• Online Features  This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (58)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • Psychiatry  • Psychiatry, Other  • Radiologic Imaging  • Magnetic Resonance Imaging  • Alert me on articles by topic  Social Bookmarking   What's this?

A Pharmaco–Magnetic Resonance Imaging Study

J. F. William Deakin, PhD, FRCPsych, FmedSci; Jane Lees, BSc, MSc; Shane McKie, MEng, MSc, PhD; Jaime E. C. Hallak, MD, PhD; Steve R. Williams, BA, MA, DPhil; Serdar M. Dursun, MD, PhD, FRCPC

Arch Gen Psychiatry. 2008;65(2):154-164.

Context  Ketamine evokes psychosislike symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release.

Objectives  To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine.

Design  Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level–dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release.

Setting  Wellcome Trust Clinical Research Facility, Manchester, England.

Participants  Thirty-three healthy, right-handed men were recruited by advertisements.

Interventions  In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1.

Main Outcome Measures  Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores.

Results  Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r = 0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms.

Conclusions  These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.

Author Affiliations: Neuroscience and Psychiatry Unit (Drs Deakin, McKie, Hallak, and Dursun and Ms Lees) and Imaging Science and Biomedical Engineering (Dr Williams), The University of Manchester, Manchester, England; and Neurology, Psychiatry, and Psychological Medicine Department, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil (Dr Hallak).

CiteULike    Connotea    Delicious    Digg    Facebook    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Effects of lamotrigine on PCP-evoked elevations in monoamine levels in the medial prefrontal cortex of freely moving rats
Quarta and Large
J Psychopharmacol 2011;25:1703-1711.
ABSTRACT | FULL TEXT  

Evaluation of state and trait biomarkers in healthy volunteers for the development of novel drug treatments in schizophrenia
Koychev et al.
J Psychopharmacol 2011;25:1207-1225.
ABSTRACT | FULL TEXT  

Using MRI to measure drug action: caveats and new directions
Murphy and Mackay
J Psychopharmacol 2011;25:1168-1174.
ABSTRACT | FULL TEXT  

Thalamic Glutamate Levels as a Predictor of Cortical Response During Executive Functioning in Subjects at High Risk for Psychosis
Fusar-Poli et al.
Arch Gen Psychiatry 2011;68:881-890.
ABSTRACT | FULL TEXT  

The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia
Large et al.
J. Pharmacol. Exp. Ther. 2011;338:100-113.
ABSTRACT | FULL TEXT  

Awake Rat Pharmacological Magnetic Resonance Imaging as a Translational Pharmacodynamic Biomarker: Metabotropic Glutamate 2/3 Agonist Modulation of Ketamine-Induced Blood Oxygenation Level Dependence Signals
Chin et al.
J. Pharmacol. Exp. Ther. 2011;336:709-715.
ABSTRACT | FULL TEXT  

Glutamatergic antipsychotic drugs: a new dawn in the treatment of schizophrenia?
Stone
Therapeutic Advances in Psychopharmacology 2011;1:5-18.
ABSTRACT  

NMDA Receptor Hypofunction in the Prelimbic Cortex Increases Sensitivity to the Rewarding Properties of Opiates via Dopaminergic and Amygdalar Substrates
Bishop et al.
Cereb Cortex 2011;21:68-80.
ABSTRACT | FULL TEXT  

Dysfunction of a Cortical Midline Network During Emotional Appraisals in Schizophrenia
Holt et al.
Schizophr Bull 2011;37:164-176.
ABSTRACT | FULL TEXT  

A 1H-MR Spectroscopy Study of Changes in Glutamate and Glutamine (Glx) Concentrations in Frontal Spectra after Administration of Memantine
van Wageningen et al.
Cereb Cortex 2010;20:798-803.
ABSTRACT | FULL TEXT  

Ethanol-like effects of thiopental and ketamine in healthy humans
Dickerson et al.
J Psychopharmacol 2010;24:203-211.
ABSTRACT  

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology and Therapeutics of Mood Disorders
Machado-Vieira et al.
Neuroscientist 2009;15:525-539.
ABSTRACT