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Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: Evidence for association with aggressive and antisocial behavior
Abstract
We have recently characterized a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that is responsible for substantial variability in COMT enzymatic activity found in humans. A common low-activity variant of the enzyme contains a methionine residue at amino acid 158 of membrane-bound COMT whereas the common high activity variant has a valine at this site. Considering the role of COMT in dopamine metabolism and the involvement of dopaminergic pathways in the pathogenesis of schizophrenia and violence, we screened 37 patients with schizophrenia to determine whether or not a behavioral association with the COMT polymorphism exists. Patients were assessed for dangerousness on the basis of a history of violent and threatening behavior, crime, cocaine and alcohol abuse, and other antisocial behaviors. We found that schizophrenic patients who were homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygous for the high activity allele (Kruskal-Wallis statistic = 10.43; P = 0.003).
... COMT with low catabolic activity doesn't efficiently eliminate DA and therefore leads to increased stimulation of DA neural networks involved in the regulation of emotional arousal, affective decisionmaking and externalizing behavior, particularly those implicated in impulsivity and aggressiveness, such as the limbic structures and prefrontal cortex (Drabant et al., 2006). Different studies suggested an association between the Val 158 Met polymorphism, especially in homozygous people for the low activity allele, with the development of hostile and aggressive behavior particularly in schizophrenic patients (Kotler et al., 1999;Lachman et al., 1998;Strous et al., 1997;Volavka et al., 2004). Notably, there was a higher risk for aggressive and violent behavior in schizophrenic patients carrying the low activity Met 158 allele, with a higher risk for the Met/Met homozygous patient relative to the homozygous carriers of the high activity allele (Bhakta et al., 2012;Kotler et al., 1999;Strous et al., 1997). ...
... Different studies suggested an association between the Val 158 Met polymorphism, especially in homozygous people for the low activity allele, with the development of hostile and aggressive behavior particularly in schizophrenic patients (Kotler et al., 1999;Lachman et al., 1998;Strous et al., 1997;Volavka et al., 2004). Notably, there was a higher risk for aggressive and violent behavior in schizophrenic patients carrying the low activity Met 158 allele, with a higher risk for the Met/Met homozygous patient relative to the homozygous carriers of the high activity allele (Bhakta et al., 2012;Kotler et al., 1999;Strous et al., 1997). In addition, a strong association between the Val 158 Met polymorphism and high aggressive behavior has been demonstrated in healthy young people carrying the Met allele relative to Val-homozygotes (Albaugh et al., 2010) (Fig. 1). ...
In modern societies, there is a strive to improve the quality of life related to risk of crimes which inevitably requires a better understanding of brain determinants and mediators of aggression. Neurobiology provides powerful tools to achieve this end. Pre-clinical and clinical studies show that changes in regional volumes, metabolism-function and connectivity within specific neural networks are related to aggression. Subregions of prefrontal cortex, insula, amygdala, basal ganglia and hippocampus play a major role within these circuits and have been consistently implicated in biology of aggression. Genetic variations in proteins regulating the synthesis, degradation, and transport of serotonin and dopamine as well as their signal transduction have been found to mediate behavioral variability observed in aggression. Gene-gene and gene-environment interactions represent additional important risk factors for aggressiveness. Considering the social burden of pathological forms of aggression, more basic and translational studies should be conducted to accelerate applications to clinical practice, justice courts, and policy making.
... Of note, COMT is subject to allelic differences in expression in human brain, and the COMT haplotype implicated in SCZ is associated with lower expression of COMT mRNA [100]. One of the seminal studies on the role of COMT was performed by Strous et al. in a small sample of aggressive SCZ patients [92]. These authors found that SCZ patients who were homozygous for the low activity allele were at higher risk for aggressive behavior than those who were homozygous for the high activity allele [92]. ...
... One of the seminal studies on the role of COMT was performed by Strous et al. in a small sample of aggressive SCZ patients [92]. These authors found that SCZ patients who were homozygous for the low activity allele were at higher risk for aggressive behavior than those who were homozygous for the high activity allele [92]. Gu et al. identified an overrepresentation of the haplotype A-A-G (SNPs rs4680, rs737865, and rs165599) within the COMT gene in aggressive compared to non-aggressive SCZ patients. ...
Aggressive behavior exerts an enormous impact on society remaining among the main causes of worldwide premature death. Effective primary interventions, relying on predictive models of aggression that show adequate sensitivity and specificity are currently lacking. One strategy to increase the accuracy and precision of prediction would be to include biological data in the predictive models. Clearly, to be included in such models, biological markers should be reliably associated with the specific trait under study (i.e., diagnostic biomarkers). Aggression, however, is phenotypically highly heterogeneous, an element that has hindered the identification of reliable biomarkers. However, current research is trying to overcome these challenges by focusing on more homogenous aggression subtypes and/or by studying large sample size of aggressive individuals. Further advance is coming by bioinformatics approaches that are allowing the integration of inter-species biological data as well as the development of predictive algorithms able to discriminate subjects on the basis of the propensity toward aggressive behavior. In this review we first present a brief summary of the available evidence on neuroimaging of aggression. We will then treat extensively the data on genetic determinants, including those from hypothesis-free genome-wide association studies (GWAS) and candidate gene studies. Transcriptomic and neurochemical biomarkers will then be reviewed, and we will dedicate a section on the role of metabolomics in aggression. Finally, we will discuss how biomarkers can inform the development of new pharmacological tools as well as increase the efficacy of preventive strategies.
... Альфа-ритм хорошо видно в состоянии физического и умственного расслабления [7]. На ЭЭГ в спокойном состоянии обычно хорошо видно отдельный пик на частоте альфа-ритма (8)(9)(10)(11)(12)(13)(14). Данный параметр имеет высокую интраиндивидуальную стабильность [62; 21], а также достаточно сильную вариацию между отдельными людьми и изменчивость с возрастом [37]. ...
... Было проведено небольшое исследование социально опасного поведения пациентов, страдающих шизофренией. Результаты свидетельствуют о проявлении повышенной агрессивности у носителей мутантного М-аллеля [11]. Ассоциация M-аллеля с агрессивностью была подтверждена другим исследованием пациентов с диагнозом шизофрения или шизоидные расстройства, в котором больных, совершивших множественные нападения, сравнивали с мирными пациентами [12]. ...
The article is devoted to a theoretical overview in the field of fatigue, and in particular to recent data on psychophysiological and molecular-genetic correlates of fatigue. Nowadays there exist many methods used to assess fatigue and other functional states: subjective, behavioral and physiological methods. Earlier the studies in the area of fatigue were mainly focused on looking for an objective indicator. The current research focuses on an integral approach. Over recent years the significant progress in molecular biology has been achieved, which provided a significant impact on quality and scope of investigations. Now we can find numerous researches which reflect the link between the presence of certain polymorphisms and expression of behavioral patterns or physiological reactions. Thus, in the present study we make an attempt to reflect the existing psycho-physiological and molecular-genetic correlates of fatigue.
... Of note, COMT is subject to allelic differences in expression in human brain, and the COMT haplotype implicated in SCZ is associated with lower expression of COMT mRNA [100]. One of the seminal studies on the role of COMT was performed by Strous et al. in a small sample of aggressive SCZ patients [92]. These authors found that SCZ patients who were homozygous for the low activity allele were at higher risk for aggressive behavior than those who were homozygous for the high activity allele [92]. ...
... One of the seminal studies on the role of COMT was performed by Strous et al. in a small sample of aggressive SCZ patients [92]. These authors found that SCZ patients who were homozygous for the low activity allele were at higher risk for aggressive behavior than those who were homozygous for the high activity allele [92]. Gu et al. identified an overrepresentation of the haplotype A-A-G (SNPs rs4680, rs737865, and rs165599) within the COMT gene in aggressive compared to non-aggressive SCZ patients. ...
