of DHA vs. placebo treatment on the global severity of child and
adolescent autistic disorder, via a 12-week double blind placebo-controlled parallel study.
Global severity will be assessed by the Autism Diagnostic Observation Schedule-Generic
(ADOS-G) and additionally in younger children by the Vineland Adaptive Behavior Scale.

Aim 2. To assess the effect of DHA vs. placebo treatment on behavioral symptoms and
functional ability in children with autism. Assessment will be by the Aberrant Behavior
Checklist (ABC)-Community Version11.

Aim 3. To develop an improved protocol and study design based upon these studies for future
large scale studies of DHA in the autistic population.

Aim 4. Monitor the effects of therapy on the isoprostane biomarker. Aim 5: Develop additional
biomarkers that correlate with autism and with therapy. We will extend the analyses to
neuroprostanes and resolvins. We will measure: (i) Urinary excretion of the isoprostane
metabolites, 2,3 Dinor-5,6 dihydro-PGF2t and iPF4α-VI. (ii) DHA derived resolvins D2, D4, D5
and D6 and neuroprotectin.

Aim 6: Confirm our preliminary results by correlating increased isoprostane excretion with
GSTM1*0 copy number in individuals with autism.

Aim 7: In the same way, correlate GSTM1*0 copy number with response to therapy assessed by
diminution of isoprostane excretion during therapy.

Aim 8: Study additional biomarkers developed through Hypothesis #2 for correlation with
GSTM1*0 copy number and response to therapy to identify additional gene-biomarker
correlations.

Aim 9: Study additional polymorphisms of genes related to DHA metabolism, for association
with autism, gene-biomarker correlations, and correlation with response to therapy.

Inclusion Criteria:

- Meets DSM-IV, ADI, and ADOS criteria for autistic disorder

- Age 5-17.

- Outpatients

- Parent or legal guardian signing informed consent, and assent documented for patient
with demonstrated capacity to provide it.

- Sexually active females of childbearing potential must use an acceptable method of
birth control (oral contraceptive medications [the administration of which must be
supervised by a parent or guardian], IUD, depot medication, double barrier or tubal
ligation) and have a negative serum pregnancy test prior to entry into the study.

- Subjects with history of seizures, who have been seizure-free for more than or equal
to 6 months on a stable dose of anticonvulsant medication.Non-medicated subjects with
a history of seizures who have been seizure-free for more than or equal to 6
months.Subjects with abnormal EEG but no clinical seizures.

Exclusion Criteria:

- Subjects who are pregnant or nursing mothers.

- Sexually active females of childbearing potential who are not using adequate birth
control measures (detailed above in inclusion criteria).

- Subjects with overall adaptive behavior scores below the age of two years on the
Vineland Adaptive Behavior Rating Scale.

- Subjects with active or unstable epilepsy.

- Subjects with any of the following past or present mental disorders: schizophrenia,
schizoaffective disorder, major depressive disorder, bipolar I or II disorders or
substance abuse disorders.

- Subjects who are a serious suicidal risk.

- Subjects with clinically significant or unstable medical illness that would
contraindicate participation in the study, including hematopoietic or cardiovascular
disease, pancreatitis, liver toxicity, and polycystic ovary syndrome

- Subjects reporting history of encephalitis, phenylketonuria, tuberous sclerosis,
fragile X syndrome, anoxia during birth, pica, neurofibromatosis, hypomelanosis of
Ito, hypothyroidism, Duchenne muscular dystrophy, and maternal rubella.

- Patients with history of the following:gastrointestinal, liver, or kidney, or other
known conditions which will presently interfere presently with the absorption,
distribution, metabolism, or excretion of drugs, cerebrovascular disease or brain
trauma, clinically significant unstable endocrine disorder, such as hypo- or
hyperthyroidism, recent history or presence of any form of malignancy

- Treatment within the previous 30 days with any drug known to a well-defined potential
for toxicity to a major organ

- Subjects with clinically significant abnormalities in laboratory tests or physical
exam

- Subjects likely to require ECT.

- Subjects unable to tolerate taper from psychoactive medication if necessary.

- Subjects with a history of hypersensitivity or severe side effects associated with the
use of divalproex sodium, or other an ineffective prior therapeutic trial of omega
three fatty acids.

- Subjects who have received any of the following interventions within the prescribed
period before starting treatment-investigational drugs within the previous 30 days.

- Subjects who have begun any new alternative non-medication treatments, such as diet,
vitamins, and psychosocial therapy, within the previous three months.

- Subjects with any organic or systemic disease or patients who require a therapeutic
intervention, not otherwise specified, which would confound the evaluation of the
safety of the study medication.

- Subjects who reside in a remote geographical area who do not have regular access to
transportation to the clinical facility.

- If a patient is not doing well enough (defined by CGI-AD Severity score of 3-"mildly
ill" or better)