Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects

This double-blind, placebo-controlled, brain imaging study (MEG; n=60) found that ketamine (35mg/70kg) produced different effects in healthy (n=25) and depressed (MDD; n=35) subjects. Both had significant improvement in scores of depression, increases in resting gamma power, those with MDD and lower initial gamma scores and higher scores after ketamine improved most.

Abstract

“Ketamine’s mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5 mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to one day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post-ketamine gamma power and antidepressant response; specifically, higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine’s mechanism of action from studies of healthy controls alone.“

Authors: Allison C. Nugent, Elizabeth Ballard, Todd D. Gould, Lawrence T. Park, Ruin Moaddel, Nancy E. Brutsche & Carlos A. Zarate

Summary

Ketamine’s mechanism of action was assessed using gamma power from magnetoencephalography (MEG) in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls. Higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma.

Introduction

Over half of patients with major depressive disorder fail to respond to first-line treatments, and residual symptoms are common. Ketamine, an NMDA receptor antagonist, has rapid antidepressant and anti-suicidal effects.

Ketamine increases gamma power by silencing GABAergic inhibitory synapses and increasing glutamate release, thereby activating AMPA receptors. This may be the mechanism by which ketamine increases gamma oscillations, which have been associated with cognition, attention, the hemodynamic response, and functional connectivity.

Recent evidence suggests that disruptions in synaptic homeostasis may underlie MDD, and that this disruption may lead to neuronal atrophy, synaptic loss, altered network level connectivity, and altered volume of brain structures involved in emotional processing, all of which have been associated with MDD.

Ketamine has been shown to induce synaptogenesis and reverse synaptic deficits caused by chronic stress, thus restoring network connectivity, but its ability to restore homeostasis in patients with MDD has not yet been demonstrated.

Eligible participants included men and women ages 18 to 65 years with recurrent MDD without psychotic features. Ketamine was given intravenously to 34 patients who had not responded to at least one adequate antidepressant trial during their current episode.

Healthy control subjects were males and females, 18 – 65 years old, with no Axis I disorder and no family history of Axis I disorders in first degree relatives. They provided written informed consent before entry into the study.

Data Collection

Ketamine and placebo infusions were administered two weeks apart with ratings taken 60 minutes before and after each infusion.

The MADRS was the primary outcome measure, and additional secondary outcome measures included the 17-item Hamilton Depression Rating Scale (HAM-D17), the reduced Hamilton-Bech designed to probe rapid changes in depressive symptoms (43), the Snaith-Hamilton Pleasure Scale (SHAPS) (44), and the Temporal Experience of Pleasure Scale (TEPS) (45).

Resting state magnetoencephalography (MEG) recordings were obtained at baseline, the day of the infusion, and 11 – 13 days post-infusion. MEG is associated with enhanced spatial specificity due to the lack of distortion of neuronal magnetic fields by the skull or scalp.

Clinical Data Analysis

Clinical outcome measures were analyzed using IBM SPSS 23.0.0.3. Linear mixed models with restricted maximum likelihood estimation were used to estimate the effects of ketamine and placebo on individual time points.

Magnetoencephalography Data Analysis

The MEG data were processed using CTF software, MNE-python, Analysis of Functional NeuroImages (AFNI), and routines developed in house. The clean epochs were used for all imaging analyses and quality control measures.

MRI and MEG data were localized to source space on a 5mm grid using synthetic aperture magnetometry, and a multisphere head model was calculated from co-registered MRI scans. Gamma power was normalized by the projected noise floor of the virtual sensor.

Images were analyzed using a linear mixed model implemented in the AFNI routine 3dLME (61), with gender and age included as main effects. Additional descriptive analyses were performed on regions of interest (ROIs), as described in the Supplementary Methods.

A secondary analysis was performed using 3dLME to determine if regional gamma power was associated with response to ketamine. Additional mixed models were performed in SPSS to increase sensitivity and to assess differences between diagnostic groups with regard to the relationship between gamma power and change in MADRS score.

After the initial findings that gamma power did not correlate with MADRS response, we performed additional exploratory analyses using data previously defined ROIs. These analyses determined that baseline gamma power moderated the relationship between post-ketamine gamma power and MADRS response.

Code Availability

35 treatment-resistant patients and 26 healthy controls were included in the study. Demographic and clinical characteristics are summarized in Table 1.

