Primary Psychiatry. 2006;13(10):65-77

 
Dr. Pittenger is resident in the Department of Psychiatry at Yale University and assistant director of the Yale Obsessive-Compulsive Disorder Research Clinic in New Haven, Connecticut.

Dr. Bloch is resident in the Department of Psychiatry at Yale University and the Yale Child Study Center.

Mr. Wegner is summer undergraduate research assistant at the Yale Obsessive-Compulsive Disorder Research Clinic.

Dr. Teitelbaum is resident in the Department of Psychiatry at Yale University.

Dr. Krystal is Robert L. McNeil, Jr. professor of psychiatry and vice chair for research in the Department of Psychiatry at Yale University School of Medicine.

Dr. Coric is director of the at the Yale Obsessive-Compulsive Disorder Research Clinic, assistant clinical professor in the Department of Psychiatry at Yale University, and inpatient unit chief of the Clinical Neuroscience Research Unit at the Connecticut Mental Health Center.

 

 

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder and the tenth leading cause of disability in the world. The introduction of serotonin reuptake inhibitors (SRIs) in the 1980s represented an important advance in the treatment of OCD. However, most patients show only a partial response to existing treatments and a full remission of OCD symptoms is not frequently observed. Clinical experience and research has highlighted the role of serotonin and dopamine in OCD. The clinical observation that SRIs and augmentation with dopamine antagonists only yields a partial treatment response in most patients suggests that other neurotransmitters contribute to the neurobiology of the illness. Recent research findings raise the possibility that agents that directly reduce glutamate hyperactivity or its consequences in the central nervous system are efficacious as novel therapeutic interventions. This article reviews current treatment strategies for OCD and summarizes the growing body of research implicating glutamatergic dysfunction in OCD.

 

Introduction

Obsessive-compulsive disorder (OCD) affects approximately 3% of the United States population and is the fourth most common psychiatric disorder after substance abuse, specific phobias, and major depressive disorder (MDD).^1,2 Patients with OCD experience obsessions and/or compulsions that significantly interfere with their functioning. Obsessions are often characterized as persistent and unwanted intrusive thoughts that cannot easily be dismissed. These obsessions are generally perceived as foreign and recognized as being irrational or excessive. The anxiety associated with obsessions is often described as a feeling that something is incomplete or wrong, or that terrible consequences will ensue if specific actions are not taken. Many patients engage in repetitive, compulsive behaviors that aim to discharge the anxiety associated with obsessional thoughts.^3,4 Severely affected patients can spend many hours each day in their obsessional thinking and resultant compulsive behaviors, leading to marked disability.

Common OCD symptom clusters include obsessions of contamination, with accompanying cleaning compulsions; obsessions with symmetry or order, with accompanying ordering behaviors; obsessions of saving, with accompanying hoarding; somatic obsessions; aggressive obsessions with checking compulsions; and sexual and religious obsessions. There is mounting evidence that these symptom constellations are somewhat independent of one another⁵ and may best be conceptualized as different overlapping dimensions of the disorder, perhaps with distinct genetic associations.^6,7

Clinical experience and research studies have highlighted the role of serotonin and dopamine in OCD. The clinical observation that many patients treated with serotonin reuptake inhibitors (SRIs) and dopamine antagonists only demonstrate a partial treatment response suggests that other neurotransmitters contribute to the neurobiology of the illness. Several converging lines of evidence suggest that abnormalities in glutamatergic neurotransmission in the cortico-striato-thalamo-cortical (CSTC) circuitry may contribute to OCD. This article reviews the current treatment strategies in OCD and summarizes the growing body of research implicating glutamatergic dysfunction in OCD.

