RESUMEN
Choline acetyltransferase (ChAt) is extensively distributed throughout the CNS where, by catalyzing acetylcholine synthesis, it participates in modulating wide-ranging cholinergic-dependent functions including cognitive performance, sleep, arousal, movement, and visual information processing. Recently, compelling evidence has mounted implicating ChAt in schizophrenia. In particular, studies have identified significant reductions in ChAt activity in the nucleus accumbens and pontine tegmentum of such patients, which furthermore correlate significantly with measures of cognitive performance in the disorder. Similarly, elevated levels of choline, the acetylcholine precursor, have been identified among patients, implicating altered ChAt activity in these individuals. We sought to investigate the potential contribution of three ChAt gene polymorphisms in schizophrenia, and uncovered evidence for significant association between one of these, rs1880676G/A, and disease susceptibility among Basque individuals (genotypewise chi(2) = 20.7, P = 0.00003; allelewise chi(2) = 10.1, P = 0.002). A similar trend for association with susceptibility was observed for a second SNP, rs3810950G/A, (genotypwise chi(2) = 6.4, P = 0.05; allelewise chi(2) = 3.75, P = 0.05). Evidence was also uncovered for a potential influence of these polymorphisms on olanzapine treatment outcome among Spanish patients (F-statistic = 5.02, P = 0.03; F-statistic = 6.53, P = 0.02 respectively), and on improvements in positive symptoms in the case of rs3810950 (F-statistic = 5.3, P = 0.03) and general psychopathology in the case of rs1880676 and rs3810950 (F-statistic = 5.24, P = 0.03; F-statistic = 5.31, P = 0.03 respectively) during therapy. While more comprehensive studies are warranted to determine the precise contribution of ChAt mediated mechanisms in schizophrenia, our findings tentatively implicate a genetic influence of ChAt in the disorder's susceptibility and treatment.
Asunto(s)
Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Colina O-Acetiltransferasa/genética , Predisposición Genética a la Enfermedad , Variación Genética , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Frecuencia de los Genes , Genotipo , Humanos , Olanzapina , Polimorfismo de Nucleótido Simple , Esquizofrenia/enzimologíaRESUMEN
Psychiatric patients demonstrate varied responses to treatment. Consequently, treatment strategies are trial-and-error, which has a negative effect on prognosis and compliance. The aim of pharmacogenomic research is to enable customised drug treatment by identifying variations within multiple candidate genes (those encoding drug-targeted neurotransmitter receptors, transporters and metabolic enzymes) that are likely to confer the inter-individual differences in drug response and development of drug-induced side effects. Pharmacogenetic and pharmacogenomic research to date has identified genetic polymorphisms of dopamine (DA) and serotonin (5-HT) receptor subtypes, the serotonin transporter (5-HTT) and metabolic enzymes (cytochrome P450 [CYP] family) as important contributors to the variability in response to psychiatric drugs and the development of drug-induced side effects such as tardive dyskinesia and weight gain. It is anticipated that technological and methodological advances will provide further candidate genes and refine association analyses of existing candidates, enabling pharmacogenomic research to move towards future treatment regimes that are catered to the individual.
Asunto(s)
Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/genética , Farmacogenética/métodos , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Genética Conductual/métodos , Humanos , Trastornos Mentales/enzimología , Polimorfismo Genético , Ácido Retinoico 4-HidroxilasaRESUMEN
The involvement of specific pathways mediated through muscarinic receptor activity has been widely implicated in schizophrenia. Extensive pharmacological evidence supports the systems role in mediating antipsychotic drug efficacy, while mounting physiological evidence demonstrates the presence of significant alterations to normal muscarinic receptor integrity in the disorder. The mechanisms that facilitate the systems involvement and their magnitude, however, remain poorly understood. We have proposed that alterations to normal muscarinic receptor expression exist in schizophrenia, and that these significantly influence the physiological changes often reported for the system amongst patients. In this study, we investigate this potential, and have selected to examine the muscarinic 1 receptor, which constitutes a major target for antipsychotic action and plays a conspicuous role in those regions central to the disorders pathophysiology. Using relative gene quantification, we measured post-mortem levels of steady-state cortical muscarinic 1 receptor cDNA in patients (N = 20) and unaffected controls (N = 20), and examined group differences in expression levels. Commensurate with our hypothesis, we observed significant reductions in muscarinic 1 receptor cDNA in our patient sample (F(1,37) = 4.73, P = 0.036) and have estimated this to constitute a 28% decrease compared to the control subjects (95% CI from 2 to 47%). These results provide evidence in support of altered muscarinic 1 receptor expression in schizophrenia, though further work is needed to corroborate these findings.
Asunto(s)
Receptor Muscarínico M1/deficiencia , Esquizofrenia/metabolismo , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Corteza Cerebral/química , Cuerpo Calloso/química , ADN Complementario/análisis , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptor Muscarínico M1/genéticaRESUMEN
We report the identification of four novel histamine 1 (H1-17-C/T, -974-C/A, -1023-A/G and -1536-G/C) and four novel histamine 2 promoter polymorphisms (H2-294-A/G, -592-A/G, -1018-G/A and -1077-G/A) which we have investigated for involvement in susceptibility to schizophrenia, and in clinical response to clozapine treatment. We identified a weak independent association between variants at the H1-1536-G/C locus and schizophrenia, where an excess of the H1-1536-C allele was observed amongst such patients (P = 0.036). However upon correction for multiple testing this relationship was no longer statistically significant. Similar investigation of the H2 receptor polymorphisms revealed association between genotype at the H2-1018-G/A locus and clinical response to clozapine treatment (P = 0.027), though upon correction for multiple testing this difference was no longer significant. We have concluded that the participation of these variants in the disorder is unlikely, particularly in view of their apparent lack of function and unlikely influence on receptor expression. However their nature alludes to the potential presence of other more important alterations further along these regions, where sequences encoding alternate promoters have recently been identified for each receptor that may yet be found to harbour such polymorphisms.
Asunto(s)
Antipsicóticos/uso terapéutico , Clozapina/uso terapéutico , Regiones Promotoras Genéticas , Receptores Histamínicos H1/genética , Receptores Histamínicos H2/genética , Esquizofrenia/genética , Distribución de Chi-Cuadrado , Análisis Mutacional de ADN , Frecuencia de los Genes , Humanos , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Escalas de Valoración Psiquiátrica , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismoRESUMEN
Psychiatric treatment requires the use of drugs which are in many cases associated with severe side effects and inadequate response. In the past decade extensive research has investigated the link between gene alterations and treatment response and several strong associations have been reported. The identification of genes influencing treatment outcome will facilitate the pre-treatment selection of the most beneficial drug according to an individual's pharmacogenetic profile. Recent advances indicate that this goal is achievable in the near future. The scope of this communication is to review all the recent findings in psychopharmacogenetics leading to the individualization of treatment.
Asunto(s)
Antipsicóticos/uso terapéutico , Receptores de Neurotransmisores/genética , Sistema Enzimático del Citocromo P-450/genética , Variación Genética , Humanos , Polimorfismo Genético , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/genética , Resultado del TratamientoRESUMEN
Pharmacogenetic research into complex traits, such as response to antipsychotic treatment has proved a difficult task. Nevertheless, investigation of drug metabolic enzymes has revealed polymorphisms in specific cytochrome P450 genes responsible for treatment-induced toxic reactions. However, the picture becomes more complicated when drug target sites are investigated in search of genetic influence. Most antipsychotic drugs are multitarget, denoting a complex mechanism of action. Although individual genes have been reported to influence antipsychotic response, no single gene can account for the variability observed in treatment response. Current investigations focus on single gene variants that may be associated with particular side effects or symptoms as well as contributing to general response. The scope of this article is to review recent advances of pharmacogenetic research on antipsychotic drugs and the strategies under development for the individualization of treatment.
Asunto(s)
Antipsicóticos/uso terapéutico , Farmacogenética , Sistema Enzimático del Citocromo P-450/genética , Humanos , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
We did association studies in multiple candidate genes to find the combination of polymorphisms that give the best predictive value of response to clozapine in schizophrenic patients. A combination of six polymorphisms in neurotransmitter-receptor-related genes resulted in 76.7% success in the prediction of clozapine response (p=0.0001) and a sensitivity of 95% (+/- 0.04) for satisfactory response. These results will form the basis for a simple test to enhance the usefulness of clozapine in psychiatric treatment.