Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial

Abstract

Objective Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression. Method This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Results The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively. Conclusions Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

“…Midazolam is a benzodiazepine anesthetic agent used as an 'active placebo' in the current study to control for non-specific treatment effects related to sedation or other acute effects of anesthetic drug administration. Detailed study drug infusion methods were presented previously (Murrough et al, 2013a). A trained rater conducted symptom ratings at fixed intervals during the infusion and for 240 min following the start of the infusion.…”

“…Seventy-three individuals were randomized and n ¼ 72 received study medication and constituted the modified intention to treat sample (n ¼ 47 received ketamine, n ¼ 25 received midazolam) in the parent clinical trial (Murrough et al, 2013a). Data were missing or incomplete for four patients in the ketamine group and six patients in the midazolam group.…”

“…Ketamine is a high-affinity, noncompetitive N-methyl-Daspartate (NMDA) glutamate receptor antagonist that has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD; Mathew et al, 2010;Murrough et al, 2013a;Murrough et al, 2013b;Zarate et al, 2006). We recently reported that ketamine was superior to an anesthetic control condition (the benzodiazepine midazolam) at rapidly reducing depressive symptoms 24 h following a single intravenous (IV) infusion in a two-site randomized controlled trial (response rates to ketamine and midazolam were 64 and 28%, respectively; Murrough et al, 2013a).…”

“…We recently reported that ketamine was superior to an anesthetic control condition (the benzodiazepine midazolam) at rapidly reducing depressive symptoms 24 h following a single intravenous (IV) infusion in a two-site randomized controlled trial (response rates to ketamine and midazolam were 64 and 28%, respectively; Murrough et al, 2013a). Randomized controlled trials have also found positive therapeutic effects of ketamine in bipolar depression (Zarate et al, 2012) and posttraumatic stress disorder (PTSD; Feder et al, 2014).…”

“…At the sub-anesthetic doses utilized in depression studies (most commonly 0.5 mg/kg administered as a slow 40-min infusion), ketamine results in acute dissociative and cognitive effects that typically peak immediately following drug administration and resolve within minutes or up to 2 h following cessation of the drug (Mathew et al, 2010;Murrough et al, 2013a;Murrough et al, 2013c;Zarate et al, 2006). In healthy volunteers, ketamine reliably results in acute impairments in learning and memory (Krystal et al, 1994;Krystal et al, 1999;Krystal et al, 2005;Morgan et al, 2004;Parwani et al, 2005;Perry et al, 2007).…”