Glutamate abnormalities in obsessive compulsive disorder: Neurobiology, pathophysiology, and treatment

Abstract

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.

Investigation of Cortical Glutamate–Glutamine and γ-Aminobutyric Acid in Obsessive–Compulsive Disorder by Proton Magnetic Resonance Spectroscopy

“…Thus, decreased GABA levels could reflect fewer GABAergic interneurons and result in reduced MPFC inhibitory tone, consistent with reports of cortical inhibitory dysfunction in OCD (Greenberg et al, 2000;Richter et al, 2012). Reduced MPFC inhibitory tone is also consistent with current OCD models that posit abnormal frontostriatal activation (Maia et al, 2008;Pittenger et al, 2011;Ting and Feng, 2011;Wu et al, 2012), as reduced MPFC inhibitory tone could generate abnormal striatal activation either directly due to ACC projections to the striatum or indirectly due to ACC projections to the OFC (Price and Drevets, 2010;Schmahmann and Pandya, 2006). On the other hand, acute psychological stress has recently been shown to decrease MPFC GABA levels in healthy controls (Hasler et al, 2010).…”

“…To assess regional specificity, we also measured Glx and GABA in the dorsolateral prefrontal cortex (DLPFC), a brain region not directly implicated in most OCD models. Following MRS findings in unmedicated pediatric OCD patients (2004) and consonant with current OCD models (Pittenger et al, 2011;Wu et al, 2012), we hypothesized that unmedicated adult OCD patients would have decreased Glx in the MPFC compared with healthy controls. Exploratory analyses examined whether there were group differences in MPFC GABA levels, and whether MPFC Glx or GABA levels were associated with OCD severity, OCD symptom dimensions or age of OCD onset.…”

“…Studies measuring blood flow or glucose metabolism by positron emission tomography and hemodynamic response by functional magnetic resonance imaging find increased activity in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and striatum in people with OCD (reviewed in Maia et al, 2008). This increased activity may reflect primary abnormalities in glutamatergic neurotransmission (Carlsson, 2001;Pittenger et al, 2011;Rosenberg and Keshavan, 1998;Wu et al, 2012). At the same time, the inhibitory neurotransmitter g-aminobutyric acid (GABA) modulates cortical glutamatergic neurons (GonzalezBurgos and Lewis, 2008), and abnormalities in cortical inhibitory processes have been reported in OCD (Greenberg et al, 2000;Richter et al, 2012).…”

Serum IL-1, IL-2, IL-4, IL-6, IL-10, TNF- and #945;, and IFN- and #947; levels in drug-free, comorbidity-free obsessive-compulsive disorder patients

“…Although the pathophysiology of this condition is unknown, recent studies have focussed primarily on neurotransmitters, such as serotonin, dopamine, 1 and glutamate. 2,3 Studies show that certain environmental triggers, such as psychosocial stressors, trauma, and other infectious and inflammatory processes alter gene expression in a way that influences the serotoninergic and dopaminergic systems, catecholamine modulation, and glutamate pathways. [4][5][6] It is thought that this alteration occurs via various epigenetic mechanisms and can result in OCD symptoms through changes in the circuits that process corticostriatal information.…”

Add-on Memantine Treatment for a Complicated Case of Juvenile Bipolar Mood Disorder with Co-morbid Obsessive-compulsive Disorder

“…We were caught in a limbo, when we introduced SSRI to tackle her bothersome OCD symptoms, she incurred a manic shift and when we attempted avidly stabilizing her shooting mood swings with a combo of atypical antipsychotic, two conventional mood stabilizers (lithium and anticonvulsant) and benzodiazepine, she plunged into depression with resurfacing of distressing OCD symptoms. Instead of rechallenging her with SSRI, which remains a viable option though, we thought of trying anti-glutamate pharmacotherapy, given the growing body of evidence highlighting role of glutamate dysfunction in neurobiology of OCD [5] and hence successful use of the anti-glutamate, memantine (Ebixa®) in refractory OCD [6] which would also address refractory BMD as heaps of papers abound in the literature describing utility of memantine as a 'mood stabilizer' [7][8][9][10][11]. What was also encouraging to embark on that trial is to help with the cognitive problems incurred by the illness itself [12] and negative impact of psychotropic drugs in this student by virtue of its cognitive enhancer activity resonating with reports of using it as add-on to stimulants in adult ADHD [13].…”