Association between the serotonin transporter gene (5-HTTLPR) and anger-related traits in Korean schizophrenic patients.
ABSTRACT The serotonin transporter-linked polymorphic region (5-HTTLPR) short allele confers a general sensitivity to environmental stimuli, and anger is suspected to have a direct influence on aggressive behavior in schizophrenia. In the present study, we investigated whether the 5-HTTLPR gene was associated with aggression and/or anger-related traits in schizophrenia.
A total of 103 schizophrenic patients, including 46 aggressive and 57 nonaggressive patients, were recruited from psychiatric hospitals in Korea. All of the aggressive patients had committed at least 2 significant violent acts requiring repeated confinement in each of the 2 weeks preceding study inclusion, as well as 2 or more serious assaults on others. Blood samples were collected from all patients for 5-HTTLPR genotyping, and all patients underwent clinical assessments for symptoms of schizophrenia, aggressive behavior and anger-related traits.
There was no significant difference in the distribution of the 5-HTTLPR genotype/alleles between the aggressive and nonaggressive patients. Aggressive patients carrying the s allele exhibited more anger-related traits than those with the l/l homozygotes, but this difference was not significant after correction for multiple testing. Furthermore, there was a dose-dependent relationship between the s allele and high angry temperament subscale scores in the aggressive patients.
These findings seem to support the idea that 5-HTTLPR predisposes aggressive patients to exhibit more anger-related traits, though they do not support the existence of a direct association between 5-HTTLPR and aggressive behavior in schizophrenia in the Korean population; however, larger studies are needed.
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ABSTRACT: Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling aggression. Impaired regulation of each subtype of 5-HT receptor, 5-HT transporter, synthetic and metabolic enzymes has been linked particularly to impulsive aggression. The current summary focuses mostly on recent findings from pharmacological and genetic studies. The pharmacological treatments and genetic manipulations or polymorphisms of a specific target (e.g., 5-HT(1A) receptor) can often result in inconsistent results on aggression, due to "phasic" effects of pharmacological agents versus "trait"-like effects of genetic manipulations. Also, the local administration of a drug using the intracranial microinjection technique has shown that activation of specific subtypes of 5-HT receptors (5-HT(1A) and 5-HT(1B)) in mesocorticolimbic areas can reduce species-typical and other aggressive behaviors, but the same receptors in the medial prefrontal cortex or septal area promote escalated forms of aggression. Thus, there are receptor populations in specific brain regions that preferentially modulate specific types of aggression. Genetic studies have shown important gene-environment interactions; it is likely that the polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT (e.g., MAOA) determine the vulnerability to adverse environmental factors that escalate aggression. We also discuss the interaction between the 5-HT system and other systems. Modulation of 5-HT neurons in the dorsal raphe nucleus by GABA, glutamate and CRF profoundly regulate aggressive behaviors. Also, interactions of the 5-HT system with other neuropeptides (arginine vasopressin, oxytocin, neuropeptide Y, opioid) have emerged as important neurobiological determinants of aggression. Studies of aggression in genetically modified mice identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT(1B), 5-HT transporter, Pet1, MAOA) or indirectly [e.g., BDNF, neuronal nitric oxide (nNOS), αCaMKII, Neuropeptide Y]. The future agenda delineates specific receptor subpopulations for GABA, glutamate and neuropeptides as they modulate the canonical aminergic neurotransmitters in brainstem, limbic and cortical regions with the ultimate outcome of attenuating or escalating aggressive behavior.Current topics in behavioral neurosciences. 02/2012;
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ABSTRACT: Alterations in serotonin (5-HT) neurochemistry have been implicated in the aetiology of all major neuropsychiatric disorders, ranging from schizophrenia to mood and anxiety-spectrum disorders. This review will focus on the mulifaceted implications of 5-HT-ergic dysfunctions in the pathophysiology of aggressive and suicidal behaviours. After a brief overview of the anatomical distribution of the 5-HT-ergic system in the key brain areas that govern aggression and suicidal behaviours, the implication of 5-HT markers (5-HT receptors, transporter as well as synthetic and metabolic enzymes) in these conditions is discussed. In this regard, particular emphasis is placed on the integration of pharmacological and genetic evidence from animal studies with the findings of human experimental and genetic association studies. Traditional views postulated an inverse relationship between 5-HT and aggression and suicidal behaviours; however, ample evidence has shown that this perspective may be overly simplistic, and that such pathological manifestations may reflect alterations in 5-HT homeostasis due to the interaction of genetic, environmental and gender-related factors, particularly during early critical developmental stages. The development of animal models that may capture the complexity of such interactions promises to afford a powerful tool to elucidate the pathophysiology of impulsive aggression and suicidability, and find new effective therapies for these conditions.Neuroscience 02/2013; 236:160-185. · 3.12 Impact Factor
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ABSTRACT: Antipsychotic drugs are the neuroleptics currently used in the treatment of schizophrenia (SCZ) and psychotic disorders. SCZ has a heritability estimated at 70%-90%; and pharmacogenomics accounts for 60%-90% variability in the pharmacokinetics and pharmacodynamics of psychotropic drugs. Personalized therapeutics based on individual genomic profiles in SCZ entails the characterization of 5 types of gene clusters and their related metabolomic profiles: 1) genes associated with disease pathogenesis; 2) genes associated with the mechanism of action of drugs; 3) genes associated with drug metabolism (phase I and II reactions); 4) genes associated with drug transporters; and 5) pleiotropic genes involved in multifaceted cascades and metabolic reactions. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single-nucleotide polymorphisms in microRNA genes, mitochondrial DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. Approximately 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4. About 10% - 20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6 + CYP2C19 + CYP2C9 genes. Efficacy and safety issues in the pharmacological treatment of SCZ are directly linked to genetic clusters involved in the pharmacogenomics of antipsychotic drugs and also to environmental factors. Consequently, the incorporation of Pharmacogenomic procedures both to drugs under development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system disorders.Open Journal of Psychiatry 01/2013; 3:46-139.