Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder

Context: A variety of indirect evidence has implicated the central muscarinic-cholinergic system, and more specifically the type 2 muscarinic (M-2) 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 M-2 receptor binding was compared between unmedicated subjects with major depressive disorder or bipolar disorder during depression vs healthy controls, using positron emission tomography and [F-18]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 M-2 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 [F-18] FP-TZTP distribution volume, which is proportional to the product of receptor density and affinity and, in the case of [F-18] 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 (F-55=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 M-2 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 M-2 receptor density or affinity or an elevation in endogenous acetylcholine levels. To our knowledge, these data provide the first direct evidence that altered M-2 receptor function contributes to mood dysregulation in bipolar disorder.