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

Abstract

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.

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Authors

Contributions

SP made significant contributions to data collection, analysis, and manuscript preparation. BJR contributed key statistical analyses and critical review for intellectual content. SLF contributed to the drafting of the manuscript as well as key intellectual contributions. AB made contributions to data collection and analyses. AW contributed to the interpretation of key results and critical review for intellectual content. DHM assisted with analytical methods and critical review for intellectual content. TFM made key contributions to data collection, data analysis, manuscript preparation, and final approval of the version to be published.

Drs. Fryer, Wallace, Mathalon, and Marton are US Government employees. The content is solely the responsibility of the authors and does not necessarily represent the views of the Department of Veterans Affairs.

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Correspondence to Tobias F. Marton.

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Cite this article

Pennybaker, S., Roach, B.J., Fryer, S.L. et al. Age affects temporal response, but not durability, to serial ketamine infusions for treatment refractory depression. Psychopharmacology 238, 3229–3237 (2021). https://doi.org/10.1007/s00213-021-05939-z

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Keywords

  • Ketamine
  • Psychopharmacology
  • Geropsychiatry
  • Aging
  • Depression