Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression

This open-label study (n=23) found that a long (96 hours (4 days)) infusion of ketamine (10mg/70kg/h up to 42mg/70kg/h) significantly improved depressive symptoms (MADRS) for those suffering from treatment-resistant depression. This effect held up to two weeks later and the study also reported on the associated neurobiological changes.

Abstract

“Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe.”

Authors: Joshua S. Siegel, Ben J. A. Palanca, Beau M. Ances, Evan D. Kharasch, Julie A. Schweiger, Michael D. Yingling, Abraham Z. Snyder, Ginger E. Nicol, Eric J. Lenze & Nuri B. Farber

Summary

Ketamine produced a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown.

Introduction

Until recently, approved antidepressant medications have targeted the brain monoamine systems, but they work slowly and require compliance. Novel pharmacologic approaches have been developed to treat depression.

Ketamine has generated substantial attention as a novel treatment for depression due to its rapid and robust antidepressant action. A 96-h ketamine infusion for treatment-resistant depression was demonstrated to produce rapid improvement in 7/10 subjects and sustained clinical response in 4/10 subjects at 8 weeks.

Ketamine’s rapid antidepressant action arises through activation of the neurotrophic cascade, which involves AMPA receptor signaling, eEF2 signaling, mTOR signaling, and GSK-3 signaling. This mechanism may be similar to the mechanism of action of serotonergic antidepressants and electroconvulsive therapy.

Functional connectivity (FC) within the default mode network (DMN) has been shown to be a cortical marker of depression, and normalization of FC within the subgenual anterior cingulate cortex (sgACC) has been linked with antidepressant response across diverse treatment modalities.

Ketamine’s effects on brain connectivity have been explored in a small number of studies. These studies have found that ketamine decreases FC between the sgACC and DMN in non-depressed adults, and increases FC between the limbic and cortical executive networks in depressed individuals.

We recruited 23 participants with treatment-resistant depression and administered a 96-h ketamine infusion. We used validated clinical assessments to assess clinical response, and used rsfMRI to assess potential neurobiological correlates of ketamine’s antidepressant effects.

Methods and materials

Enrollment

We enrolled adults with major depressive disorder who had failed at least two antidepressant medications and were willing to continue taking them for at least 6 weeks.

Healthy subjects were enrolled and assessed at our center for the purposes of providing controls for imaging studies. They were matched to the ketamine clinical trial participants on demographic and imaging data quality criteria.

Ketamine infusion and measurements

Participants received a continuous 96-h infusion of intravenous ketamine, titrated as tolerated twice daily to a target rate of 0.6 mg/kg/h, and were started on oral clonidine 7 days prior to the infusion.

Psychiatric and cognitive assessments

Researchers used the Brief Psychiatric Rating Scale (BPRS), an adverse events checklist, and the Clinical Global Impressions Improvement scale (CGI-I) to assess psychotomimetic and other side effects of ketamine infusion.

Resting-state functional MRI acquisition and processing

Neuroimaging was performed on a Siemens Trio 3-T TIM scanner to assess baseline FC variability and reliability. Two EPI runs were acquired at each of the three timepoints: the 2 pre-infusion and the 2-week post-infusion time point.

Surface generation and brain areal parcellation

We generated spherical regions of interest for the limbic system and expanded the amygdala, anteromedial thalamus, nucleus accumbens, anterior hippocampus, posterior hippocampus to cover the entire anatomical structure.

Network FC analysis

Based on a review of the effects of both depression and ketamine on FC, we hypothesized that FC within the DMN, sgACC, and limbic system would decrease in patients whose depression improved after ketamine treatment. We then conducted an exploratory FC analysis to visualize connectivity between the three targets.

Volumetric analysis

We assessed the relationship between pre-ketamine volume of limbic structures and response to ketamine using a Pearson correlation.

Statistical approach

This study assessed improvements in MADRS and CGI-I scores, and compared MADRS to other variables (e.g., serum concentrations of total ketamine, s- and r-ketamine, s- and r-norketamine, total norketamine, BPRS positive scale averaged across infusion days) using Pearson correlations.

Functional connectivity data from depression subjects were entered into a linear mixed effects model to assess the relationships between time, treatment response, and functional connectivity. Eight primary outcomes were chosen, and statistics are reported as raw (uncorrected) p values generated by their respective model.

