PMID- 25980482
OWN - NLM
STAT- MEDLINE
DCOM- 20160602
LR  - 20181202
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 232
IP  - 21-22
DP  - 2015 Nov
TI  - Ketamine induces a robust whole-brain connectivity pattern that can be 
      differentially modulated by drugs of different mechanism and clinical profile.
PG  - 4205-18
LID - 10.1007/s00213-015-3951-9 [doi]
AB  - Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been studied 
      in relation to the glutamate hypothesis of schizophrenia and increases 
      dissociation, positive and negative symptom ratings. Ketamine effects brain 
      function through changes in brain activity; these activity patterns can be 
      modulated by pre-treatment of compounds known to attenuate the effects of 
      ketamine on glutamate release. Ketamine also has marked effects on brain 
      connectivity; we predicted that these changes would also be modulated by 
      compounds known to attenuate glutamate release. Here, we perform task-free 
      pharmacological magnetic resonance imaging (phMRI) to investigate the functional 
      connectivity effects of ketamine in the brain and the potential modulation of 
      these effects by pre-treatment of the compounds lamotrigine and risperidone, 
      compounds hypothesised to differentially modulate glutamate release. Connectivity 
      patterns were assessed by combining windowing, graph theory and multivariate 
      Gaussian process classification. We demonstrate that ketamine has a robust effect 
      on the functional connectivity of the human brain compared to saline (87.5 % 
      accuracy). Ketamine produced a shift from a cortically centred, to a 
      subcortically centred pattern of connections. This effect is strongly modulated 
      by pre-treatment with risperidone (81.25 %) but not lamotrigine (43.75 %). Based 
      on the differential effect of these compounds on ketamine response, we suggest 
      the observed connectivity effects are primarily due to NMDAR blockade rather than 
      downstream glutamatergic effects. The connectivity changes contrast with 
      amplitude of response for which no differential effect between pre-treatments was 
      detected, highlighting the necessity of these techniques in forming an informed 
      view of the mechanistic effects of pharmacological compounds in the human brain.
FAU - Joules, R
AU  - Joules R
AD  - Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, 
      Kings College London, De Crespigny Park, London, SE5 8AF, UK. 
      richard.joules@kcl.ac.uk.
FAU - Doyle, O M
AU  - Doyle OM
AD  - Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, 
      Kings College London, De Crespigny Park, London, SE5 8AF, UK.
FAU - Schwarz, A J
AU  - Schwarz AJ
AD  - Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
AD  - Department of Psychological and Brain Sciences, Indiana University, Bloomington, 
      IN, USA.
FAU - O'Daly, O G
AU  - O'Daly OG
AD  - Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, 
      Kings College London, De Crespigny Park, London, SE5 8AF, UK.
FAU - Brammer, M
AU  - Brammer M
AD  - Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, 
      Kings College London, De Crespigny Park, London, SE5 8AF, UK.
FAU - Williams, S C
AU  - Williams SC
AD  - Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, 
      Kings College London, De Crespigny Park, London, SE5 8AF, UK.
FAU - Mehta, M A
AU  - Mehta MA
AD  - Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, 
      Kings College London, De Crespigny Park, London, SE5 8AF, UK.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150519
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Dopamine Antagonists)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Triazines)
RN  - 690G0D6V8H (Ketamine)
RN  - L6UH7ZF8HC (Risperidone)
RN  - U3H27498KS (Lamotrigine)
SB  - IM
MH  - Adult
MH  - Brain/*drug effects
MH  - Brain Mapping
MH  - Cross-Over Studies
MH  - Dopamine Antagonists/pharmacology
MH  - Double-Blind Method
MH  - Excitatory Amino Acid Antagonists/*pharmacology
MH  - Humans
MH  - Ketamine/*pharmacology
MH  - Lamotrigine
MH  - Magnetic Resonance Imaging/methods
MH  - Male
MH  - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
MH  - Risperidone/pharmacology
MH  - Triazines/pharmacology
MH  - Young Adult
PMC - PMC4600469
OTO - NOTNLM
OT  - Connection
OT  - Drug discrimination
OT  - Glutamate
OT  - Imaging
OT  - NMDA receptor
OT  - Schizophrenia
OT  - Thalamus
OT  - fMRI
EDAT- 2015/05/20 06:00
MHDA- 2016/06/03 06:00
PMCR- 2015/05/19
CRDT- 2015/05/19 06:00
PHST- 2014/11/14 00:00 [received]
PHST- 2015/04/27 00:00 [accepted]
PHST- 2015/05/19 06:00 [entrez]
PHST- 2015/05/20 06:00 [pubmed]
PHST- 2016/06/03 06:00 [medline]
PHST- 2015/05/19 00:00 [pmc-release]
AID - 10.1007/s00213-015-3951-9 [pii]
AID - 3951 [pii]
AID - 10.1007/s00213-015-3951-9 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2015 Nov;232(21-22):4205-18. doi: 
      10.1007/s00213-015-3951-9. Epub 2015 May 19.