Keypoint: Higher IV ketamine doses do not outperform standard doses for treatment resistant depression.
Intravenous (IV) ketamine for treatment resistant depression is effective at lower doses of 0.2 to 0.5 mg/kg, without significantly increased benefit at 1 mg/kg. Conversely, the efficacy of intranasal (IN) esketamine for reducing depressive symptoms increases with doses above 28 mg, reaching optimal response between 56 and 84 mg. These findings from a systematic review and meta-analysis were published in the Journal of Affective Disorders.
Both IV ketamine and IN esketamine have been associated with rapid antidepressant effects among patients with treatment resistant depression. However, optimal dose ranges have not yet been defined for either treatment.
To address this knowledge gap, investigators from the Mayo Clinic in Rochester, Minnesota searched publication databases through June 2023 for randomized controlled trials (RCTs) that evaluated esketamine or ketamine for treatment resistant depression. The investigators categorized IV ketamine doses as low dose (£0.2 mg/kg), standard dose (>0.2 to 0.5 mg/kg), and high dose (>0.5 mg/kg) for analyses. The efficacy outcomes were changes in depressive symptoms 24 hours after IV ketamine and 28 days following IN esketamine, respectively.
For IV ketamine, the investigators included 5 RCTs, for a pooled sample size of 262 participants (IV ketamine: n=196; control: n=66). The doses of IV ketamine ranged from 0.1mg/kg to 1 mg/kg. For IN esketamine, 7 RCTs were included with a total study population of 1372 participants (IN esketamine: n=718; control: n=655), and doses ranged from 28 mg to 84 mg.
Relative to control, the mean effect size of IV ketamine was 1.58 (95% CI, 0.94-2.22; I2, 78%; P <.001) and IN esketamine was 0.31 (95% CI, 0.17-0.44; I2, 22%; P <.001).
For IV ketamine, low (Hedges g, 1.2; P =.02), standard (Hedges g, 1.54; P =.01), and high (Hedges g, 2.5; P =.003) doses were all superior to control. The investigators did not observe significant differences in overall effect at different dose ranges. These findings suggest that high IV ketamine doses are not more efficacious than standard doses.
When stratified by IN esketamine dose, the investigators found that 28 mg did not outperform the control conditions (Hedges g, 0.26; P =.23). However, a dose of 56 mg (Hedges g, 0.37; P =.03), flexible dosing between 56 and 84 mg (Hedges g, 0.27; P =.001), and a dose of 84 mg (Hedges g, 0.45; P =.03) were all more effective than control.
The most common side effects for both treatments were dizziness, headache, dissociative symptoms, and dysgeusia. In addition, transient elevation of blood pressure tended to occur at higher doses.
The investigators concluded, “The available data does not provide sufficient evidence that the higher IV ketamine doses (>0.5 mg/kg) are more efficacious than standard dose (0.5 mg/kg).”
The major limitation of this analysis was the small sample sizes for each dose group.
Note: This article originally appeared on Psychiatry Advisor