The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder

Abstract

Obsessive-compulsive disorder (OCD) is a common and often debilitating neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (compulsions) and excessive anxiety. While the neurobiology and etiology of OCD has not been fully elucidated, there is growing evidence that disrupted neurotransmission of glutamate within corticalstriatal-thalamocortical (CSTC) circuitry plays a role in OCD pathogenesis. This review summarizes the findings from neuroimaging, animal model, candidate gene and treatment studies in the context of glutamate signaling dysfunction in OCD. First, studies using magnetic resonance spectroscopy are reviewed demonstrating altered glutamate concentrations in the caudate and anterior cingulate cortex of patients with OCD. Second, knockout mouse models, particularly the DLGAP3 and Sltrk5 knockout mouse models, display remarkably similar phenotypes of compulsive grooming behavior associated with glutamate signaling dysfunction. Third, candidate gene studies have identified associations between variants in glutamate system genes and OCD, particularly for SLC1A1 which has been shown to be associated with OCD in five independent studies. This converging evidence for a role of glutamate in OCD has led to the development of novel treatment strategies involving glutamatergic compounds, particularly riluzole and memantine. We conclude the review by outlining a glutamate hypothesis for OCD, which we hope will inform further research into etiology and treatment for this severe neuropsychiatric condition.

Figure 1. Proposed glutamate dysfunction model and pharmacological evidence

A) A simplified diagram of the Cortical Striatal Thalamic Cortical (CSTC) circuit B) Proposed glutamate dysfunction model. Evidence supporting various components of the model outlined with references listed below C) Glutamate in OCD: proposed pharmacological sites of action. The mechanisms of action for each pharmacological agent are also given.

Figure 1. Proposed glutamate dysfunction model and pharmacological evidence

A) A simplified diagram of the Cortical Striatal Thalamic Cortical (CSTC) circuit B) Proposed glutamate dysfunction model. Evidence supporting various components of the model outlined with references listed below C) Glutamate in OCD: proposed pharmacological sites of action. The mechanisms of action for each pharmacological agent are also given.