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

Abstract

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: ClinicalTrials.gov NCT00088699.

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

Conflict of interest statement

Conflict of Interest

All other authors have no conflict of interest to disclose, financial or otherwise.

Published by Elsevier B.V.

Figures

Figure 1. Baseline Shank3 as a biomarker for antidepressant response to ketamine

Higher baseline Shank3 plasma levels were associated with greater improvements after ketamine treatment, as measured by decrease in Montgomery-Asberg Depression Rating Scale (MADRS) scores (n=26) at Days 1 (r=−.39, p=.047) and 3 (r=−.48, p=.01) post-ketamine infusion.

Figure 2. Baseline peripheral Shank3 levels were correlated with increased glucose metabolism in the hippocampus and amygdala post-ketamine infusion

a) Axial view showing regions of interest acquired from FDG-PET in the hippocampus (blue) and amygdala (red). Higher baseline Shank3 levels were associated with greater glucose metabolism (n=17) in the b) hippocampus (r=.50, p=.04) and c) amygdala (r=.57, p=0.02). rMRGlu=regional metabolic rate of glucose.