Divalproex Sodium ER in Adult Autism

Based on positive research with divalproex in children/adolescents with autism, we would like
to extend this research to autistic adults with high levels of aggression, irritability,
affective instability, or agitation. We aim to have 10 adult autistic patients enrolled in
our study of the treatment of aggression/irritability with divalproex sodium ER. This will be
an open treatment for adult patients to determine if the tolerability of divalproex sodium is
better with the extended release. We propose this open label design because previous
double-blinded studies of divalproex sodium were only done in children, not adults. These
results will serve as pilot data for a future blinded study for autistic adults with the
extended release formulation. This naturalistic design will allow for prior stable (3 months)
use of concomitant medications. Our objective is to determine how well these patients can
tolerate the prescribed doses and what added benefits can be attributed to divalproex sodium
ER.

Inclusion Criteria:

1. Meet DSM-IV, ADI, or ADOS criteria for autism spectrum disorder.

2. Age 18-65.

3. Be seen as outpatients

4. Demonstrate capacity to provide authorized informed consent or provide consent for
participation by an approved surrogate on the autistic individual's behalf

5. Sexually active females of childbearing potential must use an acceptable method of
birth control and have a negative serum pregnancy test prior to entry into the study.

6. Score at least 4 (moderately ill) on the Clinical Global Impression-Severity Scale for
Autistic Disorder (CGI-AD).

7. Subject meets the following criteria at pre-study diagnostic assessment and baseline
assessment: OAS-M 6 (raw scores).

8. Subjects on a stable dose of their current psychotropic medication for at least 3
months before entering the study, with the understanding that they must remain on a
stable dose throughout the trial. If a subject chooses to taper off their current
medications, they will be closely monitored by the study psychiatrist and must be
medication free for 2 weeks prior to beginning the study. Additionally, if a subject
is currently taking a medication with a known drug interaction with Divalproex Sodium,
he/she will be tapered off of that medication under the supervision of the study
psychiatrist before undergoing treatment.

Exclusion Criteria:

1. Subjects who are pregnant or nursing mothers. Sexually active women of childbearing
potential who are not using adequate birth control measures.

2. Subjects with active or unstable epilepsy.

3. Subjects with any of the following past or present mental disorders: schizophrenia,
schizoaffective disorder, bipolar disorder, or organic mental disorders.

4. Subjects who are a serious suicidal risk.

5. 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.

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

7. 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

- Subjects with an unstable history of seizures cannot participate in the study.
However, subjects who have been seizure-free for at least 6 months on a stable
dose of anticonvulsant medication other than divalproex sodium or related
formulations (e.g., depakene) may participate, along with non-medicated subjects
with a history of seizures who have been seizure-free for at least 6 months.
Subjects with abnormal EEG but no clinical seizures are also eligible.

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

9. Subjects with clinically significant abnormalities in laboratory tests or physical
exam.

10. 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
divalproex sodium (serum levels within range of 50-100 ug/ml for 6 weeks).

11. Subjects who are currently taking a medication with a known drug interaction with
Divalproex Sodium (betamipron, chaparral, cholestyramine, clarithromycin, comfrey,
ethosuximide, evening primrose, felbamate, fosphenytoin, germander, ginkgo, jin bu
huan, kava, mefloquine, panipenem, pennyroyal, primidone, rifampin, rifapentine, and
zidovudine) and refuse to taper off of that medication.

12. Subjects who are already being treated with Divalproex Sodium.

13. 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.

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