title: Modulatory effects of ketamine, risperidone and lamotrigine on resting brain perfusion in healthy human subjects.
abstract: BACKGROUND
  Resting brain perfusion, measured using the MRI-based arterial spin labelling (ASL) technique, is sensitive to detect central effects of single, clinically effective, doses of pharmacological compounds. However, pharmacological interaction experiments, such as the modulation of one drug response in the presence of another, have not been widely investigated using a task-free ASL approach.
  
  
  OBJECTIVE
  We assessed the effects of three psychoactive compounds (ketamine, risperidone and lamotrigine), and their interaction, on resting brain perfusion in healthy human volunteers.
  
  
  METHODS
  A multivariate Gaussian process classification (GPC) and more conventional univariate analyses were applied. The four pre-infusion conditions for each subject comprised risperidone, lamotrigine and two placebo sessions. The two placebo conditions enabled us to evaluate the classification performance in a test-retest setting, in addition to its performance in distinguishing the active oral drugs from placebo (direct effect on brain perfusion). The post ketamine- or saline-infusion scans allowed the effect of ketamine, and its interaction with risperidone and lamotrigine, on brain perfusion to be characterised.
  
  
  RESULTS
  The pseudo-continuous ASL measurements of perfusion were sensitive to the effects of ketamine infusion and risperidone. The GPC captured consistent changes in perfusion across the group and contextualised the univariate changes with a larger pattern of regions contributing to accurate discrimination of ketamine from placebo.
  
  
  CONCLUSIONS
  The findings argue against perfusion changes confounding in the previously described evoked BOLD response to ketamine and emphasise the blockade of the NMDA receptor over neuronal glutamate release in determining the perfusion changes induced by ketamine.
authors.affiliation: Tailored Therapeutics - Neuroscience, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Shcherbinin
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
authors.forename: Orla
authors.initials: O
authors.lastname: Doyle
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
authors.forename: Fernando O
authors.initials: FO
authors.lastname: Zelaya
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: de Simoni
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
authors.forename: Mitul A
authors.initials: MA
authors.lastname: Mehta
authors.affiliation: Tailored Therapeutics - Neuroscience, Eli Lilly and Company, Indianapolis, IN, 46285, USA. a.schwarz@lilly.com.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Schwarz
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid; D064368:Healthy Volunteers; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D000077213:Lamotrigine; D008297:Male; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D018967:Risperidone / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D018698:Glutamic Acid; D007649:Ketamine; D018967:Risperidone; D000077213:Lamotrigine
keywords: Brain imaging; Drug; MRI; Mapping; Modulation; Patterning; Recognition; Schizophrenia