... 48,49 This is in line with reports that the Met allele is associated with disorders implying dysfunctional cognitive control of impulsive and aggressive behavior. 50,51 In contrast, Blasi et al 52 reported that the Met allele was associated with better performance in a new test for assessment of attentional control. However, in that study, the key variable was response accuracy, as opposed to RT in our study. ...
... However, the TFAP2Β signalling mechanisms that underlie such association have not been fully elucidated. The repressing effect of AP-2β on monoamine-degrading enzymes, such as COMT and MAO might explain such an association since several reports have revealed that lowered expression of MAO-A, or MAO-A KO mice, as well as lower activity of COMT or COMT-deficiency in mice are associated with higher aggression [177][178][179][180][181][182]. Furthermore, activation of DBH expression by AP-2β may also play a part in provoking high aggression. ...
Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2β, gene: TFAP2Β). AP-2β regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2Β has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2β, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2β as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2β as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs.
... Many studies suggest an association between the COMD gene and DRD4 variant dopaminergic system genes and extraversion or NS only in women. Research on men suggests that COMT polymorphism is associated with interpersonal aggression and suicide [30,31]. In animal studies, there was a gender difference in behavior associated with the COMT gene. ...
The environment is a very significant factor in early childhood development. Season of birth (SOB) is a proxy viable for the environment to which the babies are exposed, thus also significant in early development. This study investigates the association between SOB and personality. A total 2,962 college students were included as study participants. The participants were classified into four seasonal groups based on their birth month and underwent a personality assessment using the Temperament and Character Inventory (TCI). Statistical analysis was performed using one-way analysis of variance (ANOVA) and multinomial logistic regression analysis. The male participants born in autumn scored high on the Disorderli-ness (NS4) subscale (β = 0.055, P = 0.042) and the male participants born in summer and winter scored high on the Extravagance (NS3) subscale (summer: β = 0.072, P = 0.01, winter: β = 0.078, P = 0.003). The difference observed indicates a relationship between the SOB and temperament, especially NS. Our findings suggest that environmental factors may affect temperament in early development, although further research is likely needed to clarify the causality between them.
... Research aimed at identifying the potential linkage between RAGE-like phenotype to specific genotype have been extended to humans. Concurring with the findings from animal studies, COMT and 5-HTTPR genotype were found associated to enhanced aggressive behavior in humans (Strous et al., 1997;Han et al., 2004). The RAGE phenotype resulted linked also to an upergulation of DARP-32 (dopamine and cAMP regulated phosphoprotein of 32 kDa, DARPP-32) T allele (TT) in a study on non psychiatric population. ...
There has been a perennial debate about whether aggression is learned or innate. The power of extreme arguments in this area has diminished as all are beginning to recognize that both evolution and learning contribute much to our tendency to be aggressive in various distinct ways, including impulsive anger, premeditated predatory behavior in its many forms, as well as our seeking of dominance as exemplified best in inter-male jousting. Here we will be almost exclusively concerned with the biological roots of the type of impulsive aggression that arises from our genetically prescribed capacity for anger, and affective state that we label the RAGE circuitry of the brain.
... In 1997, Strous and associates evaluated 37 patients with schizophrenia based on a history of violent and threatening behaviour, crimes committed, cocaine and alcohol abuse as well as other antisocial behaviour. The aforementioned group of authors found an association between low COMT activity polymorphisms and a higher risk for aggressive and dangerous behaviour compared to patients who were homozygous for high activity [20]. Furthermore, Gogos and associates demonstrated a significant influence of COMT in some aspects of emotional and social behaviour on the knockout mouse model. ...
Schizophrenia is a chronic disorder that ultimately leads to a decline in cognitive, social and emotional functioning. Although the aetiology of the disorder is still unknown, it is most likely multifactorial, with equal importance of environmental and genetic factors. It has been hypothesized that those same factors influence aggressive symptomatology and possibly even violence in schizophrenia. The association between schizophrenia and aggressive behaviour is well documented; however, the impact of genetic alterations and gene polymorphisms on the incidence and type of violence in this group of patients has rarely been the focus of scientific research. Both violence and aggression are complex behavioural patterns that lead to difficulties in the comparability of genetic studies and limits their clinical applicability. In this review paper we systematically presented findings from studies examining the association between gene polymorphisms of the dopamine and serotonin systems and aggressive symptoms and violent behaviour in schizophrenia.
... vi) The COMT gene: Polymorphism in catechol-O methyl transferase (COMT) gene was not directly linked to schizophrenia but associated with aggressive and antisocial behaviour. Rael D Strous found that COMT activity in schizophrenics was reduced and there was Valine to methionine amino acid change [41]. vii) Cytochrome P450 genes: Ivanova et al., studied that polymorphic variants of cytochrome P450 (CYP1A2 and CYP2D6) genes in schizophrenics with Tardive Dyskinesia (TD) and hyperprolactinemia. ...
:Schizophrenia (SCZ) is a strong heritable disorder that involves multiple gene combination, each conferring a little
increase in the burden to the disease. Due to the complexity of disease, it is difficult to find susceptible genes and promising
biomarker. The true etiology of SCZ is still not fully understood, however, recent studies on SCZ molecular genetics, with a
focus on candidate genes approach affirms and predicate association with SCZ. Some investigators have reported the involvement of environment factors in the formation and progression of the Schizophrenia. Literature has been surveyed that reports
association between genetic variation and SCZ also between genetic polymorphisms and clinical outcomes. The present study
focuses on human populations to review SNPs of various genes which show best association with the disease. We have identified 60 published case control studies that have studied association of various SNPs in different population.
Keywords: Association studies, Schizophrenia, SNPs, Genes, Inheritance
... (vi) The COMT gene: Polymorphism in catechol-O methyl transferase (COMT) gene was not directly linked to schizophrenia but associated with aggressive and antisocial behavior. Rael D Strous found that COMT activity in schizophrenics was reduced and there was Valine to methionine amino acid change (Strous et al. 1997). (vii) Cytochrome P450 genes: Ivanova et al. studied that polymorphic variants of cytochrome P450 (CYP1A2 and CYP2D6) genes in schizophrenics with Tardive Dyskinesia (TD) and hyperprolactinemia. ...
The following article has been retracted from publication in the Taylor & Francis journal New Genetics and Society. I. Priya, S. Sharma, I. Sharma, R. Mahajan and N. Kapoor, A review of 45 candidate genes: association of single nucleotide polymorphism to schizophrenia risk, New Genetics and Society https://doi.org/10.1080/14636778.2018.1481740. Version of Record published online 13 July 2018.
The editorial office of the journal inadvertently processed the paper through the online submission system without proper peer review or requisite checks. This has now been remedied and the journal and publishers apologise to the authors that this occurred. Journal processes and checks have now been reviewed and updated so that all best efforts are made to ensure this does not occur again.
© Taylor & Francis/Journal owner
... Beim Tragen des 158A-Allels zeigte sich im Vergleich zur Homozygotität für das 158G-Allel eine Abnahme der Enzymaktivität um das Vierfache, wobei die Verteilung beider Allele gleichmäßig auftrat (Lachmann 1996, Syvanen 1997. In weiteren Studien (Strous, Bark et al. 1997;Lachmann 1998;Kotler, Barak et al. 1999) (Blednov, Stoffel et al. 2001). GIRK1 und -4 sind zudem in atrialen Zellen des Herzens zu finden. ...
