Effects of low-dose and very low-dose dose ketamine among patients with major depression: a systematic review and meta-analysis.

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 abstracted independently by two 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 Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials.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 (0.5 mg/kg intravenous) and three tested very low dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1-0.4 mg/kg intravenous and another assessed 0.1-0.5 mg/kg intravenous, intramuscular or subcutaneous). At day 3, the reduction in depression severity score was less marked in the very low dose trials (P homogeneity <0.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk [RR] 3.4, 95% CI 1.6-7.1, p=0.001), as were remission rates (RR 2.6, CI 1.2-5.7, p=0.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (p=0.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both p<0.01) but not day 7.

CONCLUSIONS:

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 one 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.