Predicting Treatment Response to Memantine in Autism Spectrum Disorder Using MR Spectroscopy

Background and Rationale

Autism Spectrum Disorder (ASD) is a behaviorally defined complex neurodevelopmental disorder characterized by early childhood onset of marked deficiencies in social and communication skills and presence of restrictive, repetitive behaviors. Its phenotypic heterogeneity makes studying ASD and its treatment a challenging task. Currently, only two FDA approved drugs, risperidone and aripiprazole, are available to treat ASD that manage irritability associated with the disorder. None have shown conclusive benefit for core features of social and communication deficits.

Research indicates that a disrupted balance between excitation (glutamate) and inhibition (gamma amino-butyric acid, GABA) is likely to be one of the underlying mechanisms of ASD. This hypothesis is supported by a number of magnetic resonance spectroscopy studies that report an excess of glutamatergic excitation and/or a reduction in GABAergic inhibition observed in different brain regions including the limbic system and the anterior cingulate cortex. Similar findings have also been reported in post mortem studies of the ASD brain.Thus, it is expected that drugs targeting this imbalance could be beneficial. For example, the GABAB agonist, arbaclofen, was tested in ASD for this reason and showed promising results but a large trial failed to show improvement on the primary endpoints of lethargy and social withdrawal.

Memantine, a moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist, is known to improve communication in patients with Alzheimer's disease and is an FDA approved treatment for that disease. Examination of the efficacy of memantine in treating ASD has also been driven by the excitatory (glutamate) - inhibitory (gamma amino-butyric acid, GABA) imbalance hypothesis of ASD pathology. Memantine binds to the glutamatergic NMDA receptors and attenuates glutamatergic excitation. This reduction in excessive glutamatergic activation is thought to decrease the "noise" in the neural network system and facilitate learning and memory. A few small studies have shown effectiveness for memantine in the treatment of social and communication aspects of ASD spectrum disorder (ASD) as well. However, one large clinical trial using memantine in ASD reported a failure to respond. These discrepancies in results could possibly be due to the heterogeneity in the excitatory-inhibitory imbalance between ASD patients thereby causing a variation in response. In such a scenario, having a biomarker to predict an individual's treatment response would be invaluable.

MR Spectroscopy is a non-invasive tool used to examine the biochemical profile of brain tissue associated with different psychiatric and neurological conditions including ASD. Specifically, 1H-MRS studies in ASD demonstrated the excitatory-inhibitory imbalance in various cortical and subcortical regions of the brain, a finding also reported in post mortem brain tissue studies. The use of this technique to determine if Glutamate/GABA concentrations in certain regions of the brain can predict response to treatment with memantine would be an innovative breakthrough in providing more effective individualized treatment for patients since very little research has been done to explore this possibility.