We conducted a post hoc analysis of functional connectivity between matched controls and depression subjects at baseline and after ketamine to better understand the effects of intervention on brain network connectivity.

Results

Prolonged ketamine infusion is tolerated and produced target drug concentrations

23 participants were enrolled, 1 failed to meet inclusion criteria, 3 withdrew consent prior to the infusion, and 5 did not tolerate the maximum target infusion rate. The mean final dose was 0.54 mg/kg/h (SD = 0.13).

Side effects were mild, improved over the course of the infusion, and subsided quickly after stopping infusion. Blood pressure and psychotomimetic effects were mild, peaked on infusion day 3, and tended to decline during infusion days 4 – 5.

Prolonged ketamine infusion induced persistent improvements in depression severity

After the ketamine infusion ended, MADRS scores fell significantly and then rose slowly over the next 8 weeks. Most subjects showed response to ketamine, with 73% showing response after one day, 52% at 2 weeks, and 33% at 8 weeks. Participants’ BPRS positive scale scores showed an inverse relationship to MADRS change at 1 day post-infusion, but the relationship was no longer significant at 2 and 8 weeks.

Effects of ketamine on DMN FC

We first assessed change in DMN FC in response to ketamine infusion. We found that responders showed a trend toward larger decreases in DMN connectivity than non-responders.

Ketamine reduces subgenual anterior cingulate cortex to DMN FC

Ketamine decreased connectivity between the bilateral sgACC and the rest of the DMN across cortical hemispheres, and responders showed a larger decrease in sgACC-DMN connectivity than non-responders.

Ketamine reduces connectivity within the limbic system

Limbic regions had lower raw rsfMRI signal and higher noise than cortex, but following our image processing approach, signal in limbic regions was no different from cortical areas known to have signal dropout.

Ketamine infusion caused a decrease in FC within the limbic system of depressed individuals. The decrease was mainly in the anterior thalamus and other limbic structures, but also in the frontal components of the cingulo-opercular network.

Depression-related hyperconnectivity in the default network and limbic system

We found depression-related hyperconnectivity in the hypothesized systems in pre-treatment TRD subjects compared to healthy matched controls. No difference was seen between healthy controls and post-ketamine TRD patients in any of the four systems tested.

Right hippocampus volume predicts ketamine response

We explored the relationship between limbic structural volumes and clinical response to ketamine, and found that right hippocampal volume predicted greater improvement in response to ketamine.

Discussion

Long infusion paradigm

In a study of adults with treatment-resistant depression, a 96-h, high-dose ketamine infusion provided a persistent antidepressant effect that lasted 8 weeks without any further treatment. This is consistent with previous studies of long ketamine infusions for chronic pain that have reported responses lasting many months.

A higher total ketamine dose and a longer period of NMDA receptor blockade may reduce the relapse rate following cessation of treatment.

This study showed that high-dose ketamine reduced depression-related hyperconnectivity in the limbic system and other brain areas, and may be a potential mechanism underlying ketamine’s antidepressant effects.

Subgenual cingulate and DMN

Ketamine treatment decreased connectivity between the sgACC and the DMN, and this decrease was greater in responders than non-responders. This decrease may reflect a general effect of recovery from depression.

Limbic system

Ketamine effects on FC within the limbic system, particularly the anterior thalamus and anterior hippocampus, may be a ketamine-specific effect, as evidenced by the large FC decreases within the limbic system and in particular between the anterior thalamus and other limbic structures.

Past neuroimaging studies have found limbic FC to correspond to stress-related measures. Ketamine’s antidepressant effects may depend on activation of hippocampal-prefrontal projections, which may explain the decrease in limbic FC observed after ketamine.

A smaller hippocampal volume predicted a better response to ketamine in our exploratory analysis, similar to previous results. This finding may be of clinical importance in choosing between treatment strategies.

Limitations and conclusions

The greatest limitation of this study is that no placebo condition was used. However, response data are similar to that seen in a prior study using a 40-min ketamine infusion control group, suggesting that the observed response is not an artifact.

Future studies are needed to determine optimal parameters of treatment and to understand clinical outcomes. Moreover, clonidine may have an effect on the antidepressant properties of ketamine.

A 96-h ketamine infusion may be practical for hospitalized patients with chronic pain, but may be unrealistic for outpatients. Further clinical development may focus on optimizing patient selection via an enrichment strategy, and on identifying and validating neurobiological predictors of therapeutic response.