Shank3 as a potential biomarker of antidepressant response to ketamine and its neural correlates in bipolar depression

J Affect Disord. 2015 Feb 1;172:307-11. doi: 10.1016/j.jad.2014.09.015. Epub 2014 Oct 16.


Background: Shank3, a post-synaptic density protein involved in N-methyl-d-aspartate (NMDA) receptor tethering and dendritic spine rearrangement, is implicated in the pathophysiology of bipolar disorder. We hypothesized that elevated baseline plasma Shank3 levels might predict antidepressant response to the NMDA receptor antagonist ketamine.

Methods: Twenty-nine subjects with bipolar depression received a double-blind, randomized, subanesthetic dose (.5 mg/kg) ketamine infusion. Of the patients for whom Shank3 levels were collected, 15 completed baseline 3-Tesla MRI and 17 completed post-ketamine [(18)F]-FDG PET.

Results: Higher baseline Shank3 levels predicted antidepressant response at Days 1 (r=-.39, p=.047), 2 (r=-.45, p=.02), and 3 (r=-.42, p=.03) and were associated with larger average (r=.58, p=.02) and right amygdala volume (r=.65, p=.009). Greater baseline Shank3 also predicted increased glucose metabolism in the hippocampus (r=.51, p=.04) and amygdala (r=.58, p=.02).

Limitations: Limitations include the small sample size, inability to assess the source of peripheral Shank3, and the lack of a placebo group for baseline Shank3 levels and comparative structural/functional neuroimaging.

Conclusions: Shank3 is a potential biomarker of antidepressant response to ketamine that correlates with baseline amygdala volume and increased glucose metabolism in the amygdala and hippocampus.

Trial registration: NCT00088699.

Keywords: Bipolar depression; Ketamine; MRI; PET; Shank3.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Amygdala / metabolism
  • Antidepressive Agents / therapeutic use*
  • Biomarkers / blood
  • Bipolar Disorder / blood*
  • Bipolar Disorder / drug therapy*
  • Double-Blind Method
  • Female
  • Humans
  • Ketamine / therapeutic use*
  • Male
  • N-Methylaspartate / therapeutic use
  • Receptors, N-Methyl-D-Aspartate / blood*
  • Treatment Outcome


  • Antidepressive Agents
  • Biomarkers
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Ketamine

Associated data