The International Journal of Neuropsychopharmacology

Thematic Section: New Aspects in the Treatment of Affective Disorders

Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial

Sanjay J. Mathewa1 c1, James W. Murrougha1, Marije aan het Rota1, Katherine A. Collinsa1, David L. Reicha2 and Dennis S. Charneya1a3a4a5

a1 Mood & Anxiety Disorders Program, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

a2 Department of Anesthesiology, Mount Sinai School of Medicine, New York, NY, USA

a3 Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

a4 Department of Pharmacology & Systems Therapeutics, Mount Sinai School of Medicine, New York, NY, USA

a5 Office of the Dean, Mount Sinai School of Medicine, New York, NY, USA


The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine may have rapid, albeit transient, antidepressant properties. This study in patients with treatment-resistant major depression (TRD) aimed to (1) replicate the acute efficacy of single-dose intravenous (i.v.) ketamine; (2) test the efficacy of the glutamate-modulating agent riluzole in preventing post-ketamine relapse; and (3) examine whether pretreatment with lamotrigine would attenuate ketamine's psychotomimetic effects and enhance its antidepressant activity. Twenty-six medication-free patients received open-label i.v. ketamine (0.5 mg/kg over 40 min). Two hours prior to infusion, patients were randomized to lamotrigine (300 mg) or placebo. Seventeen patients (65%) met response criterion (⩾50% reduction from baseline on the Montgomery–Asberg Depression Rating Scale) 24 h following ketamine. Lamotrigine failed to attenuate the mild, transient side-effects associated with ketamine and did not enhance its antidepressant effects. Fourteen patients (54%) met response criterion 72 h following ketamine and proceeded to participate in a 32-d, randomized, double-blind, placebo-controlled, flexible-dose continuation trial of riluzole (100–200 mg/d). The main outcome measure was time-to-relapse. An interim analysis found no significant differences in time-to-relapse between riluzole and placebo groups [log-rank χ2=0.17, d.f.=1, p=0.68], with 80% of patients relapsing on riluzole vs. 50% on placebo. The trial was thus stopped for futility. This pilot study showed that a sub-anaesthetic dose of i.v. ketamine is well-tolerated in TRD, and may have rapid and sustained antidepressant properties. Riluzole did not prevent relapse in the first month following ketamine. Further investigation of relapse prevention strategies post-ketamine is necessary.

(Received September 22 2008)

(Reviewed December 19 2008)

(Revised December 22 2008)

(Accepted February 03 2009)

(Online publication March 17 2009)


c1 Address for correspondence: S. J. Mathew, M.D., Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place Box 1217, New York, NY 10029, USA. Tel.: (212) 241-4480 Fax: (212) 241-3354 Email: