Doi:10.1016/j.biopsych.2005.04.043

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 Ͼ35% 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
levels are elevated in components of the CST in OCD patients, disorder, major depressive disorder, riluzole and glutamatergic elevations decline with effective treatment Normalization of CST activity may be afinal common pathway for treatment.
Although serotonin reuptake inhibitors (SRIs), cognitive– We hypothesized that a drug that reduced glutamatergic behavioral therapy (CBT), and augmentation with dopa- neurotransmission would augment the efficacy of SRIs in treating mine antagonists have proven efficacy in the treatment of OCD symptoms. Riluzole is a potent antiglutamatergic agent that obsessive– compulsive disorder (OCD), treatment-resistant OCD reduces glutamatergic neurotransmission in several ways, includ- remains a common and debilitating problem. Current clinical ing inhibition of glutamate release, inactivation of voltage- interventions significantly reduce symptoms in approximately dependent sodium channels in cortical neurons, and blockade of 40%– 60% of patients with OCD; however, a substantial number of patients remain dramatically symptomatic even with the initiated an open-label study of riluzole augmentation therapy in combination of pharmacotherapy and CBT . More- patients with treatment-resistant OCD to test the preliminary over, a therapeutic response in most treatment trials is defined as efficacy and safety of an antiglutamatergic strategy in this popu- symptom reduction by 20%– 40% with many treatment respond- lation. We have previously published a case report describing a ers remaining markedly symptomatic Treatment- significant improvement in mood and anxiety symptoms using 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 Methods and Materials
studies that implicate glutamatergic hyperactivity in the increased Thirteen patients were recruited from the Yale OCD Research regional brain metabolism associated with OCD Clinic. Patient characteristics and inpatient– outpatient status are listed in All patients provided written informed consent tently identified increased blood flow, glucose metabolism, and before study participation. The study was approved by the Yale brain activity in the cortico–striato–thalamic (CST) network of University Human Investigations Committee, New Haven, Con- individuals with OCD Given the stoichiomet- necticut. Patients aged between 18 and 65 with a primary DSM-IV ric relationship between cerebral glucose metabolism and gluta- diagnosis of OCD who had failed to clinically respond to at least 8 weeks of treatment with SRIs were eligible for study participa- reduces glutamatergic neurotransmission may attenuate the re- tion. Treatment failure was defined by a Yale–Brown Obsessive gional CST hyperactivity observed in patients with OCD. Consis- Compulsive Scale (Y-BOCS) score Ͼ16 despite at least 8 weeks tent with a glutamatergic hypothesis, recent 1H magnetic reso- of treatment with the maximum tolerated dose of an SRI medi- nance spectroscopy (1H-MRS) studies suggest that glutamate cation. Additionally, OCD symptoms had to be present for atleast 1 year and at least of moderate severity on the ClinicalGlobal Impression Scale severity of illness item. Patients with a From the Department of Psychiatry, Yale University School of Medicine, New primary psychotic disorder, prior psychosurgery for OCD, illicit substance use over the past 1 month, seizure disorder, significant Address reprint requests to Vladimir Coric, M.D., Clinical Neuroscience Re- search Unit, Yale University School of Medicine/Connecticut Mental head trauma, acute medical illnesses, or elevated baseline liver Health Center, 34 Park Street, New Haven CT 06519; E-mail: function tests (LFTs; i.e., greater than twice the upper limits of normal) were excluded from study participation. Diagnoses were Received August 19, 2004; revised January 27, 2005; accepted April 22, 2005.
confirmed using the Structured Clinical Interview for Axis I Table 1. Clinical Characteristics of Patients with OCD Treated with Riluzole Addition to SRI
Hrd, sym/ext, chk, rpt, cnt, ord/arr, ntk Cln/was, cnt, sym/ext, chk, cnt, rpt, hrd Sym/ext, ctm, cln/was, hrd, chk, rpt, ord/arr, ntk AA, African-American; Agg, aggressive; chk, checking; cln/wsh, cleaning/washing; cnt, counting; ctm, contamination; F, female; GAD, generalized anxiety disorder; hrd, hoarding; M, male; m, maternal; MDD, major depressive disorder; ntr, need to touch, tap, OCD, obsessive– compulsive disorder; ord/arr,ordering/arranging; or rub; p, paternal; panic, panic disorder; rel. religious; rpt, repeating; sex, sexual; som, somatic; sym/ext, symmetry/exactness; Tic, ticdisorder, W, Caucasian; and y, years.
