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

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. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.

Keywords: Depression; Functional connectivity; Hippocampus; Ketamine; Limbic system; Subgenual anterior cingulate cortex.

Fig. 1

Clinical response to 96 h ketamine infusion. MADRS scores were significantly improved by ketamine (repeated measures ANOVA p < 0.001). Mean MADRS was 29 pre-infusion, 9 one day post-infusion, 13 and 15 at 2 and 8 weeks post-infusion, respectively. Black line shows mean and SD. Double asterisk indicates p < 0.001 for all post-infusion timepoints versus baseline. Red bar indicates infusion period; @ indicates neuroimaging timepoints. Below, percent of patients meeting criteria for response, remission, and CGI-I of 1-2 (much or very much improved), as well as total number of subjects at each timepoint

Fig. 2

Connectivity between subgenual anterior cingulate (sgACC) and Default Mode Network (DMN) decreases with ketamine infusion. a Regions included in bilateral sgACC and DMN are shown. b Blue lines on the left represent normal variability of FC between the sgACC and DMN in depressed patients (open circles are individuals with a single pre timepoint). Blue lines on the right represent change in FC resulting from ketamine infusion. Asterisk indicates that main effect of time (pre-infusion vs post-infusion) was significant (p = 0.001). c FC change in TRD patients (post-infusion minus pre-infusion). Error bars = SD of FC change. d Maps of cortical FC of bilateral sgACC (target symbol) before and after ketamine. e Comparison of FC change between responders (greater than 50% reduction in MADRS) and non-responders (less than 50% reduction in MADRS). Asterisk indicates the interaction of time-by-response was significant (p = 0.028). Error bars = SD

Fig. 3

Connectivity within the limbic system decreases after ketamine infusion. a Regions of interest included in the limbic network. b Blue lines on the left represent normal variability of limbic FC (open circles are individuals with a single pre timepoint, black lines are mean of patients with both timepoints). Blue lines on the right represent change in FC resulting from ketamine infusion. Asterisk indicates that main effect of time (pre-infusion vs post-infusion) was significant (p = 0.003). c FC change in TRD patients (post-infusion minus pre-infusion). Error bars = SD of FC change. d Matrix of FC change between limbic regions. Colored squares in the matrix indicate pairs of limbic regions whose connectivity changes as a result of ketamine infusion (red indicates increased FC, blue indicates decreased FC). The matrix shows t-statistics thresholded by p < 0.1. e Group-average seed FC between limbic network and cortical regions before and after ketamine are projected on the right hemisphere. The difference map is also shown for both hemispheres

Fig. 4

Depression-related hyperconnectivity is seen in the three hypothesized systems, but not the visual system. The four clusters of bars indicate group mean and SD of functional connectivity within (1) the entire DMN, (2) subgenual anterior cingulate to DMN, (3) the limbic system, and (4) the visual system for matched controls (cream) and for patients before (cyan, two timepoints), and after ketamine treatment (blue). Black asterisks indicate a difference (2-tailed t test; p < 0.05 uncorrected) between groups. Error bars = SD. sgACC, subgenual anterior cingulate cortex; DMN, default mode network

Fig. 5

Pre-treatment hippocampal volume predicts treatment response. The x-axis depicts volume of the hippocampus as a proportion of intracranial volume; the y-axis reflects change in MADRS score from baseline to two weeks post-infusion. p values are not corrected for multiple comparisons (6 comparisons done)