Effects of Ketamine on Mood – MDD

Ketamine significantly improved symptoms across a wide variety of domains in MDD subjects, including anhedonia, anxiety, post-traumatic stress disorder (PTSD), suicidality, and quality of life.

Effects of Ketamine on Mood – Healthy Controls

Healthy control subjects exhibited an unexpected increase in depressive symptoms following ketamine infusion, with significant main effects of drug, time, and a drug by time interaction. The increase in depressive symptoms was primarily driven by anxiety, emotional blunting, and anhedonia.

Consistent with MDD patients, healthy controls demonstrated acute increases in depressive symptoms post-ketamine, which were not correlated with dissociative side effects.

Electrophysiology – MEG Results

Figure 2a shows that MDD subjects exhibited increases post-ketamine to levels commensurate with those seen in healthy control subjects following placebo infusion. Figure 2b shows the same contrast in the healthy control group.

We used MADRS scores as a covariate in a mixed model to examine the relationship between gamma power and MADRS response. We observed no significant relationship between gamma power and MADRS response in either group.

Electrophysiology – Exploratory Analysis of Gamma Power and Antidepressant Response

We hypothesized that heterogeneity within the MDD sample might have contributed to the lack of association between antidepressant response and gamma power, and used baseline gamma power to investigate this.

We examined the effect of baseline gamma power on MADRS response using baseline gamma power and absolute change in MADRS score from the -60 to +40-minute time points as covariates. We observed a significant interaction between baseline gamma power and MADRS response in 8 of 11 regions. Figure 3a and 4b show the relationship between gamma power post-ketamine and MADRS response for patients with increasing baseline gamma power.

Discussion

In this study, ketamine produced a robust, rapid, and relatively sustained antidepressant response in MDD patients, but also increased depressive symptoms in healthy control subjects lasting up to 24 hours post-infusion. However, baseline gamma power moderated the relationship between change in gamma power post-ketamine and antidepressant response in multiple regions.

Ketamine infusion in healthy control subjects has been used extensively as a model for schizophrenia, but only one study specifically assessed depressive symptoms. In our study, ketamine infusion acutely reduced depressive symptoms in MDD subjects, but gamma power was still elevated six to nine hours after ketamine infusion.

The extant literature investigating ketamine’s influence on resting gamma oscillations has primarily examined acute response. Although few studies have investigated time points occurring hours or days post-infusion, gamma band synaptic potentiation has been observed six to seven hours post-infusion, although only the motor cortex was examined.

Ketamine’s effects in healthy controls may represent a potential model for dysphoria, and one cannot presume that biological findings in healthy controls will accurately represent the biology of the antidepressant response.

Within the MDD subject group, baseline gamma power moderated the relationship between increased gamma power post-ketamine and antidepressant response in multiple regions. However, gamma power has not been identified as a biomarker for MDD, and there is likely high inter-subject variability. Substantial evidence for biologically-based MDD subpopulations exists, and may reflect altered glutamatergic function as well as inhibition/excitation balance.

Gamma power was increased in regions relating to the SN, CEN, and DMN in healthy controls and MDD subjects, and this increase was correlated with MADRS response. The thalamus and insula were also associated with gamma power in MDD patients.

While tantalizing, our exploratory results should be treated with caution, as they do not provide a biomarker for response to ketamine, and there is no clear “ideal” value for raw gamma power post-ketamine, given that the range of resting gamma power in healthy subjects is relatively broad.

Ketamine infusion in healthy control subjects robustly and rapidly induced depressive symptoms across multiple symptom domains, and gamma power was increased even six to nine hours post-ketamine infusion in both healthy controls and MDD subjects, potentially identifying gamma power as a marker for synaptic homeostasis.

Figure 1.

Ketamine increased depressive symptoms in major depressive disorder subjects and healthy controls at 40, 80, and 120 minutes post-infusion and at Day 1. There was a significant drug by time interaction at 40 minutes post-ketamine infusion in healthy controls.

Figure 2.

Patients with major depressive disorder (MDD) showed increases in gamma power following ketamine infusion to a level commensurate with that of the healthy controls following placebo infusion. Healthy controls showed increases in gamma power in the posterior cingulate and thalamus, regions related to the default mode network (DMN), and in the insula.

Figure 3.

In a mixed model of major depressive disorder patients, baseline gamma power in the right thalamus was significantly associated with change in Montgomery sberg Depression Rating Scale score following ketamine infusion, as well as an interaction between baseline gamma power and MADRS response.