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

This double-blind placebo-controlled study (n=48) investigated the antidepressant efficacy of ketamine (14 or 35mg/70kg) in patients with depression and found evidence that its rapid antidepressant effects at 40 and 240 minutes post‐treatment were facilitated by glutamatergic neurotransmission in the prefrontal cortex.

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 ¹⁸F‐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 ¹⁸F‐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.”

Authors: Cheng‐Ta Li, Mu‐Hong Chen, Wei‐Chen Lin, Chen‐Jee Hong, Bang‐Hung Yang, Ren‐Shyan Liu, Pei‐Chi Tu, and Tung‐Ping Su

Summary

INTRODUCTION

Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, is an anesthetic agent with a rapid onset and a short duration of action. It has been shown to improve depressive symptoms in patients with treatment-resistant depression (TRD) and reduce anhedonia in 40 min.

The prefrontal cortex and the subcortical and limbic brain regions are critically involved in the neurocircuitry of depression. Patients with TRD have a hypoactive PFC and a hyperactive amygdala, which persists even after treatment.

Ketamine may have rapid antidepressant effects on TRD, and this study utilized 18F-FDG-PET to investigate cerebral glucose uptake following ketamine or placebo injection. Ketamine may affect the glutamatergic system of mood circuitry in the human brain.

Subjects

Eligible subjects were adult patients with a DSM-IV-TR diagnosis of major depressive disorder who had failed at least three different antidepressants and had no major medical or neurological illnesses.

Study Procedures

Patients underwent detailed psychiatric and medical history-taking, a diagnostic interview, and brain structural imaging by magnetic resonance imaging (MRI) at baseline, and a 40-min acute treatment phase was conducted.

TRD patients were randomized to receive 0.5 mg/kg of ketamine, 0.2 mg/kg of ketamine, or normal saline. Depressive symptoms were rated at baseline, 40, 80, 120, and 240 min post-ketamine administration, and ketamine-induced neuroimaging findings were correlated with primary outcomes.

Imaging Procedures

MR and PET images were acquired using a 3.0 GE Discovery 750 whole-body high-speed imaging device and a 3D brain mode on a PET/CT scanner. A group-specific MRI-aided 18F-FDG template was created and used to normalize each subject’s PET images.

We used the standardized uptake value (SUV) method to correct for FDG activity at the time of injection in order to compare the changes in brain metabolic activity in the first hour after IV infusion treatment.

Region of Interest Analysis of PET Data

To test our hypothesis, region of interest (ROI) analysis was performed using unsmoothed SUV images in the standard stereotactic space. The PFC and amygdala were delineated using an automated anatomical labeling template (AAL template) to prevent bias from inter- or intra-rater reliability issues.

Voxel-Wise Analysis of PET Data

We performed a voxel-wise analysis using SPM8 to compare the SUV changes between the three groups, with ketamine treatment as the main factor. We also performed a paired t-test to visualize the relative changes between the 1st and 2nd SUV images.

Statistical Methods

Statistical analysis was performed using SPSS 16.0 to compare demographic and clinical data between groups (ketamine groups). To investigate the relationship between improvements in depression and differences in before-versus-after SUV in the PFC and amygdala, Pearson’s correlation analysis was performed, two-way repeated measures ANOVA was conducted, and linear regression was performed with age, sex, baseline HDRS-17 scores, and ketamine groups as independent factors.

RESULTS

48 subjects were recruited from December 2012 to April 2014 and participated in the entire study. The active ketamine infusion groups exhibited better antidepressant responses immediately following ketamine treatment than the placebo group.

Ketamine treatment had no between-group significance regarding changes in BPRS positive symptoms, but more cases of floating sensation occurred in Group A.

Region of Interest Analysis of Brain SUV

The ANOVA analysis showed that the low-dose ketamine groups were more associated with PFC activation than the placebo group, but that the amygdala was not. The antidepressant outcomes correlated well with differences in the SUV in the PFC, but not in the amygdala.

The SUV differences in the PFC were negatively correlated with the differences in the amygdala in patients who received active ketamine treatment.

Voxel-Wise Analysis of Brain SUV

The results showed that the PFC, SMA, dACC, and PCG were the main areas affected by low-dose ketamine IV treatment, and that the 0.5 mg/kg group had a greater increase in SUV in these areas than the 0.2 mg/kg group.

Ketamine increased SUV in the bilateral PFC, thalamus, posterior cingulate cortex, parietal cortex, temporal cortex, and occipital cortex, and decreased SUV in the amygdala, hippocampus, cerebellum, and pons.

Linear Regression Results

The most significant factors predicting antidepressant effects after administration of ketamine were the changes in SUV in the PFC and being in a ketamine group, but not the amygdala, age, or sex.

Strengths of the Study

In a double-blind randomized study, the effects of low-dose ketamine on brain mechanisms were investigated. The results indicated that activation of the PFC was involved in the rapid antidepressant effects.

Prefrontal Changes were the Most Important Finding

Although most previous studies administered intravenous ketamine at a dose of 0.5 mg/kg, our data suggest that lower doses of 0.2 mg/kg are also effective in treating TRD. The increased glutamatergic neurotransmission in the PFC was critical to the ketamine-specific rapid antidepressant effect. Structural and functional deficits of the PFC have been found to be associated with TRD, and ketamine can increase PFC activity in TRD patients. However, ketamine’s antidepressant action occurs only in a small- and low-dose range.

Ketamine’s rapid antidepressant effects may be due to a decrease in limbic hyperactivity and thus improve depressive symptoms. The changes in the SUV of the PFC were negatively correlated with SUV changes in the amygdala.

Previous neuroimaging investigations have demonstrated that beliefs and expectations can markedly regulate functional activity in brain regions that are involved in perception and various aspects of emotion processing. The findings related to changes in the posterior brain regions could be attributed to individual expectation and memory.

Potential Psychotomimetic Effects From Ketamine on Imaging Findings?

Ketamine injection was associated with some side effects, such as floating sensations, dissociative symptoms, dizziness, nausea, chest discomfort, and crying. However, the increases in SUVs in the bilateral sensory cortex and the attention system were greater in the 0.5 mg/kg ketamine group than the placebo and 0.2 mg/kg groups. Ketamine increases the number and function of new spine synapses in the periaqueductal gray (PFC) of rats within 24 h of a single-dose intravenous injection of low-dose ketamine (0.3 mg/ kg).

Limitations

The current study could be considered an add-on ketamine study because the original medication regimen that the TRD patients had failed to respond was not discontinued during the ketamine treatment and PET scans. However, the study’s main finding was that ketamine increased the PFC SUV within the first hour. Third, the results of the present study suggest that PFC activation is related to the initial antidepressant effects of low-dose ketamine in human TRD subjects.