Glutamate Antagonism at NMDA Receptors is Not Effective in Huntington's Disease
Based on the available evidence, antagonism of glutamate transmission at NMDA receptors has not been found to be effective in treating Huntington's disease, despite its theoretical neuroprotective potential.
Evidence for Ineffectiveness of NMDA Receptor Antagonists
Theoretical Basis vs. Clinical Reality
- Huntington's disease (HD) involves excitotoxicity mediated through glutamate receptors, particularly NMDA receptors, which theoretically makes them targets for intervention 1
- Despite this pathophysiological rationale, clinical trials have consistently shown disappointing results with NMDA receptor antagonists
Clinical Evidence
- A Cochrane systematic review specifically evaluated glutamate receptor antagonists among other interventions for HD and found "no clear effectiveness" 2
- Multiple clinical trials of NMDA receptor antagonists have produced negative or disappointing results 3
- Specific NMDA antagonists tested in HD include:
Ketamine Study Findings
- A controlled study of ketamine (an NMDA receptor antagonist) in HD patients demonstrated that:
- At intermediate doses, it actually worsened memory and verbal fluency
- At higher doses, it increased psychiatric symptoms and impaired eye movements
- These findings suggest NMDA antagonism may worsen certain aspects of HD 5
Other Therapeutic Approaches in HD
Effective Interventions
- Tetrabenazine (anti-dopaminergic) is the only agent with clear efficacy for controlling chorea in HD 2, 4
- Dopamine antagonists (typical and atypical antipsychotics) have shown some efficacy for chorea control, though with significant side effects 4
Other Approaches Under Investigation
- GABA transmission bolstering has shown some promise but requires further investigation
- Mitochondrial metabolism enhancement strategies are being explored due to the energy metabolism deficits in HD 1
Molecular Mechanisms
The ineffectiveness of NMDA antagonists may be related to complex interactions between:
- Mutant huntingtin protein and postsynaptic density proteins (PSD-95, SAP102)
- Altered NMDA receptor trafficking and surface expression
- Enhanced association between PSD-95 and NR2B subunits in HD 6
Clinical Implications
When managing HD patients:
- Focus on symptomatic control with proven agents like tetrabenazine for chorea
- Be aware that NMDA receptor antagonists may worsen cognitive symptoms
- Consider that the complex pathophysiology of HD requires targeting multiple mechanisms rather than glutamate transmission alone
- Recognize that despite the theoretical basis for glutamate antagonism, clinical evidence does not support its use
This therapeutic failure highlights the complexity of HD pathophysiology and the challenges in translating mechanistic understanding into effective treatments.