Cognitive effects of rapid-acting treatments for resistant depression: Just adverse, or contributing to clinical efficacy?

J Psychiatr Res. 2021 Aug;140:512-521. doi: 10.1016/j.jpsychires.2021.06.026. Epub 2021 Jun 15.


Major Depressive Disorder is a major public health problem and has a high rate of treatment resistance. Fear conditioning has been proposed as a potential mechanism sustaining negative affect in mood disorders. With the aim of exploring cognitive effects of rapid-acting antidepressant treatments as a potential mechanism of action that can be targeted by neuromodulation, we performed a narrative review of the extant literature on effects of electroconvulsive therapy, ketamine or esketamine, and sleep deprivation on emotional/fear memory retrieval-reconsolidation. We explore interference with reconsolidation as a potential common pathway that explains in part the efficacy of rapid-acting antidepressant treatments with disparate mechanisms of action. We propose the testable hypothesis that fear learning circuits can be specifically targeted by neuromodulation to attempt rapid amelioration of depressive symptoms (especially repetitive negative thinking) while limiting unspecific, untoward cognitive side effects.

Keywords: Depression; Memory reconsolidation; Neuroimaging; Neuromodulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Antidepressive Agents / therapeutic use
  • Cognition
  • Depression
  • Depressive Disorder, Major* / drug therapy
  • Depressive Disorder, Treatment-Resistant* / drug therapy
  • Humans
  • Treatment Outcome


  • Antidepressive Agents