BRIEF REPORT Riluzole Augmentation in Treatment-Resistant Obsessive–Compulsive Disorder: An Open-Label Trial Vladimir Coric, Sarper Taskiran, Christopher Pittenger, Suzanne Wasylink, Daniel H. Mathalon, Gerald Valentine, John Saksa, Yu-te Wu, Ralitza Gueorguieva, Gerard Sanacora, Robert T. Malison, and John H. Krystal Background: Most patients with obsessive– compulsive disorder (OCD) show only partial reduction of symptoms with standard therapy. Recent imaging data suggests glutamatergic dysfunction in the corticostriatal pathway in OCD. We investigated the efficacy of augmentation therapy with riluzole, a glutamate-modulating agent, in treatment-resistant OCD. Methods: Thirteen patients aged between 18 and 65 years with a primary diagnosis of OCD that had proven resistant to standard treatment were treated with the addition of riluzole to their existing pharmacotherapy. Yale–Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Depression Inventory (HAM-D), and Hamilton Anxiety Inventory (HAM-A) scores were obtained weekly. Results: Thirteen treatment-resistant OCD patients received riluzole 50 mg twice a day. Y-BOCS scores improved significantly over time. Of 13 patients, 7 (54%) demonstrated a 35% reduction in Y-BOCS scores, and 5 (39%) were categorized as treatment responders. HAM-D and HAM-A scores for the group also significantly improved over time. Riluzole was well tolerated with no serious adverse effects noted. Conclusions: Riluzole appears to have significant antiobsessional, antidepressant, and antianxiety properties. The addition of this agent may be of practical clinical benefit in patients with OCD. Key Words: Anxiety disorders, glutamate, obsessive– compulsive disorder, major depressive disorder, riluzole A lthough serotonin reuptake inhibitors (SRIs), cognitive– behavioral therapy (CBT), and augmentation with dopa- mine antagonists have proven efficacy in the treatment of obsessive– compulsive disorder (OCD), treatment-resistant OCD remains a common and debilitating problem. Current clinical interventions significantly reduce symptoms in approximately 40%– 60% of patients with OCD; however, a substantial number of patients remain dramatically symptomatic even with the combination of pharmacotherapy and CBT (Jenike 2004). More- over, a therapeutic response in most treatment trials is defined as symptom reduction by 20%– 40% with many treatment respond- ers remaining markedly symptomatic (Jenike 2004). Treatment- resistant OCD is one of the few psychiatric indications for neurosurgical intervention. Novel therapeutic strategies are ur- gently needed. This pilot study is based on preclinical and neuroimaging studies that implicate glutamatergic hyperactivity in the increased regional brain metabolism associated with OCD (Baxter et al 2001; McGrath et al 2000). Neuroimaging studies have consis- tently identified increased blood flow, glucose metabolism, and brain activity in the cortico–striato–thalamic (CST) network of individuals with OCD (Baxter et al 2001). Given the stoichiomet- ric relationship between cerebral glucose metabolism and gluta- matergic neurotransmission (Magistretti et al 1999), a drug that reduces glutamatergic neurotransmission may attenuate the re- gional CST hyperactivity observed in patients with OCD. Consis- tent with a glutamatergic hypothesis, recent 1 H magnetic reso- nance spectroscopy ( 1 H-MRS) studies suggest that glutamate levels are elevated in components of the CST in OCD patients, and glutamatergic elevations decline with effective treatment (Rosenberg et al 2000). Normalization of CST activity may be a final common pathway for treatment. We hypothesized that a drug that reduced glutamatergic neurotransmission would augment the efficacy of SRIs in treating OCD symptoms. Riluzole is a potent antiglutamatergic agent that reduces glutamatergic neurotransmission in several ways, includ- ing inhibition of glutamate release, inactivation of voltage- dependent sodium channels in cortical neurons, and blockade of GABA reuptake (Jehle et al 2000; Urbani and Belluzzi 2000). We initiated an open-label study of riluzole augmentation therapy in patients with treatment-resistant OCD to test the preliminary efficacy and safety of an antiglutamatergic strategy in this popu- lation. We have previously published a case report describing a significant improvement in mood and anxiety symptoms using this approach (Coric et al 2003). Methods and Materials Thirteen patients were recruited from the Yale OCD Research Clinic. Patient characteristics and inpatient– outpatient status are listed in Table 1. All patients provided written informed consent before study participation. The study was approved by the Yale University Human Investigations Committee, New Haven, Con- necticut. Patients aged between 18 and 65 with a primary DSM-IV diagnosis of OCD who had failed to clinically respond to at least 8 weeks of treatment with SRIs were eligible for study participa- tion. Treatment failure was defined by a Yale–Brown Obsessive Compulsive Scale (Y-BOCS) score 16 despite at least 8 weeks of treatment with the maximum tolerated dose of an SRI medi- cation. Additionally, OCD symptoms had to be present for at least 1 year and at least of moderate severity on the Clinical Global Impression Scale severity of illness item. Patients with a primary psychotic disorder, prior psychosurgery for OCD, illicit substance use over the past 1 month, seizure disorder, significant head trauma, acute medical illnesses, or elevated baseline liver function tests (LFTs; i.e., greater than twice the upper limits of normal) were excluded from study participation. Diagnoses were confirmed using the Structured Clinical Interview for Axis I From the Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Address reprint requests to Vladimir Coric, M.D., Clinical Neuroscience Re- search Unit, Yale University School of Medicine/Connecticut Mental Health Center, 34 Park Street, New Haven CT 06519; E-mail: vladimir.coric@yale.edu. Received August 19, 2004; revised January 27, 2005; accepted April 22, 2005. BIOL PSYCHIATRY 2005;58:424 – 428 0006-3223/05/$30.00 doi:10.1016/j.biopsych.2005.04.043 © 2005 Society of Biological Psychiatry