DSM-IV Disorders Major depression was the most com- alone or in combination, included the following: fluoxetine 80 mon comorbid diagnosis, occurring in 10 of the 13 patients.
mg (n ϭ 4), clomipramine 262.5 mg (n ϭ 4), escitalopram 20 mg Patients had to have failed at least 8 weeks of treatment on their (n ϭ 2), fluvoxamine 300 mg (n ϭ 3), buspirone 30 mg (n ϭ 1), current SRI medication. Concomitant psychotropic medications risperidone 5 mg (n ϭ 1), olanzapine 11.3 mg (n ϭ 2), were permitted only if prescribed at a stable dose for at least 1 quetiapine 50 mg (n ϭ 1), and clonazepam 1.3 mg (n ϭ 5). Mean Y-BOCS score of patients entering the study was 30.7 (Ϯ 6.6), Study duration was initially 6 weeks. After results from initial indicating severe OCD symptoms. Data from one patient was subjects suggested ongoing therapeutic response with time, the study was extended to 9 weeks and then to 12 weeks.
illustrates the mean Y-BOCS score for all study Riluzole was initiated and maintained at a dose of 50 mg twice participants. Mean Y-BOCS for the group at baseline was 30.7 (Ϯ a day. Subjects were evaluated weekly with clinician-adminis- 6.6) and at end of study was 17.7 (Ϯ 8.6), representing an overall tered rating scales: Y-BOCS, Clinical Global Impression/Global 42% reduction for the entire cohort. Y-BOCS scores improved Improvement item (CGI/GI), Hamilton Depression Inventory (HAM-D), and Hamilton Anxiety Inventory (HAM-A). Liver func- patients, 7 (54%) demonstrated aϾ35% reduction in Y-BOCS tion tests were monitored at baseline and every 3 weeks through- scores; 5 of 13 (39%) were categorized as treatment responders, out the study. Because of the variable time of treatment (6 –12 as defined by a 35% or greater reduction in baseline Y-BOCS, a weeks), Y-BOCS, HAM-D, and HAM-A were analyzed in SAS final Y-BOCS of 16 or less, and consensus of the treating PROC MIXED using mixed-effects models with time (baseline to clinicians. Percent reduction in baseline Y-BOCS scores at the week 9) as fixed effect and a structured variance– covariance end of the study ranged from 38% to 76% in responders. Two of the five responders were characterized predominantly by hoard- The CGI/GI was analyzed using the same model ing behaviors. Clinician administered CGI/GI scores significantly with time (baseline to week 7) as fixed effect. The best fitting ϭ 20.99, p ϭ .0003). Mean baseline variance-covariance matrix according to the Akaike Information CGI/GI was 4 (Ϯ 0), week 6 CGI/GI was 3.2 (Ϯ .6), week 9 CGI/GI was 2.66 (Ϯ .5), and week 12 CGI/GI was 2.33 (Ϯ 1).
Mean HAM-D at baseline was 30 (Ϯ 13.7) and at end of study was 19.7 (Ϯ 6.0). HAM-D scores for the entire group improved Thirteen patients entered the study, and only one subject, a ϭ 9.12, p ϭ .012); 6 of 13 patients treatment responder, dropped out at week 9 because of a family demonstrated clinically significant improvements in HAM-D situation. Previous SRI treatment trials, history of augmentation scores with 36%– 83% reductions in baseline HAM-D scores by strategies, previous CBT, dosage of concomitant medications, the end of the study. Mean HAM-A at baseline was 18.2 (Ϯ 6.2) and outcome variables for each patient are shown in The and at end of study was 12 (Ϯ 2.5). HAM-A scores improved mean number of previously failed medication trials included 3.5 ϭ 7.9, p ϭ .017). Riluzole was well (Ϯ 1.7) SRI/serotonin-norepinephrine reuptake inhibitor (SNRI)/ tolerated, and no serious adverse events were noted. Asymptom- tricyclic trials and 1.3 (Ϯ 1.5) dopamine antagonist augmentation atic, transient increases in at least one LFT were noted in 4 of 13 trials. Additionally, 12 of 13 subjects failed previous trials of CBT.
patients. One patient experienced a ninefold increase in alanine Mean doses of concomitant medications during the study, dosed aminotransferase (ALT); repeat ALT in that patient revealed a Table 2. Treatment Data of Patients with OCD treated with Riluzole Addition to SRI
paroxetine, citalopram,sertraline, venlafaxine citalopram, paroxetine,escitalopram,clomipramine,fluvoxamine Bid, two times a day; CGI, Clinical Global Impressions; Ham-A, Hamilton Anxiety Rating Scale; Ham-D, Hamilton Depression Rating Scale; OCD, obsessive– compulsive disorder; qid, four times a day; qhs, given at bedtime; SRI, serotonin reuptake inhibitor; tid, three times a day; YBOCS, Yale–Brown Obsessive Compulsive Scale.
aStudy duration 6 weeks.
bStudy duration 9 weeks.
cStudy duration 12 weeks.
dSubject enrolled for 12 week study, responded to treatment, and dropped from study at week 9 due to family situation (represents the only study drop-out).
eϾ35% reduction in pre/post rating scales.