Persönlichkeit wird zum einen durch genetische Einflüsse, zum anderen durch Erziehung und Umweltfaktoren geprägt. In heutigen Tagen ist es weitestgehend akzeptiert, dass das menschliche Naturell und die Persönlichkeit durch vielfältige genetische Faktoren beeinflusst werden. In der vorliegenden Arbeit wurde eine Genotypisierung an einer Patientenstichprobe, bestehend aus Patienten der Universitätsklinik Würzburg, mit der gesicherten Diagnose einer Persönlichkeitsstörung, und einem Kollektiv aus gesunden Probanden (Bevölkerungskollektiv) durchgeführt. Es wurden zwei verschiedene Gen-Polymorphismen (rs7275707 und rs722557) des Kandidatengens KCNJ6 hinsichtlich ihrer Beteiligung an Persönlichkeitsstörungen untersucht. Das von diesem Gen codierte Protein ist ein G-protein aktivierter einwärtsgleichrichtender Kaliumkanal (GIRK2). Es konnte zwar ein signifikanter Zusammenhang zwischen einem Single-Nukleotid-Polymorphismus (SNP) in dem Kandidatengen KCNJ6 und der antisozialen sowie Borderline-Persönlichkeitsstörung nachgewiesen werden, die molekulargenetischen Entstehungswege bis hin zur phänotypischen Ausprägung der Persönlichkeitsstörung sind allerdings multifaktoriell und an viele Rezeptor- und Neurotransmittersysteme gekoppelt. Der Ursprung kann auf den Austausch bzw. die Variation einer einzelnen Base im DNA-Strang zurückgeführt werden, im Ganzen betrachtet bleiben die Entstehung der Persönlichkeit und die daran gekoppelten Störungen aber ein multidimensionaler Prozess.
... 8,9 Notably, both the expression and function of COMT can be affected by genetic polymorphisms and a variety of phytochemicals and therapeutic drugs, as well as environmental and pathological factors. 10,11 However, limited by the lack of an available COMT probe with high sensitivity and good reactivity, it is still difficult to identify and characterize COMT modulators, as well as to investigate the functional changes in physiological and pathological states. ...
Catechol-O-methyltransferase (COMT) is a druggable biological target and COMT modulators have been widely applied in the treatment of various central and peripheral nervous system disorders. The interspecies differences of COMT were carefully investigated using 3-BTD (a newly developed fluorescent probe of COMT) methylation as the probe reaction, and liver S9 from humans and seven experimental animals including monkeys, dogs, mice, rats, minipigs, guinea pigs and New Zealand rabbits as the enzyme source. Metabolite profiling demonstrated that all the tested liver S9 samples from the different animals could catalyse 3-BTD methylation but displayed significant differences in reaction rate. Also, the differential effects of tolcapone (a potent inhibitor against COMT) on 3-BTD methylation among various species were observed. The apparent kinetic parameters and the maximum intrinsic clearances (Clint) for 3-BTD methylation in liver S9 from the different animals were determined, and the order of the Clint values for the formation of 3-BTD was RLS9 > DLS9 ≈ PLS9 > MLS9 > CyLS9 > RaLS9 > GpLS9 > HLS9. These findings are helpful for further exploring COMT-associated biological processes in animal models, as well as for developing therapeutic molecules that target COMT.
... It should be noted that studies on the influence of the COMT Val 158 Met polymorphism on human aggression have mostly used various indirect measures of aggression. Common methods are aggression score questionnaires, such as the Overt Aggression Scale (OAS), 36,37 the Risk Assessment for Dangerousness (RAD), 38 or the Buss-Durkee Hostility Inventory (BDHI). 30,39 Difficulties with comparing and interpreting these results as well as in defining and measuring aggression have been pointed out. 5 Issues in human studies arise from not differentiating between antisocial and aggressive behavior, questionnaire heterogeneity and the use of self-reported ratings instead of data on the actual expression of aggressive behavior. ...
The COMT Val158Met polymorphism is one of the most widely studied genetic polymorphisms in humans implicated in aggression and the moderation of stressful life event effects. We screened a wild primate population for polymorphisms at the COMT Val158Met site and phenotyped them for aggression to test whether the human polymorphism exists and is associated with variation in aggressive behavior. Subjects were all adults from four study groups (37 males, 40 females) of Assamese macaques (Macaca assamensis) in their natural habitat (Phu Khieo Wildlife Sanctuary, Thailand). We collected focal animal behavioral data (27 males, 36 females, 5 964 focal hours) and fecal samples for non-invasive DNA analysis. We identified the human COMT Val158Met polymorphism (14 Met/Met, 41 Val/Met, 22 Val/Val). Preliminary results suggest that COMT genotype and dominance rank interact to influence aggression rates. Aggression rates increased with rank in Val/Val, but decreased in Met/Met and Val/Met individuals, with no significant main effect of COMT genotype on aggression. Further support for the interaction effect comes from time series analyses revealing that when changing from lower to higher rank position Val/Val individuals decreased, whereas Met/Met individuals increased their aggression rate. Contradicting the interpretation of earlier studies, we show that the widely studied Val158Met polymorphism in COMT is not unique to humans and yields similar behavioral phenotypes in a non-human primate. This study represents an important step towards understanding individual variation in aggression in a wild primate population and may inform human behavioral geneticists about the evolutionary roots of inter-individual variation in aggression.
... The hyper-responsivity of this circuitry to the release of dopamine in schizophrenia has been related to positive symptoms, excessive pleasure seeking, substance abuse, and impulsivity, aspects that are known be involved with increased risk for violence. Moreover, the association of an over-active dopaminergic system with violence has been linked to the role of the catechol O-methyl-transferase (COMT) enzyme in the termination of dopamine activity in the prefrontal cortex (Strous et al., 1997). The rate of dopamine termination, and thus its availability in the synaptic space, is variably associated with three Val 158 Met allelic variants of the COMT gene localized to chromosome 22q11.1-q11.2 ...
This chapter outlines the brief definitions of aggression and violence and their subtypes. Conceptions and misconceptions regarding the association of mental illness with aggression and violence are considered in three major mental illnesses: schizophrenia, personality disorders and autism. The chapter highlights the key neurobiological features that are putatively linked with the propensity to commit acts of violence and aggression. It examines whether the presence of additional, comorbid disorders aggravates the risk for violence and aggression. The chapter discusses some common underlying psychological and neurobiological causes, highlighting the social brain network as a possible neuro-biological framework to understanding violence and aggression in these disorders. The overlap between brain networks implicated in aggression and the processing of socio-cognitive abilities suggest that pathological aggression can be conceptualized as a disorder of the social brain. Aggression and antisocial behavior are a likely consequence of mental illnesses affecting the social brain.
... For COMT, a common functional polymorphism has been found in which a valine residue is substituted by methionine at amino acid 158, causing a lower activity of the COMT enzyme [Strous et al., 1997]. An association of the low-activity variant with severe affective disorders was reported by Li et al. [1997], Mynett-Johnson et al. [1998], Papolos et al., [1998], Kirov et al. [1998], andOhara et al. [1998a] but no association was found by the Biomedical European Bipolar Collaborative Group [1997], Gutierrez et al. [1997], Kunugi et al. [1997. ...
In a community sample of 2,327 Caucasians, we tested the hypotheses that polymorphisms in the COMT and DRD3 genes are associated with personality traits conferring vulnerability to anxiety, depression, or alcohol misuse, or with current symptoms of these; and that the association is stronger in persons who also have been exposed to stressor experiences. To conserve resources and to allow replication, the genetic analysis was undertaken in two stages. For the COMT polymorphism, no statistically significant associations were found in the first sample of 862 persons. The remainder of the sample was therefore not analysed for that gene. For the DRD3 polymorphism, those in the first sample with at least one of the Ser⁹ alleles had significantly higher scores in neuroticism (p=0.006) and behavioral inhibition (p=0.003). There was a trend, failing to meet the 1% significance criterion, for those with this genotype also to have higher depression and anxiety. The groups did not differ in alcohol use. In persons with the Ser⁹ allele who were also exposed to stressors, there was a higher level of depression at the 5% level; and the depression level was higher in homozygotes. But when the remainder of the sample (1,465) was analysed, none of the associations reached statistical significance. We conclude that neither the COMT nor DRD3 polymorphisms are associated with anxiety, depression, or alcohol abuse. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:102–107, 2000 © 2000 Wiley-Liss, Inc.
