Age affects temporal response, but not durability, to serial ketamine infusions for treatment refractory depression

Rationale Ketamine is a novel, rapid-acting antidepressant for treatment refractory depression (TRD); however, clinical durability is poor and treatment response trajectories vary. Little is known about which patient characteristics predict faster or more durable ketamine responses. Ketamine’s antidepressant mechanism may involve modulation of glutamatergic signaling and long-term potentiation (LTP); these neuroplasticity pathways are also attenuated with older age. Objective A retrospective analysis examining the impact of patient age on the speed and durability of ketamine’s antidepressant effects in 49 veterans receiving serial intravenous ketamine infusions for TRD. Method The relationship between age and percent change in Beck Depression Inventory (BDI-II) scores was compared across six serial ketamine infusions (twice-weekly for 3 weeks) using a linear-mixed model. Results A significant Age-X-Infusion number interaction ( F = 3.01, p = .0274) indicated that the relationship between age and treatment response depended on infusion number. Follow-up tests showed that younger age significantly predicted greater clinical improvement at infusion #4 ( t = 3.02, p = . 004); this relationship was attenuated at infusion #5 ( t = 1.95, p = . 057) and was absent at infusion #6. Age was not a significant predictor of treatment durability, defined as percent change in BDI-II 3 weeks following infusion #6. Conclusions These data preliminarily suggest that younger age is associated with a faster response over six serial ketamine infusions; by infusion #6 and subsequent weeks of clinical follow-up, age no longer predicts ketamine’s antidepressant activity. Age may mediate the speed but not the durability or total efficacy of ketamine treatment, suggesting that dissociable mechanisms may underlie differing aspects of ketamine’s antidepressant activity.