Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder

Yale University Department of Psychiatry, New Haven, Connecticut 06508, USA.
NeuroRx 02/2006; 3(1):69-81. DOI: 10.1016/j.nurx.2005.12.006
Source: PubMed

ABSTRACT Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that produces significant morbidity. The introduction of serotonin reuptake inhibitors in the 1980s represented an important advance in the treatment of OCD. However, few patients show complete remission of their symptoms, and some patients show minimal improvement with existing treatments. We review current treatment strategies and initial data supporting the efficacy of glutamate modulating agents as a novel class of pharmaceuticals for the treatment of OCD. Functional neuroimaging studies repeatedly reported metabolic hyperactivity in the cortico-striato-thalamo-cortical circuitry in patients with OCD. Recent magnetic resonance spectroscopy studies provide evidence of elevated glutamate levels in several brain regions in patients suffering from OCD. These findings raised the possibility that agents that reduce glutamate hyperactivity or its consequences in the CNS might be efficacious as novel therapeutic interventions. Indeed, initial evidence from our group suggests that the antiglutamatergic agent riluzole (Rilutek), which was developed for the treatment of amyotrophic lateral sclerosis, is effective in treatment-resistant OCD. Case reports suggest that other agents that modulate glutamatergic activity may likewise be effective. This new application of glutamate modulating agents holds promise for the treatment of this disabling and often inadequately treated disease.

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    • "When variance in symptom profile (symptom dimensions, cognitive functioning, and co-morbidity), neural profile (structure, function, and chemistry), eventually combined with the genetic profile, and treatment mechanisms for various forms of psychotherapeutic and pharmacological treatment is more clear, one might use the individual 'fingerprint' to determine the most effective treatment strategy. Although little is known about the mechanisms of treatment effects, one might hypothesize that the various forms of psychotherapy and pharmacotherapy have diverse effects on the various implicated neurotransmitter systems, involving serotonin (Linden, 2006), dopamine (Koo et al., 2010), and glutamate (Pittenger et al., 2006), and their reciprocal influences, which could affect neural circuits in terms of both function and structure. "
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    ABSTRACT: The symptoms of obsessive-compulsive disorder (OCD) include intrusive thoughts, compulsive behavior, anxiety, and cognitive inflexibility, which are associated with dysfunction in dorsal and ventral corticostriato-thalamocortical (CSTC) circuits. Psychotherapy involving exposure and response prevention has been established as an effective treatment for the affective symptoms, but the impact on the underlying neural circuits is not clear. This systematic review used the Medline, Embase, and PsychINFO databases to investigate how successful therapy may affect neural substrates of OCD. Sixteen studies measuring neural changes after therapy were included in the review. The studies indicate that dysfunctions in neural function and structure are partly reversible and state-dependent for affective symptoms, which may also apply to cognitive symptoms. This is supported by post-treatment decreases of symptoms and activity in the ventral circuits during symptom provocation, as well as mainly increased activity in dorsal circuits during cognitive processing. These effects appear to be common to both psychotherapy and medication approaches. Although neural findings were not consistent across all studies, these findings indicate that people with OCD may experience functional, symptomatic, and neural recovery after successful treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research: Neuroimaging 05/2015; DOI:10.1016/j.pscychresns.2015.05.004 · 2.42 Impact Factor
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    • "MPEPinanimalmodelsofdepression.Comparedtothetreatmentsuccessratesforanxietydisorders ,theauthorsreportedthat only62.5–75%foundaclearantidepressanteffect,eventhough treatmentwiththeionotropicNMDAantagonistketaminehas beenshowntoleadtorapidantidepressanteffects,evenin treatmentresistantpatients(Pittengeretal.,2006). "
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    ABSTRACT: In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches-from basic neurobiological approaches to human studies-might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC). Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays an important role in systems for social functioning and the response to social stress. Finally, mGluR5's important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoC's arousal and modulatory systems domain. Glutamate was previously mostly investigated in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems.
    Frontiers in Neuroscience 03/2015; 9:86. DOI:10.3389/fnins.2015.00086 · 3.66 Impact Factor
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    • "PD rat model , which action appeared to be mediated through reducing DAergic degeneration in the SNc and improving cognitive behavior ( Hsieh et al . , 2012a , 2012b ) . Methods for reducing glutamatergic hyperactivity have therefore been suggested as possible effective therapeutic interventions for neurodegeneration and cognitive deficits in PD ( Pittenger et al . , 2006 ) . The glutamate concentration in the synaptic cleft is tightly regulated by its release and its clearance ( Hediger and Welbourne , 1999 ; Kanai and Hediger , 2003 ; Lin et al . , 2012 ) . GLT - 1 , one of the major glutamate transporters , is expressed predominantly on astrocytes and is responsible for more than 90% of glutamate clea"
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    ABSTRACT: Glutamatergic hyperactivity plays an important role in the pathophysiology of Parkinson's disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and affords neuroprotection. This study was aimed at clarifying whether ceftriaxone prevented, or reversed, behavioral and neuronal deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were injected daily with either ceftriaxone starting 5 days before or 3 days after MPTP lesioning (day 0) or saline and underwent a bar-test on days 1-7, a T-maze test on days 9-11, and an object recognition test on days 12-14, then the brains were taken for histological evaluation on day 15. Dopaminergic degeneration in the substantia nigra pars compacta and striatum was observed on days 3 and 15. Motor dysfunction in the bar test was observed on day 1, but disappeared by day 7. In addition, lesioning resulted in deficits in working memory in the T-maze test and in object recognition in the object recognition task, but these were not observed in rats treated pre- or post-lesioning with ceftriaxone. Lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, and both changes were suppressed by ceftriaxone. Increased GLT-1 expression and its co-localization with astrocytes were observed in the striatum and hippocampus in the ceftriaxone-treated animals. To our knowledge, this is the first study showing a relationship between ceftriaxone-induced GLT-1 expression, neuroprotection, and improved cognition in a PD rat model. Ceftriaxone may have clinical potential for the prevention and treatment of dementia associated with PD. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Neuropharmacology 12/2014; 91. DOI:10.1016/j.neuropharm.2014.11.023 · 5.11 Impact Factor
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