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

https://doi.org/10.1016/j.pharmthera.2011.09.006Get rights and content

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.

Introduction

Obsessive–compulsive disorder (OCD) is a common, often debilitating neuropsychiatric disorder, with an estimated lifetime prevalence of 1.8–2.5% (Robins et al., 1984, Kessler et al., 2005, Ruscio et al., 2010). OCD is characterized by obsessions and compulsions; most patients experience both, though either alone can justify the diagnosis (American Psychiatric Association, 2000). Obsessions are frequent, intrusive, stereotyped thoughts. They are typically ego-dystonic in nature – that is, they are recognized as being foreign and unrealistic – and are associated with significant anxiety. Compulsions are repetitive, often ritualized behaviors, typically associated with specific obsessions and performed to alleviate this anxiety. The performance of compulsions can transiently improve obsessional anxiety, but they themselves then become a source of disability and distress. Affected individuals can spend hours a day in this cycle of obsession and compulsion, producing substantial morbidity (Koran et al., 1996, Jenike, 2004). In a recent epidemiological survey, 65% of patients reported that their symptoms produced significant role impairment (Ruscio et al., 2010). In severe cases, this level of distress contribute to a significant risk of suicidal behavior (Kamath et al., 2007); in profoundly treatment-refractory cases, patients and treaters increasingly turn to invasive treatment approaches such as ablative neurosurgery and deep brain stimulation (Greenberg et al., 2010).

Childhood-onset and adult-onset OCD may be distinct in important ways (Geller et al., 1998, Rosario-Campos et al., 2001). Early onset, before age 10, is more common among males (e.g. Ruscio et al., 2010), is more likely to be associated with tic disorders, and may be more heritable (Rosario-Campos et al., 2005). Adolescent onset is more typical in females (Ruscio et al., 2010). This difference in age of onset leads to a male preponderance among children and adolescents; among adults, the sex ratio is ~1:1 (Jenike, 2004). Onset after age 30 is uncommon (Jenike, 2004, Ruscio et al., 2010). The disorder is phenomenologically heterogeneous. OCD symptoms fall into recognizable symptom dimensions (Mataix-Cols et al., 2005, Bloch et al., 2008a, Katerberg et al., 2009, Pinto et al., 2009); it has been suggested that symptomatic subtypes may correspond to discrete patterns of abnormal brain activation (Mataix-Cols et al., 2004, van den Heuvel et al., 2009) and treatment response (e.g. Landeros-Weisenberger et al., 2010).

Numerous hypothesized contributors to the pathophysiology of OCD have been investigated, including genetic (Bloch & Pittenger, 2010), infectious and autoimmune (Swedo et al., 2010), endocrine (Leckman et al., 1994), post-partum (Uguz et al., 2007), and post-ischemic (Carmin et al., 2002). No consensus has emerged regarding its etiology, which is likely to be heterogeneous. Genetic studies have indicated a heritability of 26–61% (Bloch & Pittenger, 2010).

There is, on the other hand, broad consensus that OCD is characterized by abnormalities of a particular brain network, the cortico-striato-thalamo-cortical (CSTC) circuitry (Fig. 1). Functional imaging studies have revealed relative metabolic hyperactivity in the striatum (caudate and putamen), anterior thalamus, anterior cingulate cortex, and orbitofrontal cortex in patients with OCD (Maia et al., 2008, Menzies et al., 2008); tellingly, in some studies this hyperactivity has been found to correlate with symptom severity and to resolve with symptomatic improvement upon treatment (e.g. Hansen et al., 2002). Morphometric studies have found abnormalities in the same group of brain regions (Menzies et al., 2008, Radua and Mataix-Cols, 2009); increased gray matter volume of the caudate nucleus may be particularly specific for OCD, as opposed to anxiety disorders more generally (Radua et al., 2009). Although it is likely that abnormalities in brain structure and activation exist outside this canonical circuit (see for example Menzies et al., 2008), these functional and morphological data have focused attention on the CSTC circuitry as we strive to understand the neuropathophysiology of OCD and to develop novel treatment strategies. For example, invasive treatment strategies for refractory disease, such as DBS, typically target this circuitry (Greenberg et al., 2010).

