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Dara M. Cannon, PhD; Richard E. Carson, PhD; Allison C. Nugent, PhD; William C. Eckelman, PhD; Dale O. Kiesewetter, PhD; Joan Williams, RN; Denise Rollis, PhD; Michele Drevets, RN; Shilpa Gandhi, BA; Gerardo Solorio, BA; Wayne C. Drevets, MD

Arch Gen Psychiatry. 2006;63:741-747.

Context  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.

Design  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.

Setting  Outpatients at the National Institutes of Health.

Participants  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.

Main Outcome Measures  The primary outcome parameter was [¹⁸F]FP-TZTP distribution volume, which is proportional to the product of receptor density and affinity and, in the case of [¹⁸F]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.

Author Affiliations: Mood and Anxiety Disorders Program, Molecular Imaging Branch, National Institutes of Mental Health (Drs Cannon, Nugent, and W. C. Drevets; Mss M. Drevets and Gandhi; and Mr Solorio), National Institute of Biomedical Imaging and Bioengineering/Positron Emission Tomography Radiochemistry Group (Dr Kiesewetter), and Warren Grant Magnuson Clinical Center, Positron Emission Tomography Imaging Center (Ms Williams and Dr Rollis), National Institutes of Health, Bethesda, Md; Positron Emission Tomography Center, Physics Department Diagnostic Radiology, Yale University School of Medicine, New Haven, Conn (Dr Carson); Molecular Tracer LLC, Bethesda (Dr Eckelman).

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