NMDA hypofunction in the posterior cingulate as a model for schizophrenia: an exploratory ketamine administration study in fMRI.
Georg Northoff, Andre Richter, Felix Bermpohl, Simone Grimm, Ernst Martin, Valentine Leslie Marcar, Constance Wahl, Daniel Hell, Heinz Boeker
Schizophrenia Research January 1, 2005 DOI: 10.1016/j.schres.2004.04.009 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind fMRI study Peer reviewed |
|---|---|
| Sample size | 16 |
| Population | Healthy human subjects |
| Interventions | Ketamine Saline |
| Dose | 0.6 mg/kg/h |
| Measures | Altered States of Consciousness Questionnaire |
| Topics | Esketamine Ketamine |
| Key points | Ketamine reduced BOLD signal increases in the posterior and anterior cingulate during episodic memory retrieval compared with placebo, and lower posterior cingulate signal increases correlated significantly with ketamine-induced psychosis-like symptoms. The authors argue this demonstrates a relationship between NMDA receptors, the posterior cingulate, and positive symptoms in humans, supporting a role for posterior cingulate NMDA receptor hypofunction in schizophrenia. |
Abstract
Based on animal data, NMDA receptor hypofunction has been suggested as a model for positive symptoms in schizophrenia. NMDA receptor hypofunction affects several corticolimbic brain regions, of which the posterior cingulate seems to be the most sensitive. However, empirical support for a crucial role of posterior cingulate NMDA hypofunction in the pathophysiology of positive symptoms is still missing in humans. We therefore conducted an fMRI study using the NMDA antagonist ketamine in healthy human subjects during episodic memory retrieval, which is supposed to activate the posterior cingulate. We investigated 16 healthy subjects which were assigned to either placebo (n = 7; saline) or ketamine (n = 9; 0.6 mg/kg/h) group in a double-blind study design. All subjects received their infusion while performing an episodic memory retrieval task in the scanner. Immediately after the fMRI session, psychopathological effects of ketamine were measured using the Altered States of Consciousness Questionnaire. The placebo group showed BOLD signal increases in the posterior and anterior cingulate during retrieval. Signal increases were significantly lower in the ketamine group. Lower signal increases in the posterior cingulate correlated significantly with positive (i.e. psychosis-like) symptoms induced by ketamine. The present study for the first time demonstrates a relationship between NMDA receptors, posterior cingulate and positive (i.e. psychosis-like) symptoms in humans. Confirming findings from animal studies, it supports the hypothesis of a pathophysiological role of NMDA receptor hypofunction in the posterior cingulate in schizophrenia.
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 16
- Psychometric Evaluation of the Altered States of Consciousness Rating Scale (OAV) PLoS One August 31, 2010
- Glutamate and the Neural Basis of the Subjective Effects of Ketamine Archives of General Psychiatry February 1, 2008
- Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action PLoS One September 24, 2012
- Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution Frontiers in Human Neuroscience May 23, 2017
- Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis Journal of Psychopharmacology March 20, 2009
and 11 more in the library
Cites 8
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- NMDA Antagonist Neurotoxicity: Mechanism and Prevention Science December 6, 1991
- The Standardized Psychometric Assessment of Altered States of Consciousness (ASCs) in Humans Pharmacopsychiatry July 1, 1998
- Ketamine activates psychosis and alters limbic blood flow in schizophrenia Neuroreport April 1, 1995
- NMDA receptor regulation of memory and behavior in humans Hippocampus October 1, 2001
and 3 more in the library