Efficacy and Safety of Memantine Hydrochloride in Enhancing the Cognitive Abilities of Young Adults With Down Syndrome
Condition: Down Syndrome
MeSH terms: Down Syndrome; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this 16-week research study is to determine whether a drug called memantine
      hydrochloride (memantine) has the potential to help improve memory and other cognitive
      abilities of young adults with Down syndrome (DS). Memantine (Namenda®) is a drug approved by
      the Food and Drug Administration (FDA) for patients with moderate to severe Alzheimer-type
      dementia. About 40 persons of both genders with Down syndrome aged 18-32 years will take part
      in this study. This is a randomized and double blind study. This means that subjects will
      have a 50/50 chance of being assigned to receive either the memantine pills or placebo
      (inactive pills). Neither the study participants nor the research personnel will know who is
      receiving active medication or placebo. Based on memantine's mode of action, current
      knowledge on brain pathology in persons with Down syndrome, and some preclinical data on
      mouse models of Down syndrome, we hypothesize that memantine may improve test scores of young
      adults with Down Syndrome on memory tests targeted at the function of the brain structure
      called the hippocampus. This research project has three specific aims: 1) investigate whether
      memantine has the potential to improve test scores on hippocampus-dependent measures in young
      adults with Down syndrome; 2) investigate whether memantine has the potential to improve test
      scores by these subjects on other cognitive measures; 3) investigate whether memantine is
      well tolerated by these subjects.
    

Detailed description: 
      Down syndrome, which is the result of the trisomy of Chromosome 21, is the most common
      genetically defined cause of intellectual disabilities. The estimated number of people with
      Down syndrome in the United States is approximately 300,000, and this figure is expected to
      continue increasing due to projected increases in the life expectancy of people with Down
      syndrome. Although this population trend reflects improvements in the general health care of
      individuals with Down syndrome, there has not been a parallel progress in the understanding
      of the pathogenesis and potential treatment of the psychological and neurological components
      of this genetic condition. These include various degrees of intellectual disability,
      increased incidence of seizure disorder in relation to the general population, motor
      dysfunction (including hypotonia), abnormal oculomotor and vestibular functions, substantial
      visual deficits, a neuropathology indistinguishable from Alzheimer disease, and increased
      incidence of major depression and dementia in adults.

      Over the last fifteen years, progress in the quantitative description of specific traits
      associated with Down syndrome, the availability of postnatal-viable aneuploid mouse models of
      Down syndrome, and our progressively more sophisticated knowledge of the human and mouse
      genomes have provided investigators in this field with a realistic opportunity to start
      bridging the gap between basic and clinical research.

      Whereas individuals with Down syndrome maintain relatively high levels of social intelligence
      and procedural learning, they often suffer from grossly impaired declarative or explicit
      memory. Not surprisingly, brain structures associated with declarative memory, namely the
      hippocampal and parahippocampal regions of the medial temporal lobe, are the most severely
      affected in persons with Down syndrome. The nature of these deficits suggests that therapies
      targeting hippocampal function would be particularly efficacious in ameliorating the
      cognitive deficits seen in persons with Down syndrome and, consequently, would enhance their
      quality of life.

      Glutamatergic neurons form the major excitatory system in the brain and play a pivotal role
      in many physiological functions. Apart from the physiological role of glutamate, excessive
      activation of its receptors can also evoke neuronal dysfunction and even damage/death. Cell
      death ascribed to an excessive activation of glutamate receptors has been termed
      'excitotoxicity' and seems to occur in acute insults such as stroke and trauma, but it may be
      also associated with chronic neurodegenerative diseases such as Alzheimer disease.
      N-methyl-D-aspartate (NMDA) receptor (NMDAR) mediated glutamate excitotoxicity is thought to
      play a major role in Aβ-induced neuronal death. This idea is part of the foundation of the
      glutamatergic hypothesis (as opposed to the cholinergic hypothesis) for Alzheimer disease.

      Memantine is an NMDAR antagonist that has been reported to be effective therapeutically in
      Alzheimer disease. It has been available in Germany as well as in most of the European Union
      for more than two decades. Recently, it has been approved for moderate to severe dementia in
      the US. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane
      hydrochloride. Memantine is an uncompetitive, moderate affinity, antagonist of NMDARs. It has
      been proposed that therapeutic doses of this drug inhibit the pathological effect of NMDAR
      activation while leaving unaffected NMDAR-mediated physiological processes involved in
      learning and memory. Recent preclinical data from the laboratory of this trial's P.I. on the
      mouse model for DS (Ts65Dn) have suggested a dysregulation of NMDAR activity in these animals
      and demonstrated improvement on learning and memory measures by the use of acute doses of
      memantine.

      In all clinical trials so far, memantine was found safe and well tolerated. The tolerability
      of an NMDAR antagonist depends upon its affinity towards the receptors, unbinding kinetics,
      and voltage dependency. Memantine is thought to improve the fidelity of synaptic
      transmission. Such action is predicted to provide both neuroprotection and symptomatic
      restoration of synaptic plasticity by one and the same mechanism.

      Recent open-label studies suggest that memantine may be clinically useful and well tolerated
      in young individuals with other conditions that produce cognitive disabilities, such as
      autism and attention deficit hyperactivity disorder (ADHD).

      Because of the ubiquity of Alzheimer disease-type pathology in persons with Down syndrome,
      the preclinical findings consistent with dysregulation of NMDAR activity in mouse models of
      Down syndrome, the safety profile of memantine (which is superior to the AChE inhibitors that
      are already being tested in persons with Down syndrome), and the possibility that memantine
      may indeed delay the onset of Alzheimer disease-type pathology in young adults with Down
      syndrome, all the professionals involved with this project decided that a small-scale
      randomized controlled clinical trial was warranted at present.

      We would like to emphasize that the goal of this study is to evaluate the efficacy,
      tolerability and safety of memantine hydrochloride in enhancing the cognitive abilities of
      young adults with Down syndrome aged 18-32 years. Therefore, the present investigation is a
      non-overlapping and complementary clinical trial to the randomized, placebo-controlled
      clinical trial on the efficacy and tolerability of memantine in preventing age-related
      cognitive deterioration and dementia in people with Down syndrome age 40 and over
      (http://www.clinicaltrials.gov/ct2/show/record/NCT00240760?term=down+syndrome&rank=15)
      currently being carried out by our colleagues in London.
    

Intervention name(s): Memantine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The drug dosage will follow memantine's standard titration schedule (i.e., 5 mg/d week one, 5 mg/BID week two, 5 & 10 mg/d divided dose week three, 10mg/BID week four).; These are identically-looking pills to those in the Memantine Arm.
Other intervention name(s): Memantine brand name in the USA is Namenda; Sugar Pills
Intervention MeSH terms: Memantine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Down syndrome; Trisomy 21; Pattern Recognition Memory (PRM); Paired Associates Learning (PAL); California Verbal Learning Test (CVLT); Test of Reception of Grammar (TROG-II); Peabody Picture Vocabulary Test (PPVT-III); Scales of Independent Behavior revised (SIB-R)