Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression

Abstract

Background: Current theory suggests that treatment-resistant depression (TRD) involves impaired neuroplasticity resulting in cognitive and neural rigidity, and that clinical improvement may require increasing brain flexibility and adaptability.

Aims: In this hypothesis-generating study, we sought to identify preliminary evidence of brain flexibility correlates of clinical change within the context of an open-label ketamine trial in adolescents with TRD, focusing on two promising candidate markers of neural flexibility: (a) entropy of resting-state functional magnetic resonance imaging (fMRI) signals; and (b) insulin-stimulated phosphorylation of mammalian target of rapamycin (mTOR) and glycogen synthase-3-beta (GSK3β) in peripheral blood mononuclear cells.

Methods: We collected resting-state functional magnetic resonance imaging data and blood samples from 13 adolescents with TRD before and after a series of six ketamine infusions over 2 weeks. Usable pre/post ketamine data were available from 11 adolescents for imaging and from 10 adolescents for molecular signaling. We examined correlations between treatment response and changes in the central and peripheral flexibility markers.

Results: Depression reduction correlated with increased nucleus accumbens entropy. Follow-up analyses suggested that physiological changes were associated with treatment response. In contrast to treatment non-responders (n=6), responders (n=5) showed greater increase in nucleus accumbens entropy after ketamine, together with greater post-treatment insulin/mTOR/GSK3β signaling.

Conclusions: These data provide preliminary evidence that changes in neural flexibility may underlie symptom relief in adolescents with TRD following ketamine. Future research with adequately powered samples is needed to confirm resting-state entropy and insulin-stimulated mTOR and GSK3β as brain flexibility markers and candidate targets for future clinical trials.

Clinical trial name: Ketamine in adolescents with treatment-resistant depressionURL: https://ichgcp.net/clinical-trials-registry/NCT02078817Registration number: NCT02078817.

Keywords: Ketamine; adolescents; depression; entropy; mTOR/GSK3β; neuroplasticity.

Conflict of interest statement

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.

Individual changes in right nucleus accumbens (rNAc) log(entropy) versus individual percentage changes in Children’s Depression Rating Scale–Revised (CDRS-R) ratings. Entropy changes were assessed for the 0.08–0.12 Hz range. With respect to baseline, all responders (n=5, blue) showed an increase in rNAc log(entropy) after ketamine, while all non-responders (n=6, red) showed a decrease in rNAc log(entropy) after ketamine. Increased rNAc log(entropy) strongly correlated with depression response.

Figure 2.

Group-level entropy changes (0.08–0.12 Hz) for depression-related regions of interest. Entropy changes with respect to baseline were assessed in the following regions of interest: left and right hippocampus (lHipp and rHipp), left and right amygdala (lAmyg and rAmyg), left and right nucleus accumbens (lNAc and rNAc), subcallosal cortex (SubCal), left and right insula (lInsula and rInsula), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), precuneus (PreC), and left and right thalamus (lThal and rThal). A significant group difference in rNAc log(entropy) change was observed between responders (n=5, blue) and non-responders (n=6, red). Error bars show the standard error of the mean.

Figure 3.

Post-ketamine percentage changes in pmTOR/mTOR versus baseline-to-post-ketamine changes in Children’s Depression Rating Scale–Revised (CDRS-R) ratings and right nucleus accumbens (rNAc) log(entropy). Responders (n=5, blue) had a significantly greater percentage change in post-ketamine pmTOR/mTOR compared with non-responders (n=5, red) (a). Post-ketamine percentage changes in pmTOR/mTOR strongly correlated with baseline-to-post-ketamine changes in CDRS-R ratings (b) and baseline-to-post-ketamine changes in rNAc log(entropy) (c), respectively. Error bars show the standard error of the mean.

Figure 4.

Post-ketamine percentage changes in pGSK3β/GSK3β versus baseline-to-post-ketamine changes in Children’s Depression Rating Scale–Revised (CDRS-R) ratings and right nucleus accumbens (rNAc) log(entropy). Responders (n=5, blue) had a significantly greater percentage change in post-ketamine pGSK3β/GSK3β compared with non-responders (n=5, red) (a). Post-ketamine percentage changes in pGSK3β/GSK3β strongly correlated with baseline-to-post-ketamine changes in CDRS-R ratings (b) and baseline-to-post-ketamine changes in rNAc log(entropy) (c), respectively. Error bars show the standard error of the mean.