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.

FIGURE 1. The CSTC circuitry implicated in OCD

Convergent evidence from functional and structural neuroimaging suggests that abnormalities in the circuitry interconnecting the cortex, basal ganglia, and thalamus. The canonical connections forming these cortico-striato-thalamo-cortical (CSTC) loops is shown in simplified form here. Projections in this circuit use both the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA, as shown. Modulatory dopamine critically modulates information flow through this circuit. Other important modulatory neurotransmitters, such as acetylcholine, serotonin, and histamine, are excluded for clarity.

FIGURE 2. The principle components of the glutamate synapse

Glutamate is the primary excitatory neurotransmitter in the adult brain. It is packaged into vesicles in axon terminals by the vesicular glutamate transporter, vGluT. Glutamate binds to both ionotropic receptors (NMDA, AMPA, and kainate) and metabotropic receptors (mGluRs), postsynaptically, extrasynaptically, and presynaptically. Glial cells, principally astrocytes, play a major role in glutamate reuptake through the transportwea EAAT1 and EAAT2, terminating the glutamate synaptic signal; the neuronal transporter EAAT3 plays a quantitatively minor role in this process. Steady-state extrasynaptic glutamate levels are also regulated by the glial cystine-glutamate antiporter (XC-). See text for further discussion.

FIGURE 3. Glutamate participates in multiple metabolic processes in different cell types

Whole-tissue glutamate, as measured by techniques such as MRS, reflects many sources of glutamate beyond synaptic neurotransmitter glutamate. In glial cells, glutamate enters through the transporters EAAT1 and EAAT2, and via the cystine-glutamate antiporter, XC-. Some is converted to glutathione, the brain principle antioxidant; this represents a link between glutamate homeostasis and redox state. Biosynthesis of glutathione, the details of which are not shown, also can include cystine (Cys) and glycine (Gly). Much glutamate taken up by glial cells is converted into glutamine (Gln), which passively diffuses back into neurons and is converted back into glutamate by the enzyme glutaminase. Neurotransmitter glutamate is packaged into vesicles by the vesicular glutamate transporter (vGluT). Vesicle fusion and glutamate release upon action potential invasion of the axon terminal through a calcium-dependent mechanism involving the SNARE proteins. In the synaptic cleft, released glutamate binds to postsynaptic receptors. Activation of the NMDA receptor also requires binding by coagonist Gly or D-serine (D-Ser) at a distinct site. Glycine levels are regulated by the glycine transporter, GlyT (not shown). Glutamate diffuses out of the synaptic cleft; most is taken up by the EAAT glutamate transporters, but some binds to extrasynaptic receptors, both postsynaptically and presynaptically. Glutamate is also closely tied to basic energy metabolism and the tricarboxylic acid (TCA_n) cycle, in all cells; it is interconvertable with the intermediate α-ketoglutarate (α-KG); other components of the TCA cycle shown here are succinate (Suc) and acetyl-coenzyme (Ac-CoA), which enters from the bloodstream and is the principle source of energy for neurons. Glutamate also enters inhibitory GABAergic neurons, shown on the left, where it is converted to neurotransmitter GABA by the enzyme glutamic acid dehydrogenase (GAD). Levels of glutamate and GABA are thus metabolically coupled. GABA is released from these neurons and binds postsynaptic and presynaptic inhibitory receptors (not shown). Synaptic GABA is taken up by the transporter GAT.

FIGURE 4. Major sites of action of glutamate-modulating drugs

The glutamate modulator riluzole acts (i) by inhibiting axonal voltage-gated sodium channels (Na⁺) – a mechanism shared with the antiepileptic agent lamotrigine – thereby limiting glutamate release; and (ii) by enhancing glial uptake of extrasynaptic glutamate. The antioxidant N-acetylcysteine (NAC) also modulates extrasynaptic glutamate; it is converted into cystine and drives the extrusion of glutamate from astrocytes via the cystine-glutamate antiporter. The NMDA blockers memantine and ketamine block the pore of the NMDA receptor, preventing cation influx. Glycine, D-serine, and D-cycloserine (D-CS), in contrast, bind to the NMDA receptor coagonist site and potentiate activation of the receptor. Sarcosine (not shown) inhibits the glycine receptor Gly-T, increasing the endogenous levels of glycine. See Figures 2 & 3 for abbreviations of components of the glutamatergic synapse, and main text for more details.