Ignite Creation Date:
2024-05-06 @ 12:22 AM
Last Modification Date:
2024-10-26 @ 10:48 AM
Study NCT ID:
NCT01555970
Status:
COMPLETED
Last Update Posted:
2014-10-24
First Post:
2012-03-14
Brief Title:
Efficacy Study of add-on Therapy With N-Acetylcysteine in Resistant Obsessive-compulsive Disorder
Sponsor:
University of Sao Paulo
Organization:
University of Sao Paulo
Study Overview
Official Title:
Serotonin Reuptake Inhibitor Augmentation With N-Acetylcysteine in Resistant Obsessive-compulsive Disorder a Double-blind Randomized and Controlled Study
Status:
COMPLETED
Status Verified Date:
2014-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
NACTOC
Brief Summary:
The primary objective of this study is to determine if N-Acetylcysteine NAC has efficacy as an augmentation agent in the treatment of treatment-resistant obsessive-compulsive disorder OCD The investigators predict that NAC will reduce OCD symptoms after sixteen weeks of add-on treatment as measured by the Yale-Brown Obsessive-Compulsive Scale Y-BOCS
Detailed Description:
OCD is a debilitating psychiatric condition with a lifetime prevalence of 2-3 It is characterized by recurrent intrusive thoughts obsessions andor repetitive stereotyped behaviors compulsions that last for at least one hour per day and significantly interfere with an individuals normal level of functioning Although cognitive behavioral therapy and pharmacotherapy with serotonin reuptake inhibitors SRI are effective treatments for many patients a subset experience minimal relief from their symptoms with these standard treatments When severe OCD is completely incapacitating with devastating consequences for patients and their families Augmentation strategies with antipsychotic medications can improve the effectiveness of SRI therapy but do no eliminate OCD symptoms Saxena et al 1996 McDougle et al 1995 and are associated with adverse effects when used chronically consequently improved pharmacological treatments are needed The clinical observation that few patients experience a complete response to SRIs or dopamine antagonists suggests that other neurochemical systems are involved in the pathophysiology of OCD
The pathophysiologic hypothesis underlying this proposal is that the well-described hyperactivity of the cortico-striato-thalamic track in OCD reflects glutamatergic hyperactivity that is addressed only partially in some OCD patients by serotonin reuptake inhibitors treatment It is thought that NAC modulates brain glutamate by stimulating the cysteine-glutamate antiporter located on glia increasing extrasynaptic glutamate levels and thereby stimulating the feedback inhibition of synaptic glutamate release Baker et al 2003 In addition to attenuating synaptic glutamate release by feedback inhibition NAC is also thought to enhance the clearance of glutamate from the synapse via its neuroprotective and growth factor promoting effects on glial cells Its glutamatergic antagonistic properties may be effective in reducing the glutamatergic hyperactivity that is thought to contribute to the pathophysiology of OCD
The proposed study is based on recent preclinical and neuroimaging studies that implicate glutamatergic hyperactivity in the pathogenesis of OCD Carlsson et al 2000 Neuroimaging studies have consistently identified increased blood flow metabolism and brain activity in the orbitofrontal cortex striatum and thalamus of individuals with OCD Baxter et al 1987 1988 1992 Swedo et al 1989 Sawle et al 1991 Rubin et al 1992 1995 Adams et al 1993 Perani et al 1995 McGuire et al 1994 Breiter et al 1996 Rausch et al 1996 Within these brain areas glutamate and GABA driven pathways are thought to be responsible for balancing neural tone The direct glutamatergic pathway is thought to modulate the initiation and sustainability of behavioral routines while the indirect GABAergic pathway modulates the cessation of these behaviors The leading explanatory model for OCD suggests that over 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 Baxter 1992 Baxter et al 1996 Clinical studies support this model Compared to controls treatment naïve OCD patients have significantly increased glutamatergic activity as measured by proton magnetic resonance spectroscopy 1H-MRS Rosenberg et al 2000 Bolton et al 2001 Moreover treatment with an SRI was associated with a significant decline in caudate glutamate concentration in those individuals who responded to SRI treatment Rosenberg et al 2000 Bolton et al 2001 These clinical findings are consistent with pharmacological studies demonstrating an SRI-induced inhibition of glutamate release Maura et al 1988 Zhang et al 1997
The investigators propose a double-blind placebo controlled study to evaluate the tolerability and efficacy of N-Acetylcysteine in the augmentation of SRI therapy in resistant OCD Four recent reports suggest that riluzole an antiglutamatergic agent possesses anti-depressant anti-obsessional and anti-anxiety properties Coric et al 2003 2005 Zarate et al 2004 Sanacora et al 2004
The rationale for exploring the efficacy of NAC in treatment resistant OCD stems from preliminary findings from the open label Riluzole study and represents an effort to explore other novel strategies for modulating brain glutamate in OCD
The pathophysiologic hypothesis underlying this proposal is that the well-described hyperactivity of the cortico-striato-thalamic track in OCD reflects glutamatergic hyperactivity that is addressed only partially in some OCD patients by serotonin reuptake inhibitors treatment It is thought that NAC modulates brain glutamate by stimulating the cysteine-glutamate antiporter located on glia increasing extrasynaptic glutamate levels and thereby stimulating the feedback inhibition of synaptic glutamate release Baker et al 2003 In addition to attenuating synaptic glutamate release by feedback inhibition NAC is also thought to enhance the clearance of glutamate from the synapse via its neuroprotective and growth factor promoting effects on glial cells Its glutamatergic antagonistic properties may be effective in reducing the glutamatergic hyperactivity that is thought to contribute to the pathophysiology of OCD
The proposed study is based on recent preclinical and neuroimaging studies that implicate glutamatergic hyperactivity in the pathogenesis of OCD Carlsson et al 2000 Neuroimaging studies have consistently identified increased blood flow metabolism and brain activity in the orbitofrontal cortex striatum and thalamus of individuals with OCD Baxter et al 1987 1988 1992 Swedo et al 1989 Sawle et al 1991 Rubin et al 1992 1995 Adams et al 1993 Perani et al 1995 McGuire et al 1994 Breiter et al 1996 Rausch et al 1996 Within these brain areas glutamate and GABA driven pathways are thought to be responsible for balancing neural tone The direct glutamatergic pathway is thought to modulate the initiation and sustainability of behavioral routines while the indirect GABAergic pathway modulates the cessation of these behaviors The leading explanatory model for OCD suggests that over 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 Baxter 1992 Baxter et al 1996 Clinical studies support this model Compared to controls treatment naïve OCD patients have significantly increased glutamatergic activity as measured by proton magnetic resonance spectroscopy 1H-MRS Rosenberg et al 2000 Bolton et al 2001 Moreover treatment with an SRI was associated with a significant decline in caudate glutamate concentration in those individuals who responded to SRI treatment Rosenberg et al 2000 Bolton et al 2001 These clinical findings are consistent with pharmacological studies demonstrating an SRI-induced inhibition of glutamate release Maura et al 1988 Zhang et al 1997
The investigators propose a double-blind placebo controlled study to evaluate the tolerability and efficacy of N-Acetylcysteine in the augmentation of SRI therapy in resistant OCD Four recent reports suggest that riluzole an antiglutamatergic agent possesses anti-depressant anti-obsessional and anti-anxiety properties Coric et al 2003 2005 Zarate et al 2004 Sanacora et al 2004
The rationale for exploring the efficacy of NAC in treatment resistant OCD stems from preliminary findings from the open label Riluzole study and represents an effort to explore other novel strategies for modulating brain glutamate in OCD
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None