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

Serotonin Reuptake Inhibitor Augmentation With N-Acetylcysteine in Resistant Obsessive-compulsive Disorder: a Double-blind, Randomized and Controlled Study

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).

Study Overview

• Status: Completed
• Conditions: Obsessive-Compulsive Disorder
• Intervention / Treatment: Drug: N-Acetylcysteine (NAC); Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • SP
    • São Paulo, SP, Brazil, 01060-970
      • Instituto de Psiquiatria do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Voluntary signed informed consent prior to the performance of any study specific procedures

2. A DSM-IV primary diagnosis of OCD that has failed to clinically respond, as defined by a Y-BOCS score of greater than 16, to at least one first-line adequate treatments, like:

   • SRI
   • CBT
   • SRI + CBT
   • SRI + atypical antipsychotic
3. OCD symptoms at least of one year's duration and of least moderate severity on the Clinical Global Impression Scale (CGI).

Exclusion Criteria:

1. Psychiatric diagnosis of a primary psychotic disorder
2. Hepatitis or any liver disease
3. Patients who have had psychosurgery
4. Recent (<1 month) change in psychotropic medications
5. Presence of clinically significant somatic disease and/or medical problem that requires frequent changes in medication.
6. History of or current diagnosis of seizure disorder
7. Evidence of Substance Use Disorder (DSM-IV) within past 1 months or current illicit drug use.
8. Active Suicidal Ideation
9. Patients who have been previously exposed to N-acetylcysteine.
10. Women who are pregnant, lactating, or of childbearing potential (not sterile nor using reliable birth control).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NAC; Patients allocated in this group will receive N-acetylcysteine 1200 mg (one 600 mg capsule twice a day) during the first week of the study. On day 8 this will increase to 4 capsules per day (2400 mg NAC; 2 capsules twice a day). Finally, on day 15 (after 1 week at 2400 mg) the dose will be increased to the target dose of 5 capsules per day (3000 mg; 2 capsules in the morning and 3 in the evening), at which dose it will be continued for the remainder of the study.	Drug: N-Acetylcysteine (NAC); 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)
Placebo Comparator: Placebo; Patients allocated in this group will receive one capsule of placebo twice a day during the first week of the study. On day 8 this will increase to 4 capsules per day (2 capsules twice a day). Finally, on day 15 the dose will be increased to the target dose of 5 capsules per day (2 capsules in the morning and 3 in the evening), at which dose it will be continued for the remainder of the study.	Drug: Placebo; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Yale-Brown Obsessive-Compulsive Scale total score	Percent reduction of baseline Y-BOCS total score at weeks 16 or at withdrawal from the study	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dimensional Yale-Brown Obsessive-Compulsive Scale score	The mean change in DYBOCS scores at week 16 or at withdrawal from the study	16 weeks
Clinical Global Impression Scale	Global Improvement score of the Clinical Global Impression Scale measured at week 16 or at withdrawal from the study	16 weeks
Beck Depression Inventory	The mean change in Beck Depression Inventory scores measured at week 16 or at withdrawal from the study	16 weeks
Beck Anxiety Inventory	The mean change in Beck Anxiety Inventory scores measured at week 16 or at withdrawal from the study	16 weeks

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Investigators: Principal Investigator: Daniel Costa, MD, University of Sao Paulo; Study Chair: Roseli Shavitt, PhD, University of Sao Paulo

Publications and helpful links

General Publications

• Costa DLC, Diniz JB, Requena G, Joaquim MA, Pittenger C, Bloch MH, Miguel EC, Shavitt RG. Randomized, Double-Blind, Placebo-Controlled Trial of N-Acetylcysteine Augmentation for Treatment-Resistant Obsessive-Compulsive Disorder. J Clin Psychiatry. 2017 Jul;78(7):e766-e773. doi: 10.4088/JCP.16m11101.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: March 14, 2012
• First Submitted That Met QC Criteria: March 14, 2012
• First Posted (Estimate): March 16, 2012

Study Record Updates

• Last Update Posted (Estimate): October 24, 2014
• Last Update Submitted That Met QC Criteria: October 23, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: Treatment; Glutamate; N-Acetylcysteine; Obsessive-compulsive disorder
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Personality Disorders; Anxiety Disorders; Disease; Compulsive Personality Disorder; Obsessive-Compulsive Disorder; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: NACTOC