Dataset Information

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.

SUBMITTER: Siegel JS

PROVIDER: S-EPMC7969576 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (TRD) and bipolar disorder. While its underlying mechanism of antidepressant action is not fully understood, modulating glutamatergically-mediated connectivity appears to be a critical component moderating antidepressant response. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with TRD and 15 healthy volunteers who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6-9 h after both drug and placebo infusions. During scanning, participants completed an attentional dot probe task that included emotional faces. Antidepressant response was measured across time points using the Montgomery-Asberg Depression Rating Scale (MADRS). Dynamic causal modeling (DCM) was used to measure changes in parameter estimates of connectivity via a biophysical model that included realistic local neuronal architecture and receptor channel signaling, modeling connectivity between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus. Clinically, ketamine administration significantly reduced depressive symptoms in TRD participants. Within the model, ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in TRD participants post-ketamine were associated with faster α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamine's antidepressant effects. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00088699?term=NCT00088699&draw=2&rank=1, identifier NCT00088699.

Project description:Major depressive disorder is a leading cause of disability and significant mortality, yet mechanistic understanding remains limited. Over the past decade evidence has accumulated from case-control studies that depressive illness is associated with blunted reward activation in the basal ganglia and other regions such as the medial prefrontal cortex. However it is unclear whether this finding can be replicated in a large number of subjects. The functional anatomy of the medial prefrontal cortex and basal ganglia has been extensively studied and the former has excitatory glutamatergic projections to the latter. Reduced effect of glutamatergic projections from the prefrontal cortex to the nucleus accumbens has been argued to underlie motivational disorders such as depression, and many prominent theories of major depressive disorder propose a role for abnormal cortico-limbic connectivity. However, it is unclear whether there is abnormal reward-linked effective connectivity between the medial prefrontal cortex and basal ganglia related to depression. While resting state connectivity abnormalities have been frequently reported in depression, it has not been possible to directly link these findings to reward-learning studies. Here, we tested two main hypotheses. First, mood symptoms are associated with blunted striatal reward prediction error signals in a large community-based sample of recovered and currently ill patients, similar to reports from a number of studies. Second, event-related directed medial prefrontal cortex to basal ganglia effective connectivity is abnormally increased or decreased related to the severity of mood symptoms. Using a Research Domain Criteria approach, data were acquired from a large community-based sample of subjects who participated in a probabilistic reward learning task during event-related functional MRI. Computational modelling of behaviour, model-free and model-based functional MRI, and effective connectivity dynamic causal modelling analyses were used to test hypotheses. Increased depressive symptom severity was related to decreased reward signals in areas which included the nucleus accumbens in 475 participants. Decreased reward-related effective connectivity from the medial prefrontal cortex to striatum was associated with increased depressive symptom severity in 165 participants. Decreased striatal activity may have been due to decreased cortical to striatal connectivity consistent with glutamatergic and cortical-limbic related theories of depression and resulted in reduced direct pathway basal ganglia output. Further study of basal ganglia pathophysiology is required to better understand these abnormalities in patients with depressive symptoms and syndromes.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets