title: Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder.
abstract: BACKGROUND
  A variety of indirect evidence has implicated the central muscarinic-cholinergic system, and more specifically the type 2 muscarinic (M2) receptor, in the pathogenesis of depressive symptoms arising in major depressive disorder and bipolar disorder.
  
  
  OBJECTIVE
  To assess the binding potential of muscarinic2 receptors in vivo during depression in subjects with major depressive disorder or bipolar disorder.
  
  
  METHODS
  The M2 receptor binding was compared between unmedicated subjects with major depressive disorder or bipolar disorder during depression vs healthy controls, using positron emission tomography and [18F]FP-TZTP (fluorodopa F 18 [3-(3-[3-fluoroproply]thio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine), a selective M2 receptor radioligand.
  
  
  METHODS
  Outpatients at the National Institutes of Health.
  
  
  METHODS
  Unmedicated subjects with current depression meeting DSM-IV criteria for either major depressive disorder (n = 17) or bipolar disorder (n = 16) and 23 healthy control subjects.
  
  
  METHODS
  The primary outcome parameter was [(18)F]FP-TZTP distribution volume, which is proportional to the product of receptor density and affinity and, in the case of [(18)F]FP-TZTP, is known to be sensitive to endogenous acetylcholine concentrations. The relationship between illness severity, as rated using the Montgomery-Asberg Depression and Hamilton Anxiety Rating scales, and distribution volume also was assessed.
  
  
  RESULTS
  The mean anterior cingulate cortex distribution volume differed across groups (F55 = 3.4; P = .04), and this difference was accounted for by significantly lower binding in bipolar disorder compared with both major depressive disorder and control groups.
  
  
  CONCLUSIONS
  The mean M2 receptor binding in subjects with bipolar disorder was reduced relative to both healthy controls and subjects with major depressive disorder, to an extent that correlated with depressive symptoms. The reduction in the bipolar disorder group could be accounted for either by a reduction in M2 receptor density or affinity or an elevation in endogenous acetylcholine levels. To our knowledge, these data provide the first direct evidence that altered M2 receptor function contributes to mood dysregulation in bipolar disorder.
authors.affiliation: Mood and Anxiety Disorders Program, Molecular Imaging Branch, National Institutes of Mental Health, National Institutes of Health, Bethesda, MD 20892-2670, USA. daracannon@mail.nih.gov
authors.forename: Dara M
authors.initials: DM
authors.lastname: Cannon
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.forename: Allison C
authors.initials: AC
authors.lastname: Nugent
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: Joan
authors.initials: J
authors.lastname: Williams
authors.forename: Denise
authors.initials: D
authors.lastname: Rollis
authors.forename: Michele
authors.initials: M
authors.lastname: Drevets
authors.forename: Shilpa
authors.initials: S
authors.lastname: Gandhi
authors.forename: Gerardo
authors.initials: G
authors.lastname: Solorio
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Drevets
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000328:Adult; D000553:Ambulatory Care; D001714:Bipolar Disorder / Q000175:diagnosis* / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D049268:Positron-Emission Tomography / Q000706:statistics & numerical data; D011725:Pyridines / Q000378:metabolism; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D013569:Synapses / Q000000981:diagnostic imaging / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D011725:Pyridines; D043585:Receptor, Muscarinic M2; D013844:Thiazoles; D019788:Fluorodeoxyglucose F18; C115177:FP-TZTP; D000109:Acetylcholine