Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment
Open accessAbstract
Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics.
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Structural abnormalities in CSTC circuits involving OFC, ACC, and striatum have been repeatedly demonstrated in OCD.
“structural abnormalities in CSTC circuits involving orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and striatum have been repeatedly demonstrated in OCD 51–53.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [51]
The role of SLC1A1 in OCD is supported by the observation that riluzole can be beneficial in the treatment of OCD and by the finding of elevated glutamate levels in the CSF of OCD patients.
“The role of this glutamate transporter gene in OCD is also supported by the observation that the anti-glutamatergic drug riluzole can be beneficial in the treatment of OCD and by the finding of elevated glutamate levels in the CSF of OCD patients (Pittenger et al. 2011).”
From The neurobiological link between OCD and ADHD (2014) · cites this paper as Pittenger et al. 2011
Various neurotransmitters, including serotonin, dopamine and glutamate, are implicated in the pathophysiology of OCD.
“Studies using neurochemical and neuroimaging methods have shown that various neurotransmitters are implicated in the pathophysiology of this disorder, including serotonin [1], dopamine [2] and glutamate [3].”
From P300 and delay-discounting in obsessive–compulsive disorder (2022) · cites this paper as [3]
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- Authors
- Pittenger, C., Bloch, M. H., & Williams, K.
- Affiliations
- Yale University (US)
- Corresponding author
- Pittenger, Christopher
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 132
- Issue
- 3
- Pages
- 314-332
- ISSN
- 0163-7258 (ISSN-L)
- PMC
- PMC3205262
- OpenAlex
- W2109125813
- Cited by
- 426
- References
- 229
- Citations by year
- 2026: 30 · 2025: 24 · 2024: 23 · 2023: 31 · 2022: 17 · 2021: 33 · 2020: 65 · 2019: 28 · 2018: 25 · 2017: 26 · 2016: 39 · 2015: 34 · 2014: 25 · 2013: 18 · 2012: 7
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R34MH083115, K08MH081190, K23MH091240, R25MH077823)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Social Sciences › Psychology › Clinical Psychology › Psychoanalysis and Psychopathology Research
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- obsessive-compulsive disorder, glutamate, glutamate dysregulation, treatment-refractory OCD, pathophysiology, excitatory neurotransmission, neuroimaging, animal models, cognitive behavioral therapy, pharmacotherapy
- MeSH terms
- Animals, Clinical Trials as Topic, Drug Evaluation, Preclinical, Humans, Neurobiology, Obsessive-Compulsive Disorder, Randomized Controlled Trials as Topic, Neurotransmitter Agents, Glutamic Acid
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