Pharmacological treatment of OCD is targeted primarily at monoaminergic neurotransmission, particularly at the serotonin and dopamine systems. The specific serotonin reuptake inhibitors (SSRIs) are the mainstay of pharmacotherapy and are of benefit in 50–60% of patients (Koran et al., 2007, Soomro et al., 2008). For reasons that remain unclear, high doses of these medications – in excess of the typical antidepressant dose range – are more efficacious and are often required (Bloch et al., 2010). The older tricyclic antidepressant clomipramine, which has greater serotonin reuptake specificity than other tricyclics, is commonly prescribed and maybe slightly more effective, though its higher side effect burden can limit its use (Koran et al., 2007). In disease refractory to these agents, pharmacological augmentation with neuroleptic drugs, which antagonize the D2 dopamine receptor, can be efficacious (Bloch et al., 2006).

Neurobiological and genetic studies have similarly focused attention on these modulatory systems, and particularly on serotonin, as important in the pathophysiology of OCD and in its treatment. Linkage of OCD risk with polymorphisms in the serotonin transporter has been reported, though the finding has not been consistently replicated (Bloch et al., 2008b). Increased serotonin in peripheral blood has been reported in OCD (Yaryura-Tobias et al., 1979, Delorme et al., 2005). A few studies have implicated specific serotonin receptor subtypes in OCD. Agonists of the serotonin 1B and 1D receptors have been found to exacerbate OCD symptoms (Koran et al., 2001, Gross-Isseroff et al., 2004, Zohar et al., 2004). PET studies suggest a reduction in the 5-HT2A receptor in the cortex in drug-naïve patients (Perani et al., 2008). A smaller number of studies suggest abnormalities in dopamine neurotransmission in OCD; for example, a recent PET study found a reduction in the dopamine D2 receptor (Perani et al., 2008).

However, therapies aimed at modulating serotonin and dopamine prove inadequate in many cases of OCD; ~25% of patients get little benefit from available treatment strategies, and many of those who are classified as ‘responders’ continue to have significant symptoms and markedly reduced quality of life (Koran et al., 1996, Jenike, 2004, Bloch et al., 2006). It is therefore of critical importance that new insights into the neurochemical, anatomical, and functional abnormalities that contribute to OCD be developed, and that therapeutic strategies based on such insights be developed for the benefit of patients refractory to existing treatments.

We (Pittenger et al., 2006) and others (Carlsson, 2000, Carlsson, 2001, Rosenberg and Hanna, 2000, Rosenberg et al., 2000, Chakrabarty et al., 2005, Ting and Feng, 2008) have proposed that abnormalities in glutamate neurotransmission and homeostasis, especially in the CSTC circuitry, may contribute to OCD. Convergent evidence gives increasing support to this proposal. As a result, there is increasing interest in the use of glutamate-modulating agents in refractory OCD. Indeed, while no agent is yet supported by a definitive, placebo-controlled study, increasing evidence supports the potential utility of riluzole, memantine, N-acetylcysteine, d-cycloserine, and other glutamate-modulating agents in the treatment of this disorder. In this review, we summarize current evidence supporting the existence of glutamate abnormalities in OCD, and we assess the potential utility of these glutamate-modulating pharmacological strategies in the treatment of refractory disease.

Section snippets

Glutamate in the central nervous system

Glutamate is the principal excitatory neurotransmitter in the adult brain. It is present in the central nervous system and in cerebrospinal fluid (CSF) at high concentrations, 8–10 mmol/kg or even higher (Snyder and Ferris, 2000, Danbolt, 2001, Sanacora et al., 2004a). Glutamatergic projections participate in virtually all circuits in the adult central nervous system, including intracortical connections, cortical-subcortical connections, and subcortical systems such as the basal ganglia,

Genetic studies

Several glutamate-related genes have been associated with OCD risk. While genetic studies were not the first to implicate glutamate neurotransmission and homeostasis in the pathophysiology of OCD, they provide the strongest evidence for a causally important role for such perturbations. Other observed abnormalities in glutamate – reviewed below – could be either consequences or causes of the pathological change associated with OCD. Definitive association of genes implicated in glutamatergic

Neurochemical studies

As described above, morphological and functional imaging studies have identified abnormalities in the CSTC circuitry in patients with OCD (Maia et al., 2008, Menzies et al., 2008, Rotge et al., 2010). Over the past 10 years, several studies have used magnetic resonance spectroscopy (MRS) to investigate levels of glutamate and related molecules in this circuitry, and have produced some evidence of glutamate dysregulation in patients with OCD.