Figure 1. Mean Yale–Brown Obsessive Compulsive
Scale (Y-BOCS) score in patients with serotonin re-
uptake inhibitor–resistant obsessive– compulsive
disorder treated with riluzole addition. *Y-BOCS
scores improved significantly over time (F
fourfold increase that normalized to within two times the upper reduce synaptic glutamate by attenuating elevations in extrasyn- limits of normal by week 3. Mean baseline asparate aminotrans- aptic glutamate levels that may arise as a consequence of ferase AST, ALT, and alkaline phospha-tase (Alk Phos) were 19.1 impairment of glial glutamate uptake Thus, (Ϯ 5.7), 22.9 (Ϯ 12.3), and 75 (Ϯ 13.5), respectively; mean week the antidepressant efficacy of riluzole could be consistent with 6 AST, ALT, and Alk Phos were 22 (Ϯ 13.84), 35.3 (Ϯ 28.3), and studies describing elevations or decreases in cortical glutamate levels. Future studiesemploying 13C-MRS that can separate glial and neuronal meta- Discussion
bolic rates will be needed to define the nature of glutamatergicdisturbances in OCD and depression This open-label study suggests that directly attenuating gluta- matergic activity may be efficacious in treatment-resistant OCD.
The most common comorbid psychiatric illness in our study Furthermore, the observed improvements in Y-BOCS, HAM-D, was major depressive disorder (MDD). Studies suggest that the and HAM-A scores after addition of riluzole is consistent with presence of MDD in patients with OCD negatively affects recent clinical reports suggesting that modulation of glutamater- gic pathways using the antiglutamatergic agent riluzole may recent estimates of the comorbidity between OCD and MDD provide symptom relief in anxiety and mood disorders Effective OCD treatment with SRI medications has been expected percentage of study subjects with these comorbid observed to lead to a reduction in glutamatergic tone in the CST disorders (77%) likely reflects the severity of treatment resistance in our study population. It is important to note that the efficacy ciated with increased activity in the CST network, it may not be of riluzole augmentation in treatment-resistant OCD remained associated with a global increase in glutamatergic function. In significant even when covarying for the magnitude of antidepres- fact, a recent report shows reduced glutamate concentrations in sant effect in our study. The clinical observation that SRIs, the anterior cingulate gyrus in both OCD and major depression dopamine antagonists, and now riluzole are useful for both mood and OCD symptoms suggests a partial overlap between whether riluzole preferentially targets components of the CST the pathophysiology of these disorders.
circuitry or has a more global effect. Additionally, the role of Riluzole was well tolerated in our study, and no patients glutamate in the pathophysiology of mood and anxiety disorders discontinued treatment because of adverse effects. Riluzole is is yet to be elucidated. The relationship between glutamate or generally associated with transient elevations in LFTs; more than Glx levels measured with 1H-magnetic resonance spectrometry 50% of patients treated with riluzole experience elevations in at (MRS) and the rate of glutamatergic neurotransmission is also far least one LFT measure, and approximately 2% experience LFT from clear Glutamate is present in all brain elevations greater than 5 times the upper limit of normal cells, where it participates in a number of cellular functions According to the Physician’s Desk Reference, LFTs should unrelated to neurotransmission. Although glutamate is the sub- be monitored every month during the first 3 months of treatment, strate for glutamatergic neurotransmission, it is not clear whether every 3 months during the remainder the first year, and then increases or decreases in glutamate levels measured by 1H-MRS periodically. Serum LFTs should be monitored more frequently reflect increased synaptic glutamate release. The extent to which in patients who develop elevations. Riluzole therapy was discon- synaptic or extrasynaptic glutamate contribute to the 1H-MRS tinued for LFT elevationsϾ5ϫ normal in amyotrophic lateral glutamate signal is unknown. We hypothesize that riluzole may sclerosis (ALS) field trials. In our study, one patient demonstrated an asymptomatic increase in ALT that exceeded 9 times normal, with obsessive– compulsive disorder and major depressive disorder.
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effects of treatment with riluzole. Finally, patients were required Gueorguieva R, Krystal JH (2004): Move over ANOVA. Progress in analyzing to have had stable medications regimens for only 4 weeks before repeated measures data and its reflection in papers. Arch Gen Psychiatry study initiation, raising the possibility that some of the treatment Jehle T, Bauer J, Blauth E, Hummel A, Darstein M, Freiman TM, Feuerstein TJ effect represented a delayed response to the earlier initiation of (2000): Effects of riluzole on electrically evoked neurotransmitter re- other medications. Despite these limitations, the significant im- lease. Br J Pharmacol 130:1227–1234.
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the Department of Veteran Affairs through its support of the Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ (2000): Decrease in caudate glutamatergic concentrations in Alcohol Research Center and National Center for PTSD, and the pediatric obsessive-compulsive disorder patients taking paroxetine.
General Clinical Research Center grant from the National Center J Am Acad Child Adolesc Psychiatry 39:1096 –1103.
of Research Resources, National Institute of Health (Grant No. Rosenberg DR, Mirza Y, Russell A, Tang J, Smith JM, Banerjee SP, et al (2004): M01-RR00125) awarded to Yale University School of Medicine. Reduced anterior cingulated glutamatergic concentrations in childhood The authors thank the staff of the Clinical Neuroscience Research OCD and major depression versus healthy controls. J Am Acad Child Unit of the Connecticut Mental Health Center, New Haven, Adolesc Psych 43:1146 –1153.
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