title: Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.
abstract: OBJECTIVE
  The neuroinflammatory hypothesis of major depressive disorder is supported by several main findings. First, in humans and animals, activation of the immune system causes sickness behaviors that present during a major depressive episode (MDE), such as low mood, anhedonia, anorexia, and weight loss. Second, peripheral markers of inflammation are frequently reported in major depressive disorder. Third, neuroinflammatory illnesses are associated with high rates of MDEs. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence of brain inflammation during MDE. Translocator protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important aspect of neuroinflammation.
  
  
  OBJECTIVE
  To determine whether TSPO VT is elevated in the prefrontal cortex, anterior cingulate cortex (ACC), and insula in patients with MDE secondary to major depressive disorder.
  
  
  METHODS
  Case-control study in a tertiary care psychiatric hospital from May 1, 2010, through February 1, 2014. Twenty patients with MDE secondary to major depressive disorder and 20 healthy control participants underwent positron emission tomography with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA). Patients with MDE were medication free for at least 6 weeks. All participants were otherwise healthy and nonsmokers.
  
  
  METHODS
  Values of TSPO VT in the prefrontal cortex, ACC, and insula.
  
  
  RESULTS
  In MDE, TSPO VT was significantly elevated in all brain regions examined (multivariate analysis of variance, F15,23 = 4.5 [P = .001]). The magnitude of TSPO VT elevation was 26% in the prefrontal cortex (mean [SD] TSPO VT, 12.5 [3.6] in patients with MDE and 10.0 [2.4] in controls), 32% in the ACC (mean [SD] TSPO VT, 12.3 [3.5] in patients with MDE and 9.3 [2.2] in controls), and 33% in the insula (mean [SD] TSPO VT, 12.9 [3.7] in patients with MDE and 9.7 [2.3] in controls). In MDE, greater TSPO VT in the ACC correlated with greater depression severity (r = 0.63 [P = .005]).
  
  
  CONCLUSIONS
  This finding provides the most compelling evidence to date of brain inflammation, and more specifically microglial activation, in MDE. This finding is important for improving treatment because it implies that therapeutics that reduce microglial activation should be promising for MDE. The correlation between higher ACC TSPO VT and the severity of MDE is consistent with the concept that neuroinflammation in specific regions may contribute to sickness behaviors that overlap with the symptoms of MDE.
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors: Elaine
authors: E
authors: Setiawan
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, University of Toronto, T.
authors: Alan A
authors: AA
authors: Wilson
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, University of Toronto, T.
authors: Romina
authors: R
authors: Mizrahi
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors: Pablo M
authors: PM
authors: Rusjan
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors: Laura
authors: L
authors: Miler
authors: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson.
authors: Grazyna
authors: G
authors: Rajkowska
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada4Institute of Medical Science, University of Toront.
authors: Ivonne
authors: I
authors: Suridjan
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, University of Toronto, T.
authors: James L
authors: JL
authors: Kennedy
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors: P Vivien
authors: PV
authors: Rekkas
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, University of Toronto, T.
authors: Sylvain
authors: S
authors: Houle
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, University of Toronto, T.
authors: Jeffrey H
authors: JH
authors: Meyer
mesh_terms: D000328:Adult; D000813:Anilides; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000378:metabolism*; D005260:Female; D006179:Gyrus Cinguli / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods; D017397:Prefrontal Cortex / Q000378:metabolism; D011725:Pyridines; D018079:Receptors, GABA / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D000813:Anilides; D015415:Biomarkers; C530438:N-(2-((N-(4-phenoxypyridin-3-yl)acetamido)methyl)phenoxy)ethyl fluoride; D011725:Pyridines; D018079:Receptors, GABA; C499229:TSPO protein, human
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