Hippocampal volume and the rapid antidepressant effect of ketamine

J Psychopharmacol. 2015 May;29(5):591-5. doi: 10.1177/0269881114544776. Epub 2014 Aug 13.


Accumulating evidence underscores the utility of ketamine in treating severely treatment-resistant depressed patients. We investigated the relationship between the rapid antidepressant effects of ketamine and hippocampal volume, a biomarker of antidepressant treatment outcome. We gave 16 medication-free, major depressive disorder (MDD) patients a single, sub-anesthetic dose infusion of ketamine (0.5 mg/kg, over 40 min). We assessed depression severity pre-treatment, and at 24 h post-treatment, with the Montgomery-Åsberg Depression Rating Scale (MADRS). Prior to treatment, patients underwent magnetic resonance imaging (MRI) to estimate their hippocampal volume: We obtained viable MRI data in 13 patients. Delta MADRS (post- minus pre-treatment) was significantly correlated with the pre-treatment volumes of the left hippocampus (r = 0.66; p = 0.01), but not the right hippocampus (r = 0.49; p = 0.09). The correlation between delta MADRS and the left hippocampus remained high (r > 0.6; p = 0.13), after controlling for several demographic and clinical variables, although the p value increased due to the reduced degree of freedom (df = 5). Ketamine exerts enhanced antidepressant effects in patients with a relatively smaller hippocampus, a patient population that has been repeatedly shown to be refractory to traditional antidepressants.

Keywords: Antidepressant; depression; hippocampus; ketamine; magnetic resonance imaging; major depressive disorder; refractory patients.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Antidepressive Agents / therapeutic use*
  • Biomarkers
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / pathology
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Depressive Disorder, Treatment-Resistant / pathology
  • Double-Blind Method
  • Female
  • Hippocampus / pathology*
  • Humans
  • Ketamine / therapeutic use*
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Psychiatric Status Rating Scales
  • Treatment Outcome


  • Antidepressive Agents
  • Biomarkers
  • Ketamine