... Schizophrenia (SZ) is a one of the most severe psychiatric disorders that affect approximately one percent of the population worldwide. Several factors, such as disrupted-in-schizophrenia 1 (DISC1) [16], Neuregulin 1 [17], catechol-o-methyltransferase (COMP) [18][19][20], and BDNF [21], among others [22], have been associated with an increased risk to develop schizophrenia. However, the overall mechanism resulting in schizophrenia remains unclear. ...
The neural cell adhesion molecule (NCAM) is modified by polysialic acid (polySia or PSA) in embryonic brains. In adult brains, polySia modification of NCAM is only observed in restricted areas where neural plasticity, remodeling of neural connections, or neural generation is ongoing although the amount of NCAM remains unchanged. Impairments of the polySia-expression and several single nucleotide polymorphisms (SNPs) of the polysialyltransferase (polyST) ST8SIA2 gene are reported to be associated with schizophrenia and bipolar disorder. Chlorpromazine (CPZ) is well-known as an agent for treating schizophrenia, and our hypothesis is that CPZ may affect the polySia expression or the gene expression of polySTs or NCAM. To test this hypothesis, we analyzed the effects of CPZ on the expression of polySia-NCAM on human neuroblastoma cell line, IMR-32 cells, by immunochemical and chemical methods. Interestingly, the cell surface expression of polySia, especially those with lower chain lengths, was significantly increased on the CPZ-treated cells, while mRNAs for polySTs and NCAM, and the amounts of total polySia-NCAM remained unchanged. The addition of brefeldin A, an inhibitor of endocytosis, suppressed the CPZ-induced cell surface polySia expression. In addition, polySia-NCAM was also observed in the vesicle compartment inside the cell. All these data suggest that the level of cell surface expression of polySia in IMR-32 is highly regulated and that CPZ changes the rate of the recycling of polySia-NCAM, leading to the up-regulation of polySia-NCAM on the cell surface. We also analyzed the effect of CPZ on polySia-expression in various brain regions in adult mice and found that CPZ only influenced the total amounts of polySia-NCAM in prefrontal cortex. These results suggest a brain-region-specific effect of CPZ on the expression of total polySia in mouse brain. Collectively, anti-schizophrenia agent CPZ consistently up-regulates the expression polySia at both cellular and animal levels.
... Нокауты по гену Comt демонстрировали повышенную агрессивность [Gogos et al., 1998]. Специфический полиморфизм по гену Comt также связан с увеличением агрессивного поведения и насилия у шизофреников [Strous et al., 1997;Kotler et al., 1999]. Имеется много данных о влиянии делеций других генов на агрессивность животных [обзоры: Nelson, Chiavegatto, 2000;Miczek et al., 2007]. ...
The monograph describes different approaches to the study of the neurobiological mechanisms of aggressive behavior as one of the basic forms of social behaviors in animals of different species. Social factors that promote or attenuate the demonstration of aggression in the provoking environmental conditions, as well as neurophysiological determinants of the predisposition to aggression in animals are discussed. Particular attention is paid to the new direction - the studying the influence of repeated experience of aggression on psychoemotional state, as well as social and individual behavior in animals. Evidences of development of psychopathology of aggressive behavior are presented. The data are considered in the framework of the social biology that studies the biological basis of various forms of social behavior. The monograph may be useful for biologists, psychologists, physiologists, ethologists.
... The Val/Val genotype of this polymorphism, which results in the higher COMT activity compared to Met/Met genotype, may lead to a decreased DA neurotransmission in PFC [219,220], characteristic for schizophrenia [221]. However, the studies yielded inconsistent results, associating both the high activity "Val", and low activity "Met" alleles with schizophrenia [215,[222][223][224][225][226], or failing to detect any association [227,228]. The more recent meta-analysis found only a weak association of this polymorphism with schizophrenia [229]. ...
Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.
... In parallel with this evidence, several reports have documented that, while the severity of manic symptoms in BD is typically higher in carriers of the Met allele (Bilder et al. 2002;Benedetti et al. 2010Benedetti et al. , 2011Lelli-Chiesa et al. 2011;Soeiro-de-Souza et al. 2012), this allele is generally predictive of lower intensity of cognitive deficits and negative symptoms in schizophrenia Bray et al. 2003;Gallinat et al. 2003;Tunbridge et al. 2006;Ehlis et al. 2007). In line with these findings, the Met allele has also been associated with alterations in behavioural functions in healthy subjects, including a decreased vulnerability for cognitive impairments (Strous et al. 1997;Goldberg et al. 2003;Blasi et al. 2005;Smolka et al. 2005), as well as higher predisposition for aggression in vulnerable individuals (Jones et al. 2001;Strous et al. 2003;Albaugh et al. 2010; but see also Chen et al. 2004, for conflicting results). ...
Objectives:
The enzyme catechol-O-methyltransferase (COMT), which catalyses the degradation of dopamine and norepinephrine, is posited to participate in the pathophysiology of bipolar disorder (BD) and schizophrenia. In support of this notion, rich evidence has documented that the severity of various BD and schizophrenia symptoms is moderated by rs4680, a single nucleotide polymorphism of the COMT gene featuring a valine (Val)-to-methionine (Met) substitution that results in lower catalytic activity. Nevertheless, the specific relevance of COMT enzymatic activity in the pathophysiology of BD and schizophrenia dimensions remains elusive.
Methods:
We measured COMT catalytic activity in post-mortem prefrontal cortices, striata and cerebella of schizophrenia and BD patients, as well as non-affected controls. These values were then correlated with rs4680 genotypes and psychopathology scores in the last week of life.
Results:
No direct correlation between COMT activity and rs4680 genotypes was found; however, the severity of manic symptoms was highly correlated with COMT activity in the striatum, irrespective of the diagnostic group.
Conclusions:
These results suggest that COMT striatal activity, but not rs4680 genotype, may serve as a biomarker for manic symptoms. Future studies are warranted to confirm these findings and assess the neurobiological links between COMT striatal activity and manic symptoms.
... COMT gene polymorphisms are associated with alterations in COMT protein activity and have long been associated with psychiatric disorders such as schizophrenia (Strous et al., 1997). Developmental Vitamin D deficiency is a known developmental risk factor for schizophrenia (McGrath et al., 2010). ...
Vitamin D regulates multiple factors including those involved in the ontogeny of dopaminergic systems. It has been shown that in neonatal rats maternally deprived of vitamin D, dopamine (DA) turnover is decreased with associated reductions in one catabolic enzyme, catechol-o-methyl transferase (COMT). To directly examine this signaling relationship, in the present study we have over-expressed the vitamin D receptor (VDR) in neuroblastoma SH-SY5Y cells in order to examine the mechanisms by which the active vitamin D hormone, 1,25(OH)2D3, via its receptor VDR, affects DA production and turnover. Our results show that VDR overexpression increases DA neuron differentiation by increasing tyrosine hydroxylase expression, DA production and decreasing the expression of NEUROG2 a marker of immature DA neurons. In the VDR-overexpressing cells, 1,25(OH)2D3 further increased the levels of the DA-metabolites 3-MT and HVA and elevated COMT gene expression. Chromatin immunoprecipitation revealed that 1,25(OH)2D3 increased VDR binding in three regions of the COMT promoter, strongly suggesting direct regulation. In addition, 1,25(OH)2D3 treatment attenuated increased levels of MAOA, DRD2 and VMAT2 gene expression caused by the VDR-overexpression. Taken together, these results show VDR and 1,25(OH)2D3 are directly involved in regulating the expression of dopaminergic-associated genes and that this in vitro neuronal model is a useful tool for identifying the role of 1,25(OH)2D3 in DA neuronal development and maturation.
