Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette’s syndrome and obsessive–compulsive disorder

McGrath, Michael J.; Campbell, Keith M.; Parks, Clinton R.; Burton, Frank H.

doi:10.1016/s0006-8993(00)02646-9

Cited by 93 publications

(64 citation statements)

References 26 publications

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“…McGrath et al (2000) have shown that MK-801, a noncompetitive NMDA receptor antagonist that indirectly stimulates cortical-limbic glutamate output, aggravated a transgenedependent abnormal behavior (repetitive climbing and leaping) in a transgenic mouse model of comorbid Tourette's syndrome and OCD, at doses insufficient to induce stereotypies, and more readily induced stereotypies and limbic seizure behaviours at higher doses.…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic Dysfunction in OCD

Chakrabarty

Bhattacharyya

Christopher

et al. 2005

Neuropsychopharmacol

301

191

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The role of glutamatergic dysfunction in the pathophysiology of OCD has hardly been explored despite recent reports implicating glutamatergic dysfunction in OCD. We decided to investigate CSF glutamate levels in adult OCD probands compared to psychiatrically normal controls. In total, 21 consenting psychotropic drug-naïve adult OCD patients, diagnosed using SCID-IV-CV, and 18 consenting psychiatrically normal controls with age within 10 years of age of the patients, who did not have any history of head injury or neurological illness, were included into the study. Aseptically collected and stored CSF samples obtained from the patients and control subjects were used for glutamate estimation, which was carried out by a modification of the procedure described by Lund (1986). CSF glutamate (mmol/l) level was found to be significantly higher [F(1,31) ¼ 6.846, p ¼ 0.014] in OCD patients (47.1274.25) compared to control subjects (41.3673.63) on analysis of covariance. There was no effect of gender, age, duration of illness, Y-BOCS score, or CGI-S score on CSF glutamate levels. Our study provides preliminary evidence implicating glutamatergic excess in the pathophysiology of OCD, which needs to be further explored by studies from other centers involving larger sample sets from different age groups.

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Section: Discussionmentioning

confidence: 99%

Glutamatergic Dysfunction in OCD

Chakrabarty

Bhattacharyya

Christopher

et al. 2005

Neuropsychopharmacol

301

191

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“…34 Mathias et al 35 found that 37.5% of patients with early-onset OCD (onset < 11 years) had comorbid tic disorders, and the prevalence of tics in both earlyand late-onset OCD was 29%. Jaisoorya et al 36 found a male preponderance in patients with TS+OCD.…”

Section: Ocd and Other Anxiety Disordersmentioning

confidence: 99%

“…25,34 Some hormones seem to play a role in the cooccurrence of TS+OCD. The onset and recurrence of TS have been associated with significant emotional contexts.…”

Section: Ocd and Other Anxiety Disordersmentioning

confidence: 99%

Tourette's syndrome and associated disorders: a systematic review

Ferreira

Pio-Abreu

Januário

2014

Trends Psychiatry Psychother.

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Objective: To compile data on Tourette's syndrome (TS), tics and associated disorders. Methods: A systematic review of the literature was conducted using the 5S levels of organization of healthcare research evidence (systems, summaries, synopses, syntheses, studies), based on the model described by Haynes. The search keywords were Tourette, tics and comorbidity, which were cross-referenced. Studies provided by publishers and articles being processed on July 31, 2013, were also included. Results: Of all studies retrieved during the search, 64 were selected because they analyzed the epidemiology, clinical features and etiopathogenesis of TS and its comorbidities. TS is classified as a hyperkinetic movement disorder, and at least 90% of the patients have neuropsychiatric comorbidities, of which attention deficit hyperactivity and obsessive-compulsive disorders are the most common. The syndrome is clinically heterogeneous and has been associated with a dysfunction of cortico-striatal-thalamic-cortical circuits involving various neurotransmitters. Although its genetic etiology has been widely studied, other factors may be important to understand this syndrome and its associated disorders. Conclusions: TS is a neurodevelopmental disorder that results from the impact of stress factors on a vulnerable biological substrate during the critical periods of neurodevelopment. The study of TS and its comorbidities may contribute, at different levels, to the understanding of several neuropsychiatric disorders of clinical and therapeutic relevance. Keywords: Attention deficit disorder with hyperactivity, comorbidity, obsessive-compulsive disorder, tics, Tourette's syndrome. ResumoObjetivo: Compilar o conhecimento existente sobre a síndrome de Tourette (ST), tiques e patologias associadas. Metodologia: Foi realizada uma revisão sistemática da literatura usando os níveis 5S (sistemas, sumários, sinopses, sínteses e estudos) de organização de evidência de pesquisa em saúde, com base no modelo proposto por Haynes. Os termos de busca foram Tourette, tiques e comorbidades, completados por pesquisa por referência cruzada. Os artigos fornecidos pelos editores e aqueles a serem processados para publicação em 31 de julho de 2013 também foram incluídos. Resultados: De todos os artigos encontrados durante a pesquisa, 64 foram selecionados porque analisavam a epidemiologia, as características clínicas e a etiopatogenia da ST. A ST define-se como um distúrbio hipercinético do movimento, e pelo menos 90% dos pacientes apresentam comorbidades neuropsiquiátricas, das quais as mais comuns são a perturbação de déficit de atenção com hiperatividade e a perturbação obsessivo--compulsiva. Esta síndrome é clinicamente heterogênea e tem sido relacionada com a disfunção dos circuitos córtico-estriado--tálamo-corticais envolvendo vários neurotransmissores. Apesar de sua etiologia genética ter sido amplamente estudada, outros fatores podem ser importantes para entender esta síndrome e as perturbações relacionadas. Conclusões: A ST resulta de uma p...

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“…78,79 MK-801, a noncompetitive use-dependent antagonist of the NMDA glutamate receptor that may indirectly increase presynaptic glutamate release, 80 has been shown to worsen these perseverative behaviors, and to induce an additional category of "limbic seizure-like" stereotypies. 81 Interestingly, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of AMPA-type glutamate receptors, does not affect baseline OCD-like behaviors in these mice or their exacerbation by MK-801, but does reduce the "seizure-like" stereotypies. Although numerous caveats must attend any interpretation of results from a limited animal model of OCD, the exacerbation of OCD-like behaviors by glutamatergic agents in this study supports an important role for increased glutamatergic tone in the pathogenesis of obsessive-compulsive disorder, and possibly in its treatment.…”

Section: Preclinical Evidence Suggesting Increased Glutamate Activitymentioning

confidence: 99%

“…The lack of efficacy of agents that block postsynaptic AMPA and NMDA receptors is consistent with mouse model data, in which neither NMDA antagonists nor AMPA antagonists alleviated OCD-like symptoms in transgenic mice (as discussed above). 81 Cannabinoids are reported by some patients to moderate obsessive symptoms and may reduce cortico-striatal glutamatergic tone through an indirect mechanism. 126 However, we found the synthetic cannabinoid agent dronabinol to be without effect in a patient with treatment-resistant OCD.…”

Section: 111mentioning

confidence: 99%

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

Pittenger

Krystal

Coric

2006

NeuroRX

188

128

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Summary: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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Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette’s syndrome and obsessive–compulsive disorder

Cited by 93 publications

References 26 publications

Glutamatergic Dysfunction in OCD

Glutamatergic Dysfunction in OCD

Tourette's syndrome and associated disorders: a systematic review

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

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