1. Among adolescents with treatment-resistant depression, an infusion of ketamine significantly reduced depressive symptoms over a two-week period compared with an infusion of midazolam.
Evidence Rating Level: 2 (Good)
Study Rundown: Major depressive disorder (MDD) has a lifetime prevalence of nearly 20% by adolescence and is associated with substantial morbidity and mortality. Furthermore, a significant number of adolescents experience treatment-resistant MDD. The glutamatergic modulator ketamine has been shown to have rapid antidepressant effects among adults; it also appears to reduce suicidality, a particular component of adolescent depression that has a controversial association with selective serotonin reuptake inhibitors (SSRIs), a commonly used class of antidepressants among both children and adults. There is, however, little data on the psychiatric use of ketamine among children and adolescents. As such, this randomized, placebo-controlled trial evaluated the safety and efficacy of using intravenous ketamine among adolescents with treatment-resistant depression.
Participants with treatment-resistant depression – defined as having failed to benefit from one prior 8-week trial of a standard antidepressant medication at a therapeutic dose – received either ketamine or midazolam on day one, and then the alternative compound two weeks later. Midazolam was chosen as the active placebo due to its similar pharmacokinetic and side-effect profiles. The primary outcome was depression symptom severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours post-infusion. It was found that ketamine significantly reduces MADRS scores compared with midazolam at day 1 after infusion. Furthermore, MADRS ratings after ketamine infusion were significantly lower than ratings after midazolam infusion at all other post-baseline time points (days 2, 3, 5, 7, 10, and 14). Significant dissociative symptoms were observed following ketamine infusion, but there were no serious adverse events overall.
A strength of this study is the inclusion of an active placebo group, an element which had been lacking in previous proof-of-concept studies related to this particular use of ketamine. Weaknesses of this study include its rather small sample size, which limits its generalizability, as well as possible unblinding due to greater dissociative and hemodynamic symptoms observed following ketamine infusion. It should be noted, though, that this is a limitation inherent to all ketamine trials, and that midazolam is considered to be the best active control currently available. In all, this trial suggests that among adolescents with treatment-resistant depression, a ketamine infusion is well tolerated and has significant short-term efficacy in reducing depressive symptoms when compared with an active placebo. More work is needed to evaluate the long-term effects of ketamine infusion both in terms of efficacy at reducing depressive symptoms and safety profile.
In-depth [randomized-controlled trial]: 16 of the 17 randomized participants (mean [SD] age = 15.5 [1.4] years, 76% female) ultimately received both infusions. They had, on average, failed 3.24 prior antidepressant treatment strategies. Ketamine significantly reduced MADRS scores compared with midazolam at day 1 post-infusion (15.44±10.07 [95% CI 10.51 to 20.37] vs. 24.13±12.08 [95% CI 18.21 to 30.04], p = 0.036). Participants were significantly more likely to respond to ketamine than to midazolam (77% vs. 35%, p = 0.046), defined as a >50% reduction in MADRS score within 3 days following infusion. The data were also reviewed in a linear mixed model. In phase A (infusion day to post-infusion day 1), the treatment-by-time interaction between ketamine and midazolam was -5.77 MADRS points per day (95% CI -12.42 to 0.89, p = 0.089), favoring ketamine, but not at the level of statistical significance. In phase B (post-infusion days 1 through 14), the difference was -0.16 MADRS points per day (95% CI -0.77 to 0.46, p = 0.62). Both cohorts maintained some level of symptomatic improvement throughout phase B but worsened in comparison to the initial improvement seen on day 1.
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