... Los pacientes con esquizofrenia que eran homocigotos Met/Met han demostrado que presentan una mayor reactividad psicótica y afectiva al estrés en comparación con los genotipos Val/Met y Val/Val. (20) También se han estudiado a: la monoamina oxidasa tipo A (MAOA), el polimorfismo A218C de la triptófano hidroxilasa y la relevancia de los esteroides neuroactivos, en la primera, se observó que la deficiencia de la MAOA, enzima que degrada a la serotonina y noradrenalina, se asocia con comportamiento agresivo en los individuos esquizofrénicos; (21) en la segunda, no encontraron asociación entre la agresión en la esquizofrenia y el polimorfismo A218C de la triptófano hidroxilasa, (22) y en la última concluyó que 3a, 5a-tetrahidroprogesterona aumenta la agresividad y hostilidad de los sujetos con esquizofrenia. (23) Las regiones del cerebro que se encuentran implicadas cuando hablamos de violencia en los sujetos con esquizofrenia son la corteza frontal, corteza temporal y el sistema límbico, incluyendo en esta última a la amígdala, hipocampo, circunvolución cingulada y porciones del tálamo. ...
Nadie es pacífico por naturaleza. Es más, el ser humano por naturaleza es conflictivo, aunque uno puede ser pacífico o violento por la cultura. (1) Se estima que aproximadamente el siete por ciento de los sujetos que presentan esquizofrenia podría presentar comportamiento violento, sin embargo, esta cifra no varía en demasía del porcentaje en que la población general podría presentar comportamiento violento sin presentar ninguna alteración mental, esta cifra es alrededor del dos por ciento; ahora bien, estas cifras se disparan hasta cuatro veces más en el sexo masculino, y hasta veintisiete veces más en el sexo femenino cuando se presenta alguna comorbilidad como psicopatía, abuso o dependencia de sustancias legales como el alcohol o ilegales. (2) Las hipótesis neurobiológicas de comportamiento violento en sujetos con esquizofrenia son, un polimorfismo en el codón 158 de la enzima Catecol-O-Metiltransferasa, que se da por la sustitución de Valina por Metionina, (3) además se ha observado que la monoamina oxidasa tipo A y a los esteroides neuroactivos, se asocian a comportamiento violento en los sujetos que presentan esquizofrenia. (4) Las regiones encefálicas que aparentemente se encuentran comprometidas son, la corteza frontal, la corteza temporal y el sistema límbico; se observa comportamiento violento en sujetos que presentan adelgazamiento cortical bilateral de la corteza frontal, además de la corteza sensioriomotora y la corteza motora, así como la reducción de la sustancia blanca en la corteza prefrontal; también se cree que existe un déficit en el circuito prefrontal límbico. (5) Esto no explica del todo el comportamiento violento de los sujetos con esquizofrenia, se cree además influye otro tipo de factores como un deficiente apoyo familiar, uso de sustancias, los síntomas productivos que provocan una mala interpretación de la realidad, el estrés, la discriminación y la mala adherencia al tratamiento. (6)
... Accordingly, this allele has been associated with aggressive behavior and emotional regulation. For example, male schizophrenics with the low activity 158A allele have a higher risk of aggressive behaviors, and variation in this allele can differentiate between outwardly and inwardly expressed anger among suicide attempters (Kotler et al., 1999;Lachman et al., 1998;Strous et al., 1997) (Rujescu et al., 2003). Furthermore, COMT knockout female mice display impairment in their emotional reactivity compared to males, which are more aggressive. ...
... The same group investigated transgenic mice deficient for COMT and found that homozygous deficient female mice displayed increased anxietylike behaviors, whereas heterozygous male mice demonstrated increased aggression (Gogos et al 1998). Interestingly, an uncontrolled study in schizophrenic patients (32 men, 5 women) found association between homozygous low-activity 472A (SNP 8) alleles and aggressive/antisocial behavior (Strous et al 1997). In this context, we hypothesized that because panic disorder is more common in women, COMT may be an intriguing candidate gene for explaining this unequal distribution of phenotype. ...
Background:
A well-characterized single nucleotide polymorphism (472G/A-Val/Met-SNP8) in the coding sequence of the catechol-O-methyltransferase (COMT) gene leads to a three- to fourfold difference in enzymatic activity and clinical and animal studies suggest a role in anxiety states like panic disorder.
Methods:
Subjects from 70 panic disorder pedigrees, and 83 "triads", were genotyped at seven single nucleotide polymorphisms (SNPs), polymorphic microsatellites in the first intron of COMT and approximately 339kb upstream of COMT (D22S944) and analyzed for genetic association and linkage.
Results:
Linkage analysis showed elevated LOD scores for 472G/A (SNP 8), silent exon 3 substitution (186C/T-SNP 5), and the marker D22S944 (2.88, 2.62, and 2.93, respectively), using a variety of diagnostic and genetic models. Association tests were not significant for the SNPs, but were highly significant for D22S944 (p =.0001-.0003). One three-marker haplotype formed from the above three polymorphisms was significantly associated with panic disorder (p =.0001), as was the "global" p value for this combination (p =.005). In addition, numerous haplotypes with combinations of D22S944 and COMT SNPs were found to be significantly associated with panic disorder.
Conclusions:
Our findings provide strong evidence for a susceptibility locus for panic disorder either within the COMT gene or in a nearby region of chromosome 22.
From a team of leading experts comes a comprehensive, multidisciplinary examination of the most current research including the complex issue of violence and violent behavior. The handbook examines a range of theoretical, policy, and research issues and provides a comprehensive overview of aggressive and violent behavior. The breadth of coverage is impressive, ranging from research on biological factors related to violence and behavior-genetics to research on terrrorism and the impact of violence in different cultures. The authors examine violence from international cross-cultural perspectives, with chapters that examine both quantitative and qualitative research. They also look at violence at multiple levels: individual, family, neighborhood, cultural, and across multiple perspectives and systems, including treatment, justice, education, and public health.
From a team of leading experts comes a comprehensive, multidisciplinary examination of the most current research including the complex issue of violence and violent behavior. The handbook examines a range of theoretical, policy, and research issues and provides a comprehensive overview of aggressive and violent behavior. The breadth of coverage is impressive, ranging from research on biological factors related to violence and behavior-genetics to research on terrrorism and the impact of violence in different cultures. The authors examine violence from international cross-cultural perspectives, with chapters that examine both quantitative and qualitative research. They also look at violence at multiple levels: individual, family, neighborhood, cultural, and across multiple perspectives and systems, including treatment, justice, education, and public health.
The article is the text of a lecture given at the Faculty of the Humanities, March 2001. It argues that one implication of recent advances in the sciences of life may be that the binary opposition of the normal and the pathological is put into question. Canguilheim’s distinction between vital and social norms is challenged and superseded by a Foucauldian genealogical approach to programs for the government of individuals, and the norms of life that emerged in the nineteenth and twentieth centuries are argued to be fundamentally social. Viewing genetics, biopsychiatry, and the commercialisation of drug development and biomedicine, the author argues that the logic of normalisation is loosing its hold, and being replaced by strategies for the continuous molecular management of variation, the modulation of susceptibilities, and the capitalisation of life itself.
