# Ketamine effects on resting state functional brain connectivity in major depressive disorder patients: a hypothesis-driven analysis based on a network model of depression

## TL;DR

This study shows that ketamine affects brain networks linked to depression, supporting its use as a fast-acting antidepressant.

## Contribution

The study demonstrates ketamine's specific impact on depression-related brain circuits using a hypothesis-driven network model.

## Key findings

- Ketamine significantly reduced depression scores 24 hours after administration.
- Ketamine caused significant changes in functional connectivity in MDD-related circuits at acute and delayed time points.
- No connectivity changes were observed in non-MDD-related circuits.

## Abstract

Ketamine demonstrates robust and rapidly occurring antidepressant effects in patients with difficult-to-treat major depressive disorder. Ketamine’s antidepressant effects and its impact on functional networks in non-resistant forms of major depressive disorder are expected to provide valuable insight into ketamine’s mechanism of action related to depression.

This study employs an existing network model of major depressive disorder to investigate the effects of ketamine on resting state connectivity in a therapy-non-resistant major depressive disorder population. In a randomized, double-blind, placebo-controlled, cross-over study, 0.5 mg/kg racemic ketamine or 0.9%NaCl was administered intravenously in 16 MDD patients. We applied resting-state functional magnetic resonance imaging (rs-fMRI) to explore changes in functional brain connectivity directly at 50, 80 and 165 min (acute) and 24 h (delayed) following ketamine administration. A clinician-rated 10-item scale (MADRS) was administered at 165 min and 24 h after ketamine administration. Connections-of-interest (COIs) were based on the previously published corticolimbic-insular-striatalpallidal-thalamic (CLIPST) circuitry model of major depressive disorder.

Compared with placebo, ketamine significantly (p < 0.0014) reduced the mean (SD) MADRS total score from 21.2 (5.9) pre-dose to 10.3 (4.6) 24 h post-dose. At both acute (p < 0.0172) and delayed (p < 0.0488) time points, significant rs-fMRI connectivity changes occurred only in MDD-related COIs as proposed by the CLIPST model. No changes in functional connectivity were found in non-CLIPST connections.

This study demonstrates that ketamine specifically affects depression-related circuitry. Analyzing functional connectivity based on a neurocircuitry model of a specific CNS disease and drug action may be an effective approach that could result in a more targeted analysis in future pharmaco-fMRI studies in CNS drug development.