Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals
A. Mkrtchian, Jennifer W. Evans, Christoph Kraus, P. Yuan, Bashkim Kadriu, Allison C. Nugent, Jonathan P. Roiser, Carlos A. Zarate
Molecular Psychiatry September 14, 2020 DOI: 10.1038/s41380-020-00878-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind, placebo-controlled, crossover trial Peer reviewed |
|---|---|
| Sample size | 58 |
| Population | 33 individuals with treatment-resistant major depressive disorder and 25 healthy volunteers |
| Intervention | Ketamine |
| Duration | 2 days post-infusion |
| Topics | Esketamine Ketamine |
| Citations | 110 |
| Key findings | Ketamine normalized fronto-striatal connectivity in treatment-resistant depression but disrupted it in healthy volunteers, independent of inflammatory changes. |
Abstract
Ketamine improves motivation-related symptoms in depression but simultaneously elicits similar symptoms in healthy individuals, suggesting that it might have different effects in health and disease. This study examined whether ketamine affects the brain’s fronto-striatal system, which is known to drive motivational behavior. The study also assessed whether inflammatory mechanisms—which are known to influence neural and behavioral motivational processes—might underlie some of these changes. These questions were explored in the context of a double-blind, placebo-controlled, crossover trial of ketamine in 33 individuals with treatment-resistant major depressive disorder (TRD) and 25 healthy volunteers (HVs). Resting-state functional magnetic resonance imaging (rsfMRI) was acquired 2 days post-ketamine (final sample: TRD n = 27, HV n = 19) and post-placebo (final sample: TRD n = 25, HV n = 18) infusions and was used to probe fronto-striatal circuitry with striatal seed-based functional connectivity. Ketamine increased fronto-striatal functional connectivity in TRD participants toward levels observed in HVs while shifting the connectivity profile in HVs toward a state similar to TRD participants under placebo. Preliminary findings suggest that these effects were largely observed in the absence of inflammatory (C-reactive protein) changes and were associated with both acute and sustained improvements in symptoms in the TRD group. Ketamine thus normalized fronto-striatal connectivity in TRD participants but disrupted it in HVs independently of inflammatory processes. These findings highlight the potential importance of reward circuitry in ketamine’s mechanism of action, which may be particularly relevant for understanding ketamine-induced shifts in motivational symptoms.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cited by 54
- Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis. Psychiatry Research May 1, 2024
- The anterior cingulate cortex as a key locus of ketamine’s antidepressant action Neuroscience & Biobehavioral Reviews May 10, 2021
- Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment Neuropharmacology January 13, 2023
- A unified model of ketamine's dissociative and psychedelic properties. Journal of Psychopharmacology December 17, 2022
- Predicting outcome with Intranasal Esketamine treatment: A machine-learning, three-month study in Treatment-Resistant Depression (ESK-LEARNING) Psychiatry Research July 29, 2023
and 49 more in the library
Cites 15
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Reviewing the ketamine model for schizophrenia Journal of Psychopharmacology November 20, 2013
- Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression Translational Psychiatry October 14, 2014
- Ketamine Has Distinct Electrophysiological and Behavioral Effects in Depressed and Healthy Subjects Molecular Psychiatry February 27, 2018
and 10 more in the library