Comorbidity with other mental disorders in patients with antisocial personality disorder (ASPD) is underappreciated despite compelling evidence that such comorbidities are more the rule than the exception in clinical practice. This chapter reviews the prevalence of comorbidities in ASPD, potential etiopathological explanations for the frequent co‐occurrence of psychiatric disorders in ASPD, and the impact thereupon on the management of these patients in clinical practice. Evidence from multiple studies points to a relationship between florid symptoms of psychosis and propensity for violence. Overall, individuals with affective disorders are less violent than those with schizophrenia, and when they become violent, it is usually during a manic episode and is characterized by agitated behavior. Explanations for the comorbidities associated with adult ASPD include shared genetics, shared vulnerability, shared environment, and learned behavior. A major implication of comorbidity with ASPD is its impact upon treatment and long‐term outcome.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
From multiple twin studies, it is known that predisposition for suicide significantly depends on the genotype, approximately for 30-50 %. Many laboratories search for the genes controlling this trait. In the present article, the obtained data are briefly reviewed. Suicidal behavior strongly associates with at least two polymorphisms: with short promoter of the SLC6a4 gene and 158Met haplotype of the CoMT gene. Moreover, the data observed lead to proposition that some manifestations of suicidal behavior are quite autonomous and therefore should be analyzed as separate traits. among them are completed suicide and its various simulations (non-lethal attempts), violent and non-violent forms of suicidal behaviour, as well as single and multiple attempts. otherwise, when suicidal behavior is analyzed in general, association approach is usually vain.
This study aimed to develop a practical two-photon fluorescent probe for highly sensitive and selective sensing the activities of COMT in complex biological samples. To this end, a series of 3-substituted 7,8-dihydroxycoumarins were designed and synthesized. Among them, 3-BTD displayed the best combina-tion of selectivity, sensitivity, reactivity and fluorescence re-sponse following COMT-catalyzed 8-O-metylation. The newly developed two-photon fluorescent probe 3-BTD can be used for determining the activities of COMT in complex biological samples and bio-imaging of endogenous COMT in living cells and tissue slices with good cell permeability, low cytotoxicity and high imaging resolution. All these findings suggest that 3-BTD holds great promise for developing therapeutic molecules that target COMT, as well as for exploring COMT-associated biological processes and its biological functions in living systems. Furthermore, the strategy also shed new lights on the development of fluorescent probes for other conjugative enzymes.
Estamos en un mundo que invita a crear un sistema de convivencia acorde a las necesidades de cada uno, en un contexto de diversidad; invitándonos a crear formas de convivir, en el cual la legitimización hace que cada uno exista en el espacio del otro en la aceptación mutua. No obstante, en la historia de nuestros ancestros hemos vivido estatus de destrucción de unos contra otros y de uno mismo, como el suicidio desde distintos modos, incluso los culturales.
En ese transcurrir histórico del hombre como ser bio-psico-social, en los ámbitos de persona, familia y comunidad, se han naturalizado algunos modos violentos que se dan en lo interpersonal, familiar e institucional.
Se considera que la violencia interpersonal es un importante problema de salud y la principal causa de muerte de adolescentes y adultos jóvenes en América Latina y el Caribe (Organización Mundial de la Salud, 2014). Por otro lado, la violencia autoinfligida es un importante problema de salud y una de las principales causas de muerte en América Latina y el Caribe. El suicidio es la cuarta causa de muerte entre los jóvenes de 10 a 19 años de edad en las Américas (Organización Panamericana de la Salud, 2014).
Tanto en nuestro país, como en Latinoamérica, las muertes violentas por homicidio son la principal causa de muerte entre los varones adolescentes y adultos jóvenes (Organización Panamericana de la Salud, 2012). En ese sentido cada día, personas, principalmente mujeres y niños, son víctimas de violencia mortal o no mortal, cuyas lesiones físicas (y psicológicas) e requieren tratamiento en servicios de urgencias.
En este contexto, muchas víctimas de maltrato físico, sexual o psicológico, no solicitan ayuda del personal de salud ni de otras autoridades, en un marco de silencio cultural.
Comprendiéndose que muchos de estos comportamientos violentos están influidos significativamente por el consumo de alcohol, la relación parento-filial y el apoyo social de los pares; siendo estos saberes importantes para idear estrategias integrales eficaces de prevención adaptadas al contexto.
Los artículos que les presentamos en esta oportunidad dan cuenta de una realidad que se vuelve tangible por los datos aportados y expresados, buscando reducir la brecha en los mismos. Consideramos que este número de la Revista Paraguaya de Psiquiatría es crucial, puesto que desafía propuestas y compromisos de todos los que trabajamos en el área de la Salud Mental.
Amnistía Internacional recuerda que la violencia contra las mujeres, tanto en el ámbito público como en el privado, constituye una violación de los derechos humanos y las libertades fundamentales y limita total o parcialmente a la mujer el reconocimiento, goce y ejercicio de tales derechos y libertades. Tal como lo expresa el preámbulo de la Convención Interamericana para Prevenir, Sancionar y Erradicar la Violencia Contra la Mujer (Convención de Belém do Pará), la violencia contra las mujeres es una ofensa a la dignidad humana y una manifestación de las relaciones de poder históricamente desiguales entre mujeres y hombres. La violencia contra las mujeres es una realidad generalizada, diaria, que experimentan las mujeres en todos los países del mundo. Sus efectos son devastadores para las mujeres, su vida, su salud, su trabajo y el bienestar de sus familias. Hoy, a casi 7 años de su presentación original, Amnistía Internacional recuerda al gobierno nacional la necesidad imperiosa de cumplir con el “Programa de 14 puntos para la prevención, sanción y erradicación de la violencia contra las mujeres”.
Permanent residents of Kharkiv (637 men and 856 women at the age of 45–65 years) are tested on the level of aggression and empathy. The average aggression level (41.7 points) is higher in migrants (born outside Kharkiv) than in indigenous people (36.3 points); the average empathy level is lower in migrants (3.2 points) than in indigenous people (5.5 points). The average values of the aggression and empathy indices are not associated with ethnicity and degree of miscegenation. The correlation between spouses (r) by these personal features is within 0.20–0.31; the marriage conjugation index (K) is 0.13–0.18. Genotyping of the married couples for the rs2235186 SNP of X-linked monoaminooxidase (MAO-A) gene detected a positive marriage assortativeness: the C × CC and T × TT pairs are developed more frequently than during panmixia; the C × TT and T × CC pairs, less frequently. The T allele is coupled with increased aggression level and decreased empathy level. The phenotypes of heterozygous women indicate the intermediate inheritance of these traits.
Evidence has accumulated since the mid 1960s from a number of different countries indicating an association between mental disorder and crime, particularly between the major mental disorders and violence. Furthermore, biological factors have been increasingly implicated as causing a predisposition toward criminal behavior. In recent years, much work has concluded that aggression and impulsivity are associated with reduced central serotonergic function. The link between reduced serotonergic function and aggression and impulsivity may also have important genetic implications: a recent study has shown that a polymorphism in the gene controlling tryptophan hydroxylase production (the rate-limiting step in 5-HT biosynthesis) is associated with both self-directed aggression and reduced CSF 5-HIAA [Nielsen et al., 1994]. Although a number of studies suggest that reduced serotonergic transmission is implicated in criminal behavior, other reports suggest that catecholamines may also play a role: recently a functional polymorphism of the catecholO-methyl-transferase (COMT) gene has been implicated in impulsive-aggressive behavior in schizophrenic patients [Strous et al., 1997]. However, since serotonergic and dopaminergic systems directly interact in the limbic system, it is reasonable to propose that both neurotransmitter pathways could have an effect on criminal behavior. The aim of this study was to evaluate the role of several polymorphisms of serotonin and dopamine receptor genes in a population of psychiatric patients with a history of violent and threatening behavior, crime, cocaine, and alcohol abuse, and other antisocial behaviors.
