Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis

Abstract

Background:Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials.Methods:A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials.Results:Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50mg intra-nasal spray, another assessed 0.1–0.4mg/kg i.v., and another assessed 0.1–0.5mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6–7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2–5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7.Conclusion:Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety.

Ketamine for Treatment-Resistant Unipolar and Bipolar Major Depression: Critical Review and Implications for Clinical Practice

“…[41] These results suggest that the antidepressive effects of ketamine may be dose-related. The antidepressive effects of four IV doses of ketamine (0.1, 0.2, 0.3, and 0.4 mg/kg infused over 2-5 min) were tested in a small, double-blind, placebo-controlled cross-over pilot study of four depressed subjects, using an ascending dose design.…”

“…3 (number needed to treat). A separate meta-analysis by Xu et al [41] also reported large effects favoring ketamine for short-term positive response (pooled response rate 50 vs. 13%, RR 2.6, 95% CI: 1.6-4.4 at 24 hrs; pooled response rate 31 vs. 7%, RR 3.4, 95% CI: 1.6-7.1 at 7 days), and remission (pooled remission rate 28 vs. 3%, RR 5.2, 95% CI: 2.1-12.9 at 24 hrs; pooled remission rates 24 vs. 6%, RR 2.6, 95% CI: 1.2-5.7 at 7 days) [42] Total (n = [43] Total (n = Xu et al 2015 [41] Total (n = Lee et al 2015 [44] Total (n = Romeo et al 2015 [45] Total (n = Coyle and Laws [46] Total (n = [47] Total (n = Fond et al 2014 [48] Total (n = Caddy et al 2014 [49] Total (n = The study sample in one reviewed study consisted of depressed patients presenting acutely to an emergency room with suicidal ideation.…”

Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

“…The dose of ketamine used in this study was derived from studies in which ketamine infusions have been shown to be effective in the rapid treatment of depression 165 and, therefore, it is possible that a different dose of ketamine may have shown benefit in terms of cognitive, or possibly efficacy, outcomes. However, as discussed in the previous paragraph, it is likely that higher doses would be associated with a less favourable AE profile (see also McGirr et al…”

“…) and the data from studies using higher doses of ketamine with ECT, 52 or as a pharmacological treatment, 165 do not suggest an efficacy benefit.…”

Novel Treatment Options in Depression and Psychosis

“…However, there is substantial heterogeneity in clinical response, and ketamine's underlying mechanisms of action are not entirely understood. 14,15 The observation that a single intravenous dose of glutamatergic modulator ketamine produces a robust and rapid AD effect was a turning point that opened the way for other, more selective glutamatergic modulators (intranasal esketamine, rapastinel). 16 …”