Efficacy Study of add-on Therapy With N-Acetylcysteine in Resistant Obsessive-compulsive Disorder

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.