The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study

Abstract

Background: Low-dose ketamine has been found to have robust and rapid antidepressant effects. A hypoactive prefrontal cortex (PFC) and a hyperactive amygdala have been suggested to be associated with treatment-resistant depression (TRD). However, it is unclear whether the rapid antidepressant mechanisms of ketamine on TRD involve changes in glutamatergic neurotransmission in the PFC and the amygdala.

Methods: A group of 48 TRD patients were recruited and equally randomized into three groups (A: 0.5 kg/mg-ketamine; B: 0.2 kg/mg-ketamine; and C: normal saline [NS]). Standardized uptake values (SUV) of glucose metabolism measured by (18) F-FDG positron-emission-tomography before and immediately after a 40-min ketamine or NS infusion were used for subsequent region-of-interest (ROI) analyses (a priori regions: PFC and amygdala) and whole-brain voxel-wise analyses and were correlated with antidepressant responses, as defined by the Hamilton depression rating scale score. The (18) F-FDG signals were used as a proxy measure of glutamate neurotransmission.

Results: The ROI analysis indicated that Group A and Group B, but not Group C, had increases in the SUV of the PFC (group-by-time interaction: F = 7.373, P = 0.002), whereas decreases in the SUV of the amygdala were observed in all three groups (main effect of time, P < 0.001). The voxel-wise analysis further confirmed a significant group effect on the PFC (corrected for family-wise errors, P < 0.05; post hoc analysis: Group A<Group C, Group B<Group C). The SUV differences in the PFC predicted the antidepressant responses at 40 and 240 min post-treatment. The PFC changes did not differ between those with and without side effects.

Conclusion: Ketamine's rapid antidepressant effects involved the facilitation of glutamatergic neurotransmission in the PFC.

Keywords: glucose; ketamine; prefrontal cortex; treatment-resistant depression.

Figure 1

ROI analysis showing the effects of ketamine on the PFC and the amygdala among different groups. A: Normalized PFC glucose uptake (PFC SUV/whole‐brain SUV) was significantly elevated in the 0.5 mg/kg and 0.2 mg/kg groups but not in the placebo group. The ROI analysis demonstrated a significant increase in the amygdala in all three groups. The bars are presented as the mean (standard deviation [SD]). B: The PFC SUV changes after treatment; the changes were significantly correlated with improvement in depression as documented by percent changes in HDRS‐17 scores. C: No correlation existed between the amygdala SUV changes and clinical improvement. P‐values of less than 0.05 were considered to be statistically significant (*P < 0.05, **P < 0.005).

Figure 2

Correlation between SUV changes in the PFC and the amygdala. This correlation was observed most significantly in the patients receiving active ketamine treatment (bottom left figure) (P < 0.05). However, this correlation was not observed in the placebo group, suggesting that the antidepressant mechanisms of the placebo differ from the antidepressant mechanisms of ketamine.

Figure 3

Voxel‐wise analysis showing a significant main effect of ketamine among the different groups and the post hoc analysis. Left panel: The significant main effect of the group was on the PFC, the supplementary motor area (SMA), the dorsal anterior cingulate cortex (dACC), and the bilateral post‐central gyrus (PCG). Right panel: The post hoc analyses showed that both of the ketamine groups had significantly greater increases in the SUV in the PFC, SMA, and parts of the PCG than the placebo group. The 0.5 mg/kg group (Group A) had a significantly greater increase in the SUV in the dACC and bilateral PCG than the 0.2 mg/kg group (Group B), but had a significantly lower increase in the SUV of the right‐side of the PFC than the 0.2 mg/kg group. The significance thresholds for voxel‐wise analysis were set at a voxel‐level family‐wise error (FWE)‐corrected level of P < 0.05 by two‐way group‐by‐time ANOVA. No significant main effect of time and no significant interaction between group and time were found. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]