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Genetic variation in the cholinergic muscarinic-2 (M-2) receptor gene (CHRM2) has been associated with the risk for developing depression. We previously reported that M-2-receptor distribution volume (V-T) was reduced in depressed subjects with bipolar disorder (BD) relative to depressed subjects with major depressive disorder (MDD) and healthy controls (HCs). In this study, we investigated the effects of six single-nucleotide polymorphisms (SNPs) for CHRM2 on M-2-receptor binding to test the hypotheses that genetic variation in CHRM2 influences M-2-receptor binding and that a CHRM2 polymorphism underlies the deficits in M-2-receptor V-T observed in BD. The M-2-receptor V-T was measured using positron emission tomography and [F-18]FP-TZTP in unmedicated, depressed subjects with BD (n = 16) or MDD (n = 24) and HCs (n = 25), and the effect of genotype on V-T was assessed. In the controls, one SNP (with identifier rs324650, in which the ancestral allele adenine (A) is replaced with one or two copies of thymine (T), showed a significant allelic effect on V-T in the pregenual and subgenual anterior cingulate cortices in the direction AA < AT < TT. In contrast, in BD subjects with the TT genotype, V-T was significantly lower than in BD subjects with the AT genotype in these regions. The BD subjects homozygous for the T -allele also showed markedly lower V-T (by 27 to 37% across regions) than HCs of the same genotype. Post hoc analyses suggested that T homozygosity was associated with a more severe illness course, as manifested by lower socioeconomic function, poorer spatial recognition memory and a greater likelihood of having attempted suicide. These data represent novel preliminary evidence that reduced M-2-receptor V-T in BD is associated with genetic variation within CHRM2. The differential impact of the M-2-receptor polymorphism at rs324650 in the BD and HC samples suggests interactive effects with an unidentified vulnerability factor for BD. Molecular Psychiatry (2011) 16, 407-418; doi:10.1038/mp.2010.24; published online 30 March 2010

Objectives: Neuropsychological studies in subjects with bipolar disorder (BD) have reported deficits on a variety of cognitive measures. However, because the majority of subjects were medicated at the time of testing in previous studies, it is currently unclear whether the pattern of deficits reported is related to BD itself or to psychotropic medication. We addressed this issue by examining cognitive performance in a group of unmedicated, currently depressed subjects with BD. Methods: Forty-nine unmedicated subjects who met DSM-IV criteria for BD, depressed phase, and 55 control subjects participated in this study. Most patients were diagnosed with bipolar II disorder. Performance on emotion-dependent, or ‘hot’, and emotion-independent, or ‘cold’, cognitive tasks was assessed using tests from the Cambridge Neuropsychological Test Automated Battery. Results: The groups were well matched with respect to general intelligence and demographic variables. Deficits in the unmedicated depressed BD group were apparent on tests tapping ‘hot’ cognitive processing, for example the Cambridge Gamble task and the Probabilistic Reversal Learning task. However, other than a deficit on the Spatial Span test in the depressed BD subjects, the groups performed equivalently on most measures of ‘cold’ cognitive processing, for example visual memory, attention, and working memory. Conclusions: These data suggest that deficits on tests involving reward processing, short-term spatial memory storage, and sensitivity to negative feedback in depressed BD subjects represent an effect of the illness itself and not mood-stabilizing medication.

Background Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. Methods The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [ 11 C]DASB was compared between unmedicated, depressed subjects with MDD ( n = 18) or BD ( n = 18) and HC ( n = 34). Results Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. Conclusions The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD.

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 [ 18 F]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 [ 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 (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.