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Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[(11)C]methyl-L-tryptophan (11C-AMT) trapping (K*) as a proxy. Recently, we reported evidence of lower normalized 11C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH2). In all, 46 healthy controls had PET 11C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH2 gene and its 5′ upstream region. Several TPH2 SNPs were associated with lower normalized blood-to-brain clearance of 11C-AMT in the OBFC. Dose-effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5′ upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC. [ABSTRACT FROM AUTHOR]

The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better longterm outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C→T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional5 and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome. [ABSTRACT FROM AUTHOR]

Verifies evidence that a genetic component may increase the predisposition to suicide and that deficiencies of the serotonin system play a significant role. Effort to replicate findings reported by Bondy and associates; Investigation of a large sample of suicide completers.