 

Current Treatment of OCD

Efficacious behavioral and pharmacologic treatments for OCD have been extensively validated in the last 2 decades.^3,8-10 Although first-line treatment for OCD can reasonably include either cognitive-behavioral therapy (CBT) or medication management, the combination of these two treatments is regarded as most effective by many clinicians.^3,11 The behavioral strategy with the best proven efficacy is exposure and response prevention (ERP). In ERP, the therapist systematically presents anxiety-inducing stimuli to patients in a controlled environment and then has the patients attempt to delay or prevent themselves from engaging in their usual compulsions.^12,13

With regard to medication management of OCD, clomipramine (the tricyclic antidepressant that is the most specific inhibitor of serotonin reuptake) and selective serotonin reuptake inhibitors (SSRIs) have clearly been shown to be effective for many patients.^3,10,14-17 Because of a more benign side effect profile, SSRIs are considered first-line pharmacotherapy for OCD despite the fact that clomipramine may offer a slightly greater efficacy.

Clinical trials and accumulated clinical experience show that the management of SRIs in OCD differs from that in depression. First, higher doses are often required before clinical improvement is seen than is the case in depression. Second, improvement is more gradual and an adequate medication trial in OCD is considered to be at least 12 weeks in duration.^3,18 For these reasons, careful trials of SSRIs and/or clomipramine at adequate doses must be completed with little or no improvement before a patient’s OCD can clearly be considered resistant to SRI pharmacotherapy.

 

Treatment-Resistant Symptoms in OCD

Despite the proven efficacy of both SRIs and CBT, a substantial percentage of patients receive little benefit from these standard approaches. In addition, treatment response to an SRI in OCD research studies is not generally defined as treatment to remission of symptoms. Response is typically defined as a decline in symptoms, as measured by a 35% reduction in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) or a decline in symptoms below a threshold of 16 (ie, the boundary between mild and moderate OCD symptoms). This means that even treatment-responsive patients may continue to have levels of symptoms in the mild-to-moderate range and spend hours daily preoccupied with their obsessions and compulsions. While definitions of acceptable treatment response vary between studies, making comparisons somewhat difficult, only 40% to 60% of patients achieve such a response in most studies when treated with an adequate trial of an SRI with or without CBT.¹⁹ The large fraction of patients without substantial response to standard treatment experiences significant morbidity.²⁰ There is a clear need for novel therapeutic avenues to target both partially responsive and treatment-resistant populations.

Numerous therapeutic strategies have been attempted in the treatment-resistant population.^19,21,22 For patients who fail to respond to treatment, three general treatment approaches are often employed to enhance treatment efficacy. They include monotherapy with different primary pharmacologic agents; augmentation with a drug of a different class; and more invasive therapies such as ablative psychosurgery and, more recently, deep-brain stimulation. While evidence exists for efficacy of several different modes of treatment in the treatment-resistant OCD population, there is currently no clear consensus as to the best method to treat patients once SRIs and CBT have proven inadequate.

 

Alternative Monotherapies

Although the role of agents that target the serotonin system has clearly been established as the standard treatment of OCD, some investigators have hypothesized that agents affecting both serotonin and norepinephrine might be more effective in treatment-resistant patients. This hypothesis is supported by the fact that clomipramine, which retains some norepinephrine reuptake inhibitory (NRI) effect relative to the SSRIs and whose metabolite desmethylclomipramine has significant NRI activity, appears to be more effective than the selective agents in meta-analyses, though not in head-to-head comparisons.^13,23 SSRIs remain more widely prescribed as first-line pharmacotherapy despite such results because of their more benign side-effect profile. Other alternative monotherapies that have been shown to be effective include treatment with venlafaxine, mirtazepine, intravenous clomipramine, and intravenous citalopram.^24-32

 

Augmentation Therapy

Many different agents have been used as augmentation strategies for standard SRI therapy in treatment-refractory OCD, with some success. In particular, agents with modes of action beyond the serotonin system have shown the capacity to significantly improve symptoms in patients with limited response to SRI therapy alone.

Augmentation with typical³³ or atypical antipsychotics^34-41 improves symptoms in a substantial fraction of patients whose symptoms are refractory to SRI treatment alone (Table 1).^{15,34,35,42-47} A recent meta-analysis by Bloch and colleagues⁴⁸ concluded that augmentation with haldol or risperidone is an effective intervention for treatment-refractory OCD and may be particularly effective in OCD patients with comorbid tics; evidence for the efficacy of olanzapine and quetiapine is equivocal in the studies performed to date.



Numerous other augmentation agents have been tried in treatment-resistant OCD, generally in small case series and with more equivocal results. Medications that have been tried either as monotherapy or as augmentation agents include clonazepam, inositol, clonidine, opioid agonists, monoamine oxidase inhibitors, and antiandrogens.⁴⁹

 

Invasive Treatment Options

SRI-resistant OCD is one of the few diagnoses in modern psychiatry for which invasive neurosurgical procedures remains part of the established treatment armamentarium. This underscores the clinical challenges posed by treatment-resistant OCD and the exquisite suffering of severely affected patients.

Neurosurgical approaches to treatment-refractory OCD have recently been reviewed^9,50 and have shown some efficacy in open trials of limited numbers of patients with treatment-resistant OCD. The development of deep-brain stimulation (DBS) techniques that can reversibly manipulate the activity of specific brain circuitry has garnered increasing interest as a possible treatment modality for OCD and other intractable neuropsychiatric conditions.^51,52 A recent 3-year outcome study examining the efficacy of DBS in highly resistant cases of OCD found significant improvements in individuals treated with DBS.⁵³

Finally, the use of electroconvulsive therapy, transcranial magnetic stimulation (TMS),⁵⁴ and vagal nerve stimulation have been explored as less invasive methods of treatment than neurosurgical intervention. None of these therapies have demonstrated marked efficacy in the limited studies done to date.

 

Limitations of Available Treatment Strategies

Despite the availability of several treatment options, treatment-resistant OCD symptoms remain a pressing clinical problem. The fact that many individuals with OCD do not fully respond to SSRIs or augmentation strategies suggests a role for other neurotransmitters in the pathophysiology of OCD. Increasing evidence suggests that the excitatory amino acid glutamate plays an important role in the underlying pathophysiology of OCD.

 

Glutamatergic Dysregulation in OCD?

Several well-replicated single photon emission computed tomography, positron emission tomography, and functional magnetic resonance imaging studies have demonstrated increased cerebral blood flow, metabolism, and activation in the cortico-striato-thalamo-cortical (CSTC) circuitry of individuals with OCD.^55-63 These well-established neuroimaging findings in OCD have led to the hypothesis that glutamatergic dysfunction contributes to the regional metabolic hyperactivity seen in OCD.^64,65 Within the CSTC circuitry, glutamate and γ-aminobutyric acid (GABA)-driven pathways are thought to be responsible for balancing neural tone. The CSTC circuitry contains parallel, partially antagonistic information-processing pathways that operate together to generate appropriately balanced control of movement and thought. The direct pathway is thought to modulate the initiation and sustainability of behavioral routines, while the indirect pathway modulates the cessation of these behaviors. The leading explanatory model for OCD suggests that increased activity in the direct pathway relative to the indirect pathway results in a disinhibited thalamus and the creation of a self-perpetuating circuit between the thalamus and the orbital cortex that drives OCD symptoms.^66,67 Since cortico-striatal projections are predominantly glutamatergic, excess glutamatergic activity may contribute to the pathophysiology of OCD. Successful treatment is associated with a reduction in the CSTC hyperactivity in those patients that respond to treatment. Moreover, the efficacy of SSRIs may be due to an inhibitory effect of serotonin on cortical and striatal glutamate release.

Recent advances in research methodologies and the availability of pharmacotherapeutic agents that directly modulate glutamate are beginning to provide more direct evidence that glutamate plays an important role in the pathophysiology of OCD.

