Efficacy Study of add-on Therapy With N-Acetylcysteine in Resistant Obsessive-compulsive Disorder
Condition: Obsessive-Compulsive Disorder
MeSH terms: Compulsive Personality Disorder; Obsessive-Compulsive Disorder
Study type: Interventional
Phase: Phase 2

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) and/or repetitive, stereotyped
      behaviors (compulsions) that last for at least one hour per day and significantly interfere
      with an individual's 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 SRI's 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.
    

Intervention name(s): N-Acetylcysteine (NAC); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Week 1: 1200 mg (one 600 mg capsule twice a day) Week 2: 2400 mg (two 600 mg capsules twice a day) Weeks 3-16: 3000 mg (two 600 mg capsules in the morning and 3 in the evening); Week 1: one capsule twice a day Week 2: two capsules twice a day Weeks 3-16: two capsules in the morning and 3 in the evening
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Obsessive-compulsive disorder; Treatment; Glutamate; N-Acetylcysteine