The CSTC circuitry uses both glutamate and GABA as its

Assessing animal models

Modeling OCD in experimental animals poses particular challenges. Some of these challenges are inherent to the modeling of psychiatric disease in general (Nestler & Hyman, 2010), but they are acute in the case of OCD.

Animal models of disease are commonly assessed on the basis of three criteria. Face validity describes the extent to which a model recapitulates the symptomatology of a pathological condition. This is a challenge in any psychiatric condition, given the inherently subjective nature

Clinical studies

The various lines of evidence summarized above have motivated substantial interest in the use of glutamate-modulating agents in the treatment of OCD, especially in disease that proves refractory to standard pharmacotherapy and psychotherapy. Fortunately, a number of glutamate-modulating agents have been developed in recent decades for other indications and are available for investigational and off-label use in this context. This has permitted a number of small clinical investigations in

Synthesis and outstanding questions

The case for dysregulation of glutamate neurotransmission and/or homeostasis in obsessive–compulsive disorder remains inconclusive; but convergent data from the many approaches summarized above are making it progressively stronger. Much remains to be established. We conclude our review by summarizing major outstanding conceptual and technical issues, to put this growing literature into context.

Conclusion

The suggestion that glutamate dysregulation may contribute to OCD has now been with us for more than a decade (Moore et al., 1998, Carlsson, 2000). Definitive evidence supporting (or contradicting) it has been slow to emerge. However, convergent evidence is increasingly supportive of the idea, and early clinical studies suggesting the possible efficacy of glutamate-modulating medications are tantalizing. The precise nature of the dysregulation, however, remains quite unclear. Further work in

Conflict of interest statement

The authors are aware of no real or apparent conflict of interest that might influence the content of this review. C. Pittenger is a consultant to F. Hoffman-La Roche and has received research support from Pfizer Pharmaceuticals. M. H. Bloch and K. Williams have no financial relationships to disclose.

References (223)

  • A.L. Brody et al.

    FDG-PET predictors of response to behavioral therapy and pharmacotherapy in obsessive compulsive disorder

    Psychiatry Res

    (1998)
  • M.L. Carlsson

    On the role of prefrontal cortex glutamate for the antithetical phenomenology of obsessive compulsive disorder and attention deficit hyperactivity disorder

    Prog Neuropsychopharmacol Biol Psychiatry

    (2001)
  • V. Coric et al.

    Riluzole augmentation in treatment-resistant obsessive–compulsive disorder: an open-label trial

    Biol Psychiatry

    (2005)
  • N.C. Danbolt

    Glutamate uptake

    Prog Neurobiol

    (2001)
  • D. Ebert et al.

    1H-magnetic resonance spectroscopy in obsessive–compulsive disorder: evidence for neuronal loss in the cingulate gyrus and the right striatum

    Psychiatry Res

    (1997)
  • N. Egashira et al.

    Effects of glutamate-related drugs on marble-burying behavior in mice: implications for obsessive–compulsive disorder

    Eur J Pharmacol

    (2008)
  • D. Eilam et al.

    Rituals, stereotypy and compulsive behavior in animals and humans

    Neurosci Biobehav Rev

    (2006)
  • C.N. Epperson et al.

    Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy

    Biol Psychiatry

    (2005)
  • E. Fumagalli et al.

    Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1

    Eur J Pharmacol

    (2008)
  • K.A. Ganasen et al.

    Augmentation of cognitive behavioral therapy with pharmacotherapy

    Psychiatr Clin North Am

    (2010)
  • D. Geller et al.

    Is juvenile obsessive–compulsive disorder a developmental subtype of the disorder? A review of the pediatric literature

    J Am Acad Child Adolesc Psychiatry

    (1998)
  • D.C. Goff et al.

    Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study

    Schizophr Res

    (2008)
  • J.E. Grant et al.

