Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial.
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 chi(2) = 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.
Mathew
Sanjay J
SJ
Mood & Anxiety Disorders Program, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA. sanjay.mathew@mssm.edu
Murrough
James W
JW
aan het Rot
Marije
M
Collins
Katherine A
KA
Reich
David L
DL
Charney
Dennis S
DS
D000328:Adult; D000368:Aged; D003863:Depression / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control*; D004347:Drug Interactions; D004351:Drug Resistance; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006213:Hallucinogens / Q000037:antagonists & inhibitors; D006801:Humans; D007275:Injections, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010919:Placebos; D019782:Riluzole / Q000627:therapeutic use*; D055502:Secondary Prevention; D013997:Time Factors; D016896:Treatment Outcome; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use
D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D010919:Placebos; D014227:Triazines; D007649:Ketamine; D019782:Riluzole; D000077213:Lamotrigine