 

Magnetic Resonance Spectroscopy Measurements of Glutamate Dysfunction in OCD

The development of methods to measure amino acid neurotransmitters in the brain has allowed levels of glutamatergic compounds and GABA to be investigated in neuropsychiatric disorders.⁶⁸ Magnetic resonance spectroscopy (MRS) allows measurement of the concentration of certain molecules in the brain and other tissues. It has come to be widely used in neurology as a tool to assess the health and cellular composition of different regions of the normal or diseased brain. Recent MRS findings implicate dysregulation of glutamate neurotransmission in CSTC circuits in OCD.

Before summarizing the MRS findings in OCD, an important methodologic consideration must be addressed to appropriately interpret these data. MRS distinguishes molecules by their chemical shift in a magnetic field. Measurement of the concentration of any given molecule therefore requires that its MRS chemical shift be clearly distinguishable from that of similar molecules with neighboring peaks in the spectrum. Under standard magnetic field strengths such resolution is difficult with glutamate and GABA, though specific identification of glutamate and GABA peaks can be achieved in some brain regions with special coils, magnetic pulse sequences, and specific editing techniques.^69-71 More commonly, an aggregate measure termed Glx is reported; Glx measurements reflect levels of glutamate, glutamine, homocaronsine, and GABA.⁷² Abnormal Glx measurements in OCD or any other neuropsychiatric disorder can therefore be interpreted to reflect perturbations in amino acid neurotransmitter levels in general, but cannot necessarily be interpreted to specifically reflect abnormal levels of glutamate.

Even accepting that increased Glx signal indicates increased tissue glutamate in MRS studies, the physiologic implication of such an alteration is unclear. Increased glutamate could represent either increased glutamatergic neurotransmission or an increased metabolic pool of glutamate. Indeed, increased glutamate could indicate intraneuronal accumulation of glutamate, and could therefore correspond to reduced glutamatergic synaptic activity. However, despite these caveats the ability of MRS to probe the levels of neurotransmitters in the intact brain is an exciting methodologic advance and has produced new insights into possible glutamatergic dysregulation in OCD.

Table 2^73-85 summarizes the MRS studies of OCD performed to date. Rosenberg and colleagues⁸⁶ have reported abnormal Glx measurements in several brain regions in OCD. Glx is increased in the striatum of patients with OCD, consistent with the known metabolic hyperactivity of the CSTC circuitry. Interestingly, this elevation in Glx has been shown to normalize in OCD subjects who respond to treatment with SRIs.^76,78 In contrast, Rosenberg and colleagues⁸³ recently found decreased Glx levels in the anterior cingulate in subjects with OCD. As the authors point out, the combined finding of reduced anterior cingulate Glx concentrations and increased caudate Glx parallels prior studies demonstrating an inverse relationship between anterior cingulate and basal ganglia volume in patients with OCD. The specific glutamatergic dysfunction in OCD remains to be elucidated and may vary between brain regions.

 

Elevated Cerebrospinal Fluid Glutamate in OCD

The most direct evidence for excessive glutamatergic activity in OCD derives from a recent study examining cerebrospinal fluid (CSF) from patients with OCD. Chakrabarty and colleagues⁸⁷ examined the CSF of 21 drug-naïve OCD patients and 18 control subjects, and found CSF glutamate levels to be significantly elevated in those subjects with OCD. This study requires replication with a larger number of patients, but it supports the MRS data in suggesting glutamatergic dysfunction as an important component of the pathophysiology of OCD.

 

Increased Cortical Excitability in OCD

Either increased glutamatergic tone or reduced GABA activity in the cortex may alter the excitatory-inhibitory balance in the cortex. This balance can be probed with TMS, by measuring the motor response to a threshold cortical stimulation and other parameters. Using this methodology, Greenberg and colleagues⁸⁸ recently demonstrated increased cortical excitability in OCD. Future TMS studies are warranted to follow up on this preliminary finding.

 

Genetic Evidence Implicating Glutamate and OCD

OCD is thought to have a strong genetic component. This is most clearly demonstrated by the higher concordance rate in monozygotic twins (80% to 87%) than in dizygotic twins (47% to 50%).⁸⁹ However, the genetics of OCD, as is the case in many psychiatric disorders, are complex, and the disorder is presumably polygenic. While OCD is believed to have a significant genetic component,⁹⁰ no clearly replicated genetic loci have been convincingly demonstrated to be causally involved in its pathogenesis to date. Nevertheless, several genes involved in glutamatergic neurotransmission have recently been implicated in association studies (Table 3).^91-97 Two linkage scans have suggested that a gene contributing to OCD may be found in chromosomal region 9p24.^92,93 Within chromosome region 9p24 is the gene Solute Carrier Family 1, Member 1 (SLC1A1), that encodes for the glutamate transporter, excitatory amino acid carrier–1 (EAAC1). EAAC1 plays a central role in maintaining normal levels of glutamate in the extrasynaptic space and terminating the action of glutamate at the synapse. Interestingly, SLC1A1 is highly expressed in the cortex, striatum, and thalamus. Additionally, recent preliminary findings from two separate groups^94,95 demonstrated an association between the glutamate transporter gene SLC1A1 and OCD. In addition to this recent association between SLC1A1 and OCD, additional research regarding glutamatergic dysfunction and OCD includes a preliminary association with the N-methyl-D-aspartate (NMDA) glutamate receptor subunit GRIN2B⁹⁶ and a negative association with a particular allele of the GRIK2 kainate receptor gene.⁹⁷ Such associations are very preliminary; however, if these or similar genetic associations with components of the glutamate neurotransmission and regulatory systems are substantiated, they would bolster the evidence that dysregulated glutamate is an important aspect of the etiology of OCD.

 

Preliminary Efficacy of Glutamate-Modulating Agents in OCD

If glutamate is indeed dysregulated in OCD, one might hypothesize that pharmacologic agents that directly modulate glutamatergic neurotransmission would be beneficial in its treatment. Candidate agents include drugs that decrease presynaptic glutamate release, increase glial uptake of glutamate, or attenuate the postsynaptic effects of glutamate. Pharmaceutical agents that directly attenuate glutamatergic outflow have only recently become available and preliminary experience with these medications suggest efficacy in the treatment of OCD (Table 4).^98-108 One such agent is riluzole, a glutamate-modulating agent that is Food and Drug Administration-approved for neuroprotection in amyotrophic lateral sclerosis (ALS).¹⁰⁹ Among its proposed mechanisms of action are inhibition of sodium currents in glutamatergic (and other) axon terminals, reducing neurotransmitter release¹¹⁰; reduction of P/Q-type calcium currents in the axon terminals, with a similar effect on transmitter release¹¹¹; extension of the open time of certain potassium channels¹¹²; and increased astrocytic uptake of glutamate.¹¹³ Although it has significant effects on glutamatergic function, riluzole does not purely target glutamatergic neurotransmission. In vitro studies suggest that it also modulates release of acetylcholine and dopamine,¹¹⁴ potentiates receptors for GABA and glycine,^115,116 and enhances expression of brain-derived neurotrophic factor.^117,118



Coric and colleagues⁹⁸ have used riluzole in treatment-resistant OCD in an open-label study (Figure). Thirteen patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition⁴ diagnosis of OCD who had shown little improvement with at least 8 weeks of adequate-dose SRI therapy were treated with the addition of riluzole to their existing medication regimen. Most patients had failed several SRI trials, augmentation strategies with dopamine antagonists, and CBT. Over the course of treatment, mean Y-BOCS scores in this treatment-resistant cohort fell from 30.7 (SEM 6.6), in the severe range, to 17.7 (SEM 8.6), representing a 42% reduction in OCD symptoms for the entire cohort (responders and nonresponders). Seven of the 13 patients (59%) demonstrated a ≥35% reduction in baseline Y-BOCS score at the end of the study, and 5 out of 13 (39%) were judged to be treatment responders with the added criteria of achieving a final Y-BOCS score <16. While limited by the open-label design, the small number of subjects, and the lack of a control group, this preliminary study lends support to the hypothesis that glutamatergic dysfunction contributes to the pathophysiology of OCD and that glutamate-modulating agents may prove to be efficacious in treatment-resistant OCD. Additionally, the effectiveness of riluzole has been reported in other compulsive behaviors such as trichotillomania, skin picking, repetitive self-injurious behaviors, and disordered eating.^119-121 These findings are consistent with a growing body of clinical evidence suggesting the efficacy of riluzole therapy in several other neuropsychiatric disorders in which excessive glutamatergic activity has been implicated. Case reports and open-label studies suggest efficacy in the treatment of MDD,^122,123 bipolar depression,^124,125 anxiety,¹²⁶ and OCD.¹²⁰



These promising early results demonstrating anti-anxiety and antidepressant effects associated with riluzole encourages further trials with riluzole and other glutamate-modulating agents in OCD. The anticonvulsant lamotrigine is thought to act by inhibiting axonal voltage-gated sodium channels and thereby reducing the release of excitatory neurotransmitters, a mechanism that overlaps with that of riluzole. However, in a small case series of eight patients in which lamotrigine was added to SRI therapy in treatment-resistant patients, only one patient reported significant improvement, and symptom improvements as measured by the Y-BOCS were marginal.¹⁰⁰ It may be that lamotrigine does not adequately dampen glutamatergic outflow despite its theoretical effects on glutamate release.

The amino acid N-acetylcysteine (NAC) is widely used for its antioxidant properties and as a treatment for acetaminophen toxicity; however, recent preclinical studies suggest that NAC also modulates CNS glutamate. NAC is converted to cystine, a substrate for the glutamate/cystine antiporter located on glial cells. The uptake of cystine by glia causes glial release of glutamate into the extrasynaptic space, where it appears to stimulate inhibitory metabotropic glutamate receptors on glutamatergic nerve terminals and thereby reduces the synaptic release of glutamate.¹²⁷ Systemic administration of NAC has been shown to reverse the susceptibility to reinstitution of compulsive cocaine use in a rodent model by restoring re-establishing normal extracellular glutamate concentrations in the nucleus accumbens.¹²⁸

In addition to attenuating synaptic glutamate release, NAC may enhance clearance of glutamate by glial cells at the synapse. Elevated levels of glutamate deplete glutathione within glial cells, impair cystine transport, and thereby increase the vulnerability of glia to oxidative stress.¹²⁹ Preclinical studies demonstrate that NAC protects glial cells against glutamate toxicity, repletes levels of glutathione, and attenuates toxic levels of glutamate.^130-132

The authors of this article hypothesize that NAC, through its inhibition of presynaptic glutamate release and protection of glial function, may be beneficial in disorders of glutamatergic dysregulation. If effective in OCD or other disorders, NAC would be an attractive treatment option because of its benign safety profile and low cost. Therefore, a small number of OCD patients have been treated with NAC, and evidence for benefit in compulsive behaviors has been found in two preliminary case reports.^102,119 As noted above, NAC also reduces the tendency toward relapse in a rat model of cocaine abuse, suggesting that it may have more general efficacy against compulsive behaviors and maladaptive habits.¹²⁸ This agent merits further investigation.

It is important to note that not all agents that modulate glutamate show evidence of benefit in treatment-resistant OCD. The antiepileptic agent topiramate blocks postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptors, among other actions, and has been reported to induce obsessive-compulsive symptoms in a case report.¹¹² The authors of this article have found the NMDA-blocking agent memantine to be without effect on obsessive-compulsive symptoms in a small number of patients (C Pittenger, MD, and V Coric, MD unpublished observations, November 2004); however, other groups have reported beneficial effects with the use of memantine in OCD (M Jenike, MD, personal communication, July 2006).^104,105 Cannabinoids are reported by some patients to moderate obsessive symptoms and may reduce cortico-striatal glutamatergic tone through an indirect mechanism.¹³³ However, the authors of this study found the synthetic cannabinoid agent dronabinol presented tolerability problems in several patients and a quickly reversible exacerbation of OCD symptoms in another patient (V Coric, unpublished observations, June 2005).

