Antidepressant Effects of NR2B in Major Depression

Even though there are many antidepressant drugs for clinical use, clinical trials indicate that 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatments despite adequate dosage, duration, and compliance. Furthermore, these medications may take weeks to months to achieve their full effects and in the meantime, patients continue to suffer from their symptoms and be at risk of self-harm as well as harm to their personal and professional lives. Thus, there is a clear need to develop novel and improved therapeutics for treatment-resistant major depression that have a rapid onset of action. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system, specifically on the NMDA receptor complex. A recent study by our group found that a single intravenous dose of the non-competitive NMDA antagonist ketamine produced a rapid, robust and relatively sustained antidepressant effect in patients with treatment-resistant major depression. Together, these data suggest that the NMDA receptor may play an important role in the mechanism of antidepressant action. Unfortunately, ketamine's psychotomimetic effects preclude its use as a chronic antidepressant; these side effects probably are a result of ketamine's effects on multiple NMDA subunits. Thus, studying selective NMDA subunit antagonists in depression is a reasonable next step. The NR2B subunit stands as a prime candidate to test in depression. Preclinical data by our group indicates that the NR2B subunit is involved in the mechanism of antidepressant action as indicated by changes in phosphorylation of serine residues in the learned helplessness model of depression and with chronic treatment with imipramine. In addition, we found that the NR2B antagonist R0 25-6981 has antidepressant-like properties in the forced swim test. We propose to examine whether the selective NR2B antagonist (MK-0657) produces rapid antidepressant effects in patients with treatment-resistant major depression but without causing psychotomimetic effects. Male and female patients, ages 18 to 55 years, with a diagnosis of major depression (without psychotic features), will be recruited for this study. This study consists of the double-blind crossover administration of either the NR2B antagonist MK-0657 (4-8 mg/day) or placebo. The specific aim of this study is to assess the efficacy of 12 days of a selective NR2B antagonist (MK-0657, 4-8 mg/day given orally) compared with placebo in improving overall depressive symptomatology in patients with treatment-resistant major depression. Our primary hypothesis is that subjects with treatment-resistant major depression who are randomized to a selective NR2B antagonist (MK-0657) will have a more rapid and superior response compared to when they are randomized to placebo. This is a proof of concept and treatment study. Approximately, 27 subjects will be randomized; the accrual ceiling for this protocol is 60 subjects.