Molecular psychiatry
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Molecular psychiatry · Nov 2006
Multicenter Study Comparative StudyAssociation of the kappa-opioid system with alcohol dependence.
Opioid receptors and their endogenous peptide ligands play important roles in the reward and reinforcement of drugs such as heroin, cocaine, and alcohol. The binding of dynorphins to the kappa-opioid receptor has been shown to produce aversive states, which may prevent the development of reinforcement. ⋯ Haplotype analyses further supported the association of PDYN. Thus, variations in the genes encoding both the kappa-opioid receptor and its ligand, OPRK1 and PDYN, are associated with the risk for alcohol dependence; this makes biological sense as variations in either should affect signaling through the kappa-opioid system.
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Molecular psychiatry · May 2006
Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills.
We examined three microsatellites in the arginine vasopressin 1a receptor gene (AVPR1a), two in the promoter region (RS1 and RS3) and an intronic microsatellite (AVR), for association with autism as well as scores on the Vineland Adaptive Behavior Scale (VABS), the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Scale-Generic (ADOS-G), measures that are widely used to diagnose autism spectrum disorders. We tested for association between the AVPR1a microsatellites and autism in 116 families (128 probands diagnosed with the ADI-R and ADOS-G using a family-based association test (UNPHASED)). Testing each individual microsatellite showed significant transmission disequilibrium in these families with the AVR intronic microsatellite (UNPHASED: LRS=11.46, global P-value=0.009, df=3). ⋯ This is the third consecutive report of an association between the AVPR1a gene and autism spectrum disorders and in the current study a third microsatellite is shown to be associated with autism spectrum disorders as well as haplotypes consisting of all three markers. Importantly, the association appears to be mainly mediated by the role of the AVPR1a gene in shaping socialization skills, similar to its role in lower vertebrates. Molecular Psychiatry (2006) 11, 488-494. doi:10.1038/sj.mp.4001812; published online 7 March 2006.
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Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. ⋯ Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder.
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Molecular psychiatry · Nov 2005
Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease.
Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD+P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-->A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-->Met substitution, has been reported to confer an increased risk for schizophrenia. ⋯ Genetic variation in COMT is associated with AD+P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.
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Molecular psychiatry · Jun 2005
Clinical Trial Controlled Clinical TrialSeparate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia.
Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition. The interest in COMT as a candidate SZ risk factor has led to numerous case-control and family-based studies, with the majority placing emphasis on examining a functional Val/Met polymorphism within this enzyme. Unfortunately, these studies have continually produced conflicting results. ⋯ Importantly, conditional analyses indicated the presence of two separate and interacting effects within this haplotype, irrespective of gender. In addition, our results indicate the Val/Met polymorphism is not disease-causing and is simply in strong linkage disequilibrium with a causative effect, which interacts with another as yet unidentified variant approximately 20 kb away. These results may help explain the inconsistent results reported on the Val/Met polymorphism and have important implications for future investigations into the role of COMT in SZ susceptibility.