Bipolar affective disorder (manic-depressive illness) and unipolar depression are common, severe, chronic and often life-threatening illnesses. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Recent preclinical and clinical studies suggest that the glutamatergic system is involved in the mechanism of action of antidepressants. In two separate trials, we tested riluzole (an inhibitor of glutamate release) and found it to have antidepressant properties in patients with unipolar and bipolar depression (Zarate et al. 2004, 2005). In another study, we found that the non-competitive NMDA antagonist (ketamine) was effective in treatment-resistant major depression. Ketamine resulted in rapid, robust and relatively sustained antidepressant effects. Response with ketamine occurred within 2 hours and last approximately 1 week (Zarate et al in press). The current protocol consists of 3 studies designed to address 3 major questions: Study 1 (Rapid improvement research in unipolar depression) OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. DESIGN: A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health.Patients Eighteen subjects with DSM-IV major depression (treatment resistant). INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. CONCLUSIONS: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Study 2 (Rapid improvement research in bipolar depression) Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant bipolar depression? Patients, ages 18 to 65 years with treatment-resistant bipolar depression will in a double-blind crossover study receive either intravenous ketamine or saline solution added to a mood stabilizer (lithium or valproate). Study 3 (Rapid and sustained improvement research in unipolar depression) Does riluzole (an inhibitor of glutamate release) prevent relapse in patients with treatment-resistant major depression who have rapidly responded to a single intravenous dose of ketamine? Patients, ages 18 to 65 years, with treatment-resistant major (unipolar) depression who have rapidly responded to a single intravenous dose of ketamine will in a double-blind study receive either riluzole or placebo to determine if the rapid response obtained can be sustained. Our primary hypotheses for these studies are: 1) rapid response (same or next day) can be achieved in patients with treatment-resistant major (unipolar) depression, 2) rapid response (same or next day) can be achieved in patients with treatment-resistant bipolar depression, and 3) rapid response (same or next day) can be sustained in patients with treatment-resistant unipolar depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH002857-02
Application #
7312929
Study Section
(LMP)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2006
Total Cost
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Zarate Jr, Carlos A; Machado-Vieira, Rodrigo (2016) GSK-3: A key regulatory target for ketamine's rapid antidepressant effects mediated by enhanced AMPA to NMDA throughput. Bipolar Disord 18:702-705
Roullet, Florence I; Wöhr, Markus; Crawley, Jacqueline N (2011) Female urine-induced male mice ultrasonic vocalizations, but not scent-marking, is modulated by social experience. Behav Brain Res 216:19-28
Holmes, M Kathleen; Erickson, Kristine; Luckenbaugh, David A et al. (2008) A comparison of cognitive functioning in medicated and unmedicated subjects with bipolar depression. Bipolar Disord 10:806-15
Zarate Jr, Carlos A; Manji, Husseini K (2008) Bipolar disorder: candidate drug targets. Mt Sinai J Med 75:226-47
Zarate, Carlos A; Manji, Husseini K (2008) Riluzole in psychiatry: a systematic review of the literature. Expert Opin Drug Metab Toxicol 4:1223-34
Du, Jing; Suzuki, Katsuji; Wei, Yanling et al. (2007) The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders. Neuropsychopharmacology 32:793-802
Zarate Jr, Carlos A; Singh, Jaskaran B; Quiroz, Jorge A et al. (2006) A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry 163:153-5
Zarate Jr, Carlos A; Singh, Jaskaran B; Carlson, Paul J et al. (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856-64
Zarate Jr, Carlos A; Quiroz, Jorge A; Singh, Jaskaran B et al. (2005) An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 57:430-2
Singh, Jaskaran; Zarate Jr, Carlos A; Krystal, Andrew D (2004) Case report: Successful riluzole augmentation therapy in treatment-resistant bipolar depression following the development of rash with lamotrigine. Psychopharmacology (Berl) 173:227-8

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