 

Conclusion

Several converging lines of research, including well-replicated neuroimaging studies; MRS findings; a CSF study; open-label clinical studies showing the preliminary efficacy of glutamate-modulating agents in the treatment of OCD; and recent genetic analyses demonstrating an association between the transmission of OCD and the gene that encodes for the glutamate transporter EAAC1 suggest that glutamate plays an important role in the pathophysiology, and perhaps treatment, of OCD. Indeed, current pharmacologic treatments for OCD may work, in part, through indirect attenuation of glutamatergic activity. For example, SRI medications may increase activity of modulatory serotonergic afferents to glutamatergic corticostriatal projections. Additionally, augmentation with dopamine antagonists may alter the balance between the direct and indirect pathways through the basal ganglia, reducing glutamatergic outflow from the thalamus to the cortex.

The suggestion that glutamate dysregulation may contribute to the pathophysiology of OCD is relatively new, and many questions remain. The precise etiology and location of glutamate dysfunction in OCD remains unclear. Additionally, more rigorous clinical trials examining the efficacy and tolerability of glutamate-modulating agents are needed. A double-blind, placebo-controlled trial of riluzole in OCD is in progress; if the results of this more rigorous trial replicate the promising findings of the initial open-label trial, glutamate-modulating agents will be confirmed to be a promising novel avenue for the substantial fraction of OCD patients whose symptoms are resistant to currently available therapies.

Recent investigations suggest that OCD represents several overlapping symptom dimensions.⁶ It may be that patients with different categories of symptoms will preferentially respond to primary therapies that target different classes of molecular targets. If further research clarifies such correlations, pharmacologic treatment for many patients could be markedly improved. Finally, other agents with glutamate modulating properties may prove equally or more efficacious in the treatment of OCD. The choice of such agents will best be informed by increasing understanding of the specific way in which glutamate neurotransmission is perturbed in OCD. Agents with more specific effects on subtypes of glutamate receptors, such as NMDA-modulating agents and ampakines, may prove to be interesting potential treatment avenues for some neuropsychiatric disorders. However, excessive blockade of these postsynaptic receptors may precipitate new psychiatric symptoms (eg, NMDA blockade by phencyclidine-producing psychotomimetic effects; the recent observation by Pittenger and colleagues¹³⁴ of the combination of riluzole, memantine, and bupropion producing visual hallucinations in a susceptible patient).

Another exciting new treatment possibility is raised by a recent study revealing the unexpected finding that β-lactam antibiotics increase the expression of glutamate transporters on glia and have neuroprotective effects in a mouse model of ALS.¹⁰¹ Because of the extensive tolerability data on such compounds, they represent an exciting and unexpected group of potential antiglutamatergic agents for use in OCD and other neuropsychiatric disorders.

The authors if this article have reviewed the evidence that glutamate neurotransmission is dysregulated in OCD. While gaps in this evidence remain, there is significant data to suggest such a disruption; furthermore, initial clinical observations with riluzole and certain other glutamate-modulating agents suggest that pharmacologic strategies that target the glutamate system hold promise for the treatment of the refractory OCD and perhaps for other psychiatric disorders. Agents targeting glutamate neurotransmission represent a qualitatively new strategy for alleviating symptoms of OCD. Patients who are refractory to treatments based on monoaminergic systems may respond to treatments aimed at a different set of molecular targets. Pharmacologic strategies aimed at modulating glutamate neurotransmission are particularly exciting candidates for treatment-resistant OCD because they represent a new perspective on its pathophysiology, distinct from the focus on the monoaminergic modulatory systems that has characterized most pharmacologic treatment strategies for the past 2 decades. The evidence implicating glutamatergic neurotransmission in the pathophysiology of OCD and other psychiatric disorders is in its infancy. Further research is warranted to better understand the role of glutamate in the pathophysiology and treatment of neuropsychiatric disorders such as OCD. PP

 

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