Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression

Summary & key facts

About 100 adults with unipolar depression who had not improved on at least one antidepressant were given a single intravenous infusion of ketamine or a saline placebo. The researchers scanned their brains before and 24 hours after the infusion using a method that measures tiny changes in gray matter called mean diffusivity, which may reflect rapid increases in the brain's ability to rewire itself. People who showed bigger decreases in mean diffusivity in several brain areas also tended to have larger drops in depression scores. Some of those links were stronger in the people who got ketamine, but the findings are associations from one dose and one day and do not prove that the brain changes caused the mood improvements.

Key facts:

• About 100 adults with unipolar depression who had failed at least one antidepressant were randomly assigned so that about twice as many people got a single intravenous ketamine infusion as got saline placebo.
• Researchers used diffusion tensor imaging to measure mean diffusivity, a brain scan metric the authors treat as an indirect sign of rapid microstructural neuroplasticity, at baseline and again 24 hours after the infusion.
• Larger decreases in mean diffusivity from before to 24 hours after the infusion were linked to larger improvements on clinician-rated and self-report depression scales.
• In the left front brain area called BA10 and in the left amygdala, the relationship between diffusivity change and mood improvement was driven mainly by the ketamine-treated group.
• In the right BA10 the same link between diffusivity change and mood improvement was seen in both the ketamine and placebo groups.
• In the left and right hippocampus the pattern was different and on the main clinician-rated scale the direction of the association in the ketamine group was the opposite of what was seen in other regions.
• The study looked at short-term effects after one ketamine dose and used an indirect imaging marker, so it shows a possible link between rapid brain changes and fast antidepressant effects but does not prove cause and does not tell us how long any changes last.

Abstract

Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of interest (left and right BA10, amygdala, and hippocampus; and ventral Anterior Cingulate Cortex) and compared to clinical response measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). Individual differences in DTI-MD change (greater decrease from baseline to 24-h post-infusion, indicative of more neuroplasticity enhancement) were associated with larger improvements in depression scores across several regions. In the left BA10 and left amygdala, these relationships were driven primarily by the ketamine group (group * DTI-MD interaction effects: p = 0.016-0.082). In the right BA10, these associations generalized to both infusion arms (p = 0.007). In the left and right hippocampus, on the MADRS only, interaction effects were observed in the opposite direction, such that DTI-MD change was inversely associated with depression change in the ketamine arm specifically (group * DTI-MD interaction effects: p = 0.032-0.06). The acute effects of ketamine on depression may be mediated, in part, by acute changes in neuroplasticity quantifiable with DTI.

Topics

Advanced MRI Techniques and Applications Functional Brain Connectivity Studies Treatment of Major Depression

Categories

Cognitive Neuroscience Life Sciences Neuroscience

Tags

Amygdala Anesthesia Antidepressant Depression (economics) Diffusion MRI Economics Hippocampus Internal medicine Ketamine Macroeconomics Magnetic resonance imaging Major depressive disorder Medicine Neuroplasticity Neuroscience Psychology Radiology Randomized controlled trial

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood