Short-term cognitive effects of repeated-dose esketamine in adolescents with major depressive disorder and suicidal ideation: a randomized controlled trial

Ketamine and its enantiomer have rapid and robust effects on depressive symptom and suicidal ideation. Little is known about their cognitive effects in adolescents. We aimed to evaluate the short-term effect of esketamine on cognition in adolescents with major depressive disorder (MDD) and suicidal ideation.

In this randomized-controlled trial, 51 participants aged 13-18 with MDD and suicidal ideation received three intravenous infusions of either esketamine (0.25 mg/kg) or midazolam (0.02 mg/kg). Four dimensions of the MATRICS Consensus Cognitive Battery (MCCB), including processing speed, working memory, verbal learning and visual learning, were assessed at Days 0, 6 and 12.

In the linear mixed model, a significant time main effect (F = 12.803, P < 0.001), drug main effect (F = 6.607, P = 0.013), and interaction effect (F = 3.315, P = 0.041) was found in processing speed. Other dimensions including working memory and verbal learning showed significant time main effect (all P < 0.05), but no significant drug or interaction effect (all P > 0.05). Esketamine group showed improvement in processing speed from baseline to Days 6 and 12, and working memory from baseline to Day 12 (all P < 0.05). The generalized estimation equation showed no significant association between baseline cognition and antidepressant or antisuicidal effect (both P > 0.05).

The present study suggested that three-dose subanesthetic esketamine infusions did not harm cognition among adolescents with MDD and suicidal ideation. Instead, esketamine may be associated with improvement in processing speed.

This trial was registered in the Chinese Clinical Trials Registry ( http://www.chictr.org.cn , ChiCTR2000041232).