REVIEW OF: Dwyer JB et al, Am J Psychiatry 2021;178(4):352–362

TYPE OF STUDY: Randomized midazolam-controlled trial

Treatment-resistant depression (TRD) is a growing concern in teenagers. Although intravenous ketamine has shown clear and immediate improvement of TRD in adults, there is little research to show its effectiveness in teens, and each infusion may cost about $450, with a total of $3000–$4000 for a course of treatment in adults (www.tinyurl.com/cv4yw77s). A recent study tried to fill the gap in the literature.

This study was conducted at the Yale Child Study Center. Researchers enrolled 17 teenagers aged 13–17 years with severe major depressive disorder but without active suicidal ideation or comorbid substance use disorder. Teens could continue their current psychotropic medications. While the participants were required to have failed only one antidepressant trial, on average they had failed three antidepressants and six total psychotropic medications, excluding ADHD medications.

The researchers conducted a randomized, double-blinded, active-controlled, crossover study. Patients were given a single infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) and switched to the other treatment after two weeks. The primary endpoint was a greater than 50% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) score 24 hours after treatment.

Subjects who received ketamine reported a remarkable improvement in depression following ketamine treatment. Their average baseline MADRS score of 33 dropped significantly lower with ketamine (to 15.4) compared to midazolam (24.1) with a strong effect size of 0.78 (p = 0.03). Overall, 75% of the group responded to ketamine compared to 35% with midazolam. Two weeks following the infusion, responders to ketamine maintained partial improvement in depression, whereas responders to midazolam returned to their baseline level of depression. The main adverse effects seen with ketamine were an increase in pulse and blood pressure during the infusion, and dissociation up to two hours after the infusion.

CCPR’s Take
Based on this small study, intravenous ketamine appears to be a promising new tool for TRD in teens. Still, we are concerned not only with the high cost of this treatment but the propensity of preliminary studies to cause families to pursue it. We need larger studies on ketamine in children and teens, especially ones that include patients with active suicidal ideation.