title: Effect of chronic antipsychotic treatment on brain structure: a serial magnetic resonance imaging study with ex vivo and postmortem confirmation.
abstract: BACKGROUND
  There is increasing evidence that antipsychotic (APD) may affect brain structure directly. To examine this, we developed a rodent model that uses clinically relevant doses and serial magnetic resonance imaging (MRI), followed by postmortem histopathological analysis to study the effects of APD on brain structures.
  
  
  METHODS
  Antipsychotic , haloperidol, and olanzapine were continuously administered to rats via osmotic minipumps to maintain clinic-like steady state levels for 8 weeks. Longitudinal in vivo MRI scanning (T₂-weighted) was carried out at baseline, 4 weeks, and 8 weeks, after which animals were perfused and their brains preserved for ex vivo MRI scanning. Region of interest analyses were performed on magnetic resonance images (both in vivo as well as ex vivo) along with postmortem stereology using the Cavalieri estimator probe.
  
  
  RESULTS
  Chronic (8 weeks) exposure to both haloperidol and olanzapine resulted in significant decreases in whole-brain volume (6% to 8%) compared with vehicle-treated control subjects, driven mainly by a decrease in frontal cerebral cortex volume (8% to 12%). Hippocampal, corpus striatum, lateral ventricles, and corpus callosum volumes were not significantly different from control subjects, suggesting a differential effect of APD on the cortex. These results were corroborated by ex vivo MRI scans and decreased cortical volume was confirmed postmortem by stereology.
  
  
  CONCLUSIONS
  This is the first systematic whole-brain MRI study of the effects of APD, which highlights significant effects on the cortex. Although caution needs to be exerted when extrapolating results from animals to patients, the approach provides a tractable method for linking in vivo MRI findings to their histopathological origins.
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Vernon
authors.forename: Sridhar
authors.initials: S
authors.lastname: Natesan
authors.forename: Mike
authors.initials: M
authors.lastname: Modo
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000494:pharmacology*; D001569:Benzodiazepines / Q000097:blood / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D002739:Chloroquinolinols / Q000097:blood / Q000494:pharmacology*; D015918:Infusion Pumps, Implantable; D020547:Lateral Ventricles / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D008409:Mastication / Q000187:drug effects; D009068:Movement / Q000187:drug effects; D000077152:Olanzapine; D009929:Organ Size / Q000187:drug effects; D011180:Postmortem Changes; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D002739:Chloroquinolinols; D001569:Benzodiazepines; D000077152:Olanzapine; C011838:halquinol