Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
Condition: Autism Spectrum Disorder
MeSH terms: Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive
Intervention: Memantine; Placebo
Intervention description: Capsule; Capsule
Intervention MeSH terms: Memantine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 84.0
Sex: All
Minimum age: 8 Years
Maximum age: 17 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Autism spectrum disorder; Treatment; Adolescents; Memantine; functional Magnetic Resonance Imaging; MRS; Neuroimaging

Summary:

      This study is a 12-week, randomized-controlled trial of memantine hydrochloride (Namenda) for
      the treatment of social impairment in adolescents with autism spectrum disorder (ASD). The
      investigators will also conduct pre- and post-treatment neuroimaging (functional magnetic
      resonance imaging [fMRI] and hydrogen magnetic resonance spectroscopy [HMRS]) to assess
      neural functional deficits in adolescents with autism spectrum disorder compared to healthy
      volunteer adolescents. This pre- and post-neuroimaging will also be used to assess any
      effects of memantine therapy on neural function in adolescents with autism spectrum disorder.
      The investigators hypothesize that short-term memantine monotherapy will be safe,
      well-tolerated, and effective in improving the core symptoms of autism spectrum disorder in
      adolescents with autism spectrum disorder. Additionally, the investigators hypothesize that
      following memantine therapy, adolescents with autism spectrum disorder will exhibit a
      decrease in glutamate (Glu) concentration in the anterior cingulate cortex (ACC) and a change
      towards normalization in altered functional connectivity of the anterior cingulate cortex and
      medial temporal lobes, consistent with improvement in social impairments in autism spectrum
      disorder. The investigators hypothesize that compared to healthy volunteer participants,
      participants with autism spectrum disorder will significantly differ on neuroimaging measures
      at baseline but that following memantine therapy, the difference between autism spectrum
      disorder and healthy volunteer neuroimaging data will decrease.
    

Eligibility criteria:

        INCLUSION CRITERIA

        All Participants:

          1. Male and female participants, ages 8-17 years (inclusive)

             Participants with Autism Spectrum Disorder:

          2. Meets Diagnostic and Statistical Manual-5 autism spectrum disorder diagnostic
             criteria, as established by clinical diagnostic interview

          3. At least moderate severity of social impairment, as measured by a total raw score of
             ≥85 on the parent/guardian-completed Social Responsiveness Scale, Second Edition
             (SRS-2) and a score of ≥4 on the clinician-administered Autism Spectrum Disorder
             Clinical Global Impression-Severity scale (ASD CGI-S)

        Healthy Control Participants:

        2. Age-, sex-, and IQ-matched with participants with autism spectrum disorder 3. No Axis I
        diagnoses, as established by the Kiddie Schedule for Affective Disorders and
        Schizophrenia-Epidemiological Version (K-SADS-E) and confirmed by clinical diagnostic
        interview 4. No significant traits of autism spectrum disorder, as measured by a total raw
        score of <60 on the parent/guardian-completed Social Responsiveness Scale, Second Edition

        EXCLUSION CRITERIA

        All Participants:

          1. IQ ≤70 based, on the Wechsler Abbreviated Scale of Intelligence, Second Edition
             (WASI-II) Vocabulary and Matrix Reasoning subtests

          2. Impaired communicative speech

          3. Current treatment with the following medications, which are known to impact glutamate
             levels:

               1. Lamotrigine

               2. Amantadine

               3. N-acetylcysteine

               4. D-cycloserine

          4. Current treatment with a psychotropic medication, not listed above, on a dose that has
             not been stable for at least 4 weeks prior to study baseline

          5. Co-administration of drugs that compete with memantine for renal elimination using the
             same renal cationic system, including hydrochlorothiazide, triamterene, metformin,
             cimetidine, ranitidine, quinidine, and nicotine

          6. Initiation of a new psychosocial intervention within 30 days prior to randomization

          7. Participants who are pregnant and/or nursing

          8. Participants with a history of non-febrile seizures without a clear and resolved
             etiology

          9. Participants with a history of or a current liver or kidney disease

         10. Clinically unstable psychiatric conditions or judged to be at serious suicidal risk

         11. Participants who meet for alcohol or drug dependence or abuse on the Kiddie Schedule
             for Affective Disorders and Schizophrenia-Epidemiological Version. If the participant
             has a recent history of substance abuse, as an added precaution, there will be a
             2-week washout period before initiating the trial. There are no known safety issues
             relating to memantine and recent history of substance abuse.

         12. Serious, stable or unstable, systemic illness, including hepatic, renal,
             gastroenterological, respiratory, cardiovascular (including ischemic heart disease),
             endocrinologic, neurologic, immunologic, or hematologic disease

         13. Participants with severe hepatic impairment (Liver Function Tests [LFTs] >3 times the
             Upper Limit of Normal [ULN])

         14. Participants with genitourinary conditions that raise urine Power of Hydrogen (pH)
             (e.g., renal tubular acidosis, severe infection of the urinary tract)

         15. Known hypersensitivity to memantine

         16. Severe allergies or multiple adverse drug reactions

         17. A non-responder or history of intolerance to memantine after treatment at adequate
             doses, as determined by the clinician

         18. Investigator and his/her immediate family, defined as the Investigator's spouse,
             parent, child, grandparent, or grandchild.