Primary: Demonstrate reduced frequency and intensity of maladaptive behaviors as measured by the Aberrant Behavior Checklist (ABC) Irritability subscale in subjects given Nuedexta 8 weeks over subjects given placebo.

Secondary: Demonstrate a trend towards reduced aggressive behavior as measured by Overt Aggression Scale (OAS).

This is a randomized placebo-controlled crossover study. The parents, neuropsychologists, clinical research coordinator (CRC) and PI will be blinded as to whether subjects are on placebo or Nuedexta.

Nuedexta will be given once daily for 7 days. If well-tolerated, it will be given every 12 hours for the next 7 weeks. Patients may also remain on the once-daily dose if desired.

The study will last 44 weeks. This includes 20 weeks for study enrollment, 8 weeks of treatment/placebo, 4 weeks for washout, and a second 8 week-period of treatment/placebo followed by 4 weeks of washout.

Subjects will be randomized to 8 weeks of Nuedexta/placebo. After the 8 week follow-up visit, there will be a 4 week washout period. At week 12 (second baseline), the groups will crossover for another 8 weeks of Nuedexta/placebo. Study endpoints will be measured in the both groups at weeks 8, 12, and 20. A final study visit will occur at week 24.

Inclusion Criteria:

1. 18 to 60 years of age
2. Have a collateral informant who can attend visit and answer questionnaires pertaining to participant behavior
3. Diagnosis of autistic spectrum disorder based on the Diagnostic and Statistical Manual, 4th edition, Text Revised (DSM-IV-TR) criteria, developmental history, and Autism Diagnostic Observation Schedule (ADOS); or confirmed diagnosis of autism during childhood through similar methods
4. Capable of giving informed consent, or have a legal guardian capable of giving consent on the subject's behalf; patient able to assent to participate
5. Mood issues and frontal lobe type perseveration issues
6. No medication changes within 30 days and no use of new medications during the course of the study except for non-related conditions approved by the investigators

Exclusion Criteria:

1. Clinically uncontrolled epilepsy
2. Cardiovascular conditions including cardiac or structural malformation heart failure, prolonged QT interval, history of torsades de pointes, or atrioventricular (AV) block
3. Known genetic disorders, fragile x, or known brain structural abnormalities, cerebral palsy, head injury, or brain tumor
4. Known allergy to either dextromethorphan or quinidine
5. Concurrent or recent use of Monoamine oxidase inhibitor (MAOI) antidepressants pt Nuedexta
6. Concurrent use of lamotrigine or felbamate or other N-Methyl-D-aspartate (NMDA) agonists or antagonists
7. Thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome
8. Pregnancy - sexually active females of childbearing potential must be on a reliable form of contraception
9. Other clinically significant abnormality on physical, neurological, laboratory, vital signs, that could compromise the study or be detrimental to the subject

Eight weeks for each intervention with 4 weeks washout in between interventions and at the end (total 24 weeks).

Safety population included all participants who received at least one dose of intervention.