    N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study

    Biol Psychiatry

    (2007)
  • W.M. Greenberg et al.

    Adjunctive glycine in the treatment of obsessive–compulsive disorder in adults

    J Psychiatr Res

    (2009)
  • J.M. Greer et al.

    Hoxb8 is required for normal grooming behavior in mice

    Neuron

    (2002)
  • D.E. Jane et al.

    Kainate receptors: pharmacology, function and therapeutic potential

    Neuropharmacology

    (2009)
  • L.M. Koran et al.

    Sumatriptan, 5-HT(1D) receptors and obsessive–compulsive disorder

    Eur Neuropsychopharmacol

    (2001)
  • M.G. Kushner et al.

    D-cycloserine augmented exposure therapy for obsessive–compulsive disorder

    Biol Psychiatry

    (2007)
  • A. Landeros-Weisenberger et al.

    Dimensional predictors of response to SRI pharmacotherapy in obsessive–compulsive disorder

    J Affect Disord

    (2010)
  • J.F. Abelson et al.

    Sequence variants in SLITRK1 are associated with Tourette's syndrome

    Science

    (2005)
  • E. Aboujaoude et al.

    Memantine augmentation in treatment-resistant obsessive–compulsive disorder: an open-label trial

    J Clin Psychopharmacol

    (2009)
  • N. Albelda et al.

    The role of NMDA receptors in the signal attenuation rat model of obsessive–compulsive disorder

    Psychopharmacology (Berl)

    (2010)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders

    (2000)
  • G.M. Anderson et al.

    Postmortem analysis of subcortical monoamines and amino acids in Tourette syndrome

    Adv Neurol

    (1992)
  • K. Aoyama et al.

    Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse

    Nat Neurosci

    (2006)
  • P.D. Arnold et al.

    Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive–compulsive disorder: a preliminary study

    Psychopharmacology (Berl)

    (2004)
  • P.D. Arnold et al.

    Glutamate transporter gene SLC1A1 associated with obsessive–compulsive disorder

    Arch Gen Psychiatry

    (2006)
  • M. Atmaca et al.

    Neurochemistry of the hippocampus in patients with obsessive–compulsive disorder

    Psychiatry Clin Neurosci

    (2009)
  • M. Banasr et al.

    Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole

    Mol Psychiatry

    (2010)
  • R. Bartha et al.

    A short echo 1H spectroscopy and volumetric MRI study of the corpus striatum in patients with obsessive–compulsive disorder and comparison subjects

    Am J Psychiatry

    (1998)
  • D.E. Bergles et al.

    Glial contribution to glutamate uptake at Schaffer collateral–commissural synapses in the hippocampus

    J Neurosci

    (1998)
  • H.A. Berlin et al.

    Double-blind, placebo-controlled trial of topiramate augmentation in treatment-resistant obsessive–compulsive disorder

    J Clin Psychiatry

    (2011)
  • S. Bhattacharyya et al.

    Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive–compulsive disorder

    Neuropsychopharmacology

    (2009)
  • O.J. Bienvenu et al.

    Sapap3 and pathological grooming in humans: results from the OCD collaborative genetics study

    Am J Med Genet B Neuropsychiatr Genet

    (2009)
  • M.H. Bloch et al.

    Predictors of early adult outcomes in pediatric-onset obsessive–compulsive disorder

    Pediatrics

    (2009)
  • M.H. Bloch et al.

    A systematic review: antipsychotic augmentation with treatment refractory obsessive–compulsive disorder

    Mol Psychiatry

    (2006)
  • M.H. Bloch et al.

    Meta-analysis of the symptom structure of obsessive–compulsive disorder

    Am J Psychiatry

    (2008)
  • M.H. Bloch et al.

    Association of the serotonin transporter polymorphism and obsessive–compulsive disorder: systematic review

    Am J Med Genet B Neuropsychiatr Genet

    (2008)
  • M.H. Bloch et al.

    Meta-analysis of the dose–response relationship of SSRI in obsessive–compulsive disorder

    Mol Psychiatry

    (2010)
  • M.H. Bloch et al.

    The genetics of obsessive–compulsive disorder

    Curr Psychiatry Rev

    (2010)
  • Cited by (271)

    View all citing articles on Scopus
    View full text