Violence and persistent aggression are serious problems in the general population and among certain psychiatric patients. Violence and persistent aggression have been associated with suicidal ideation and substance abuse, characteristics of chronically ill, and in many instances, treatment-resistant schizophrenia individuals. Assessment of dangerousness in psychiatric patients involves evaluation of sociodemographic and clinical factors. A substantial number of neurologic and psychiatric disorders are associated with pathologic anger and aggression; of these, the association between schizophrenia and violence/aggression is the best described. Neurotransmitters that have been implicated in aggressive and violent behavior include serotonin, norepinephrine, and dopamine. Current pharmacotherapy of pathologic aggression involves the use of multiple agents on a trial-and-error basis, with varying degrees of response. Unfortunately, this approach subjects patients to numerous side effects, including the extrapyramidal symptoms associated with the use of conventional antipsychotics. This paper will review evidence for the efficacy of clozapine in the treatment of aggression and violence in the treatment-refractory patient. The reduction in violence and persistent aggression with clozapine treatment should improve the chances for integration of the schizophrenia patient into the community and provide cost savings to society.
Aggression is a difficult phenotype to study. With respect to psychiatric diagnoses, it is often related to psychopathy, antisocial behaviour, personality disorder, and schizophrenia. PET and to a much lesser extent SPECT data correspond with structural brain imaging and indicate that the frontal/prefrontal lobe and temporal lobe or limbic system are involved in the development of aggression, possibly through misinterpretation of emotional stimuli or impaired control. Few neuroimaging studies have addressed neurotransmitters issues. There is some evidence for serotonergic and dopaminergic dysfunction in aggressive individuals. Neuroimaging data indicate that there is no simple association of a serotonergic dysfunction and aggression.
In patients with schizophrenia and aggression, data from the few neuroimaging studies performed to date indicate frontal and temporal lobe abnormalities. PET and SPECT data further suggest deficits in the orbitofrontal and temporal cortex. Some fMRI studies found a negative association of violent behaviour with frontal and right-sided inferior parietal activity.
Two studies have reported associations between the low activity polymorphism of the catechol-O methyltransferase (COMT) gene and violence in schizophrenia (1,2). We recruited 180 individuals (UK ethnicity) with DSM-IV schizophrenia. Violent episodes were rated from interview and case-note review, and a rating of violence obtained using the Overt Aggression Scale (OAS) (3). COMT polymorphism was determined by RFLP analysis. A significant association was found between COMT genotype and OAS score (p=0.0157), with the only significant difference between the genotypes being between the high activity homozygote and the heterozygote (p = 0.025). The odds ratio for severe violence comparing the high activity homozygote with the other genotypes was 2.07, with a 95% confidence interval of (1.03, 4.15). An association was also found between gender and OAS score (p = 0.015), with males having a higher mean score than females. There was no significant difference in the distribution of genotypes across gender or in the duration of illness compared across genotypes or gender. Our results contradict findings from the two previous studies. The larger sample in our study makes a Type II error unlikely, and highlights the need for further research in this field.
Catechol-O-methyltransferase (COMT) is a key modulator of dopaminergic and noradrenergic neurotransmission, There is a functional polymorphism of the COMT gene, Val108Met in the soluble form of the enzyme (Val158Met in the membrane-bound form). Involvement of the dopaminergic systems in alcoholism has been suggested in mice and humans, We examined associations between this polymorphism and alcoholism in 175 Japanese alcoholics and 354 age- and gender-matched Japanese controls. No significant difference in the allelic distributions in alcoholics and controls and no significant associations between antisocial behaviors in alcoholics and this polymorphism were observed, Therefore, the COMT gene is not likely to play a significant role in alcoholism. (C) 1999 Lippincott Williams & Wilkins.
Human personality traits which can be reliably measured by any of a number of rating scales, show a considerable heritable component. The tridimensional personality questionnaire (TPQ) is one such instrument and was designed by Cloninger to measure four distinct domains of temperament - Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence-that are hypothesized to be based on distinct neurochemical and genetic substrates. Cloninger proposed that individual variations in the Novelty Seeking trait are mediated by genetic variability in dopamine transmission. Individuals who score higher than average on the TPQ Novelty Seeking scale are characterized as impulsive, exploratory, fickle, excitable, quick-tempered and extravagant, whereas those who score lower than average tend to be reflective, rigid, loyal, stoic, slow-tempered and frugal. We now show that higher than average Novelty Seeking test scores in a group of 124 unrelated Israeli subjects are significantly associated with a particular exonic polymorphism, the 7 repeat allele in the locus for the D4 dopamine receptor gene (D4DR). The association of high Novelty Seeking and the 7-repeat allele was independent of ethnicity, sex or age of the subjects. This work, together with the accompanying confirmations in this issue, provides the first replicated association between a specific genetic locus involved in neurotransmission and a normal personality trait.
• A systematic method for clinical description and classification of both normal and abnormal personality variants is proposed based on a general biosocial theory of personality. Three dimensions of personality are defined in terms of the basic stimulus-response characteristics of novelty seeking, harm avoidance, and reward dependence. The possible underlying genetic and neuroanatomical bases of observed variation in these dimensions are reviewed and considered in relation to adaptive responses to environmental challenge. The functional interaction of these dimensions leads to integrated patterns of differential response to novelty, punishment, and reward. The possible tridimensional combinations of extreme (high or low) variants on these basic stimulusresponse characteristics correspond closely to traditional descriptions of personality disorders. This reconciles dimensional and categorical approaches to personality description. It also implies that the underlying structure of normal adaptive traits is the same as that of maladaptive personality traits, except for schizotypal and paranoid disorders.
This report describes a pattern of similarities among 12 patients which are felt to represent a newly recognized congenital malformation syndrome. The symptoms shown most consistently by the 12 patients were overt or submuscous clefts of the secondary palate, ventricular septal defects, typical facies, and learning disabilities. Other symptoms were noted with varying frequency. The occurrence of velopharyngeal insufficiency in all twelve patients reflected poor motion in the lateral pharyngeal walls, thus necessitating specific forms of treatment. Treatment was often dependent on the extent of cardiac lesions.
The large clinical overlap between DiGeorge syndrome and velo-cardio-facial syndrome suggests an aetiological connection. DiGeorge syndrome is associated with microdeletions of chromosome 22q11 and is therefore likely to be caused by reduced dosage of genes within this region. We present preliminary data that velocardiofacial syndrome patients have similar chromosome deletions, a finding consistent with the hypothesis that these disorders represent part of a spectrum of abnormalities seen with monosomy for 22q11.
Dopamine receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1, D2, D3) have been cloned. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine is one of the most favoured antipsychotics because it does not cause tardive dyskinesia. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.
A cDNA clone for human catechol-O-methyltransferase (hCOMT; S-adenosyl-L-methionine:catechol O-methyltransferase; EC 2.1.1.6) was isolated from a human hepatoma cell line (Hep G2) cDNA library by hybridization screening with a porcine cDNA probe. The cDNA clone was sequenced and found to have an insert of 1226 nucleotides. The deduced primary structure of hCOMT is composed of 271 amino acid residues with the predicted molecular mass of 30 kDa. At its N terminus it has a hydrophobic segment of 21 amino acid residues that may be responsible for insertion of hCOMT into the endoplasmic reticulum membrane. The primary structure of hCOMT exhibits high homology to the porcine partial cDNA sequence (93%). The deduced amino acid sequence contains two tryptic peptide sequences (T-22, T-33) found in porcine liver catechol-O-methyltransferase (COMT). The coding region of hCOMT cDNA was placed under the control of the cytomegalovirus promoter to transfect human kidney 293 cells. The endogenous COMT activity, which was approximately 9.98 units per mg of protein in the untransfected cells, increased to 206 units per mg of protein upon transfection with a plasmid containing the COMT cDNA. The COMT activity of recombinant protein was inhibited competitively (IC50 = 700 nM) by the selective COMT inhibitor Ro 40-7592. An anti-COMT monoclonal antibody recognized, on immunoblots, a major polypeptide with apparent molecular mass of 29 kDa, in reasonable agreement with the predicted molecular mass. The recombinant hCOMT was shown by immunoblot analysis to be mainly associated with the membrane fraction. RNA blot analysis revealed one COMT mRNA transcript of 1.4 kilobases in Hep G2 poly(A)+ RNA.
Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to
be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene
integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin
concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons.
In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed
in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were
reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including
enhanced aggression in males.
Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline
mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted
rape, and exhibitionism. Analysis of 24-hour urine samples indicated markedly disturbed monoamine metabolism. This syndrome
was associated with a complete and selective deficiency of enzymatic activity of monoamine oxidase A (MAOA). In each of five
affected males, a point mutation was identified in the eighth exon of the MAOA structural gene, which changes a glutamine
to a termination codon. Thus, isolated complete MAOA deficiency in this family is associated with a recognizable behavioral
phenotype that includes disturbed regulation of impulsive aggression.
Deletions of chromosome 22q11 have been seen in association with DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). In the present study, we analysed samples from 76 patients referred with a diagnosis of either DGS or VCFS to determine the prevalence of 22q11 deletions in these disorders. Using probes and cosmids from the DiGeorge critical region (DGCR), deletions of 22q11 were detected in 83% of DGS and 68% of VCFS patients by DNA dosage analysis, fluorescence in situ hybridisation, or by both methods. Combined with our previously reported patients, deletions have been detected in 88% of DGS and 76% of VCFS patients. The results of prenatal testing for 22q11 deletions by FISH in two pregnancies are presented. We conclude that FISH is an efficient and direct method for the detection of 22q11 deletions in subjects with features of DGS and VCFS as well as in pregnancies at high risk for a deletion.
Twin and adoption studies suggest that 30 to 60% of the variance in many personality traits is due to inherited factors. However, there is little knowledge of the number or identity of the responsible genes, how they differ between individuals, or how their gene products interact with the developing brain and with environmental and experiential factors to generate the complex blend of attitudes and actions that comprise human temperament. In the accompanying paper, Ebstein et al. have found a population association between a long allele of polymorphic exert III repeat sequence of the D4 dopamine receptor gene (D4DR) and the normal personality trait of Novelty Seeking. The possibility of a causal relationship between D4DR and Novelty Seeking is further supported by studies showing that the number of exon III repeats can affect the binding of ligands to the receptor; that D4DR is expressed in limbic areas involved in cognition and emotion; that dopamine mediates exploratory behaviour in experimental animals; that the rewarding effects of amphetamines and cocaine are related to dopamine release; and that Novelty Seeking is low in dopamine-deficient patients with Parkinson's disease. We investigated the relationship between D4DR exon III sequence variants and personality test scores in a population of 315 mostly male siblings, other family members and individuals from the United States. The association between long alleles of exon III and personality traits related to Novelty Seeking was confirmed. Moreover, family studies showed that this association is the result of genetic transmission rather than of population stratification.
Catechol O-methyltransferase (COMT) inactivates catecholamines by methylating their m-hydroxy group. Some previous studies using biochemical methods have found higher levels of COMT activity in schizophrenic patients. Recently, the genetic polymorphism that underlies variation in COMT activity, which results in the creation of a NlaIII restriction site in the low-activity allele, has been elucidated.
This study investigated this polymorphism in 78 unrelated schizophrenic patients and 78 comparison subjects matched for age and ethnicity. High-molecular-weight DNA was isolated from lymphocytes with routine procedures, and each individual was typed for high and low COMT activity.
The frequency of the NlaIII polymorphism was 0.51 in the schizophrenic patients and 0.53 in the comparison subjects, and no significant allelic or genotypic associations were observed.
There was no evidence for variation in COMT activity between a group of schizophrenic patients and matched comparison subjects.
Introduction. Human aggression and criminal violence: definitions and classifications. Aggression among animals. Neurotransmitters, hormones, and genes. Neurological, neuropsychological, and brain imaging correlates of violent behavior. Congenital and demographic factors. Developmental antecedents of violent behavior. Personality disorders and impulse control. Violence and psychoactive substance abuse. Violent behavior of persons with mental disorders outside of hospitals. Violent behavior of psychiatric inpatients. Biological treatments of violence. Summary and conclusions. Appendix: Statistical explanation of the actuarial method: Bayes decision. Index.
Current pharmacotherapeutic approaches to the management of violent and aggressive behavior rely mostly on agents that act as receptor agonists or antagonists at subtypes of brain dopaminergic, GABAergic, and serotonergic receptors. Ethological experimental studies in animals have shown that drugs may modulate aggression by inhibiting motor activity, by distorting aggression-provoking or -inhibiting signals, by fragmenting behavioral sequences or temporal patterning, or by increasing the rate and intensity of aggressive acts. Evidence from animal studies points to large changes in selected brain dopamine, serotonin, and GABA systems during and following aggressive and defensive behavior. However, the specificity of drugs that are currently used to control aggressive behavior through their action as agonists or antagonists at subtypes of dopamine, serotonin or GABA receptors continues to be of concern. Similar to the effects of widely used traditional neuroleptics that nonselectively antagonize dopamine receptors, the range of behaviors which is suppressed by either D1 or D2 receptor antagonists is pervasive. At present, systemic administration of dopamine receptor antagonists in animal preparations does not target aggression-specific mechanisms. The GABAA/Benzodiazepine/Chloride ionophore receptor complex is implicated in the aggression-heightening effects of alcohol and benzodiazepines. Although early reports focused on the “taming” effects of benzodiazepine anxiolytics, low doses may enhance aggression in both animals and humans. Benzodiazepine antagonists block heightened aggression after low doses of alcohol or benzodiazepines. Agonists at certain 5-HT1 receptor subtypes such as eltoprazine are potently effective in reducing aggressive behavior of males and females of various animal species under conditions that promote charging offensive-type aggression, without adversely affecting nonaggressive components of the behavioral repertoire. However, recent reports indicate that eltoprazine and related compounds may potentiate anxiety reactions in rodents, and question the behavioral specificity of these substances. Opioid receptor antagonists modulate primarily physiological and behavioral responses of defense and submission. Defeated animals show tolerance to opiate analgesia and withdrawal responses upon challenge with opioid receptor antagonists. Defensive and submissive vocalizations are potently blocked by opioid peptides. Substances that target specific receptor subtypes at serotonergic, GABAergic and opioidergic synapses are most promising for the selective modification of aggressive, defensive and submissive behavior patterns.
Low catechol-O-methyltransferase (COMT) activity (less than 8 units per milliliter) in the human erythrocyte is inherited as an autosomal recessive trait (COMTL). The average half-life of COMT in erythrocyte lysates incubated at 48 degrees C was significantly shorter in lysates from three subjects with low enzyme activity than in lysates from three subjects with high enzyme activity (12.5 +/- 0.9 minutes compared with 21.2 +/- 1.4 minutes, P less than .01). When the ratios of COMT activities in lysates heated at 48 degrees C for 15 minutes to enzyme activities in unheated samples were used as a measure of enzyme thermostability in blood samples from 316 randomly selected subjects, the ratios were significantly less for subjects with low enzyme activity than for subjects with higher enzyme activity. The presense of thermolabile COMT in blood of individuals homozygous for COMTL raises the possibility that the locus COMT may represent the structural gene for the human enzyme.
Catechol-O-methyltransferase activity was measured in blood obtained from 373 randomly selected subjects aged 16-18, 262 consecutive adult blood donors, and 201 first-degree relatives of subjects with RBC COMT activity of less than 8 U. The distribution of RBC COMT activity in a randoly selected populations was apparently bimodal with a nadir at approximately 8 U. Of a randomly selected population, 23% had low RBC COMT activity (less than 8 U), Because of previous reports of a significant sibling-sibling correlation of RBC COMT activity and because of the presence of a subgroup of subjects with low enzyme activity, RBC COMT activity was measured in blood from first-degree relatives of probands with low erythrocyte enzyme activity in 48 families. The results of segregation analyses of the data were compatible with autosomal recessive inheritence of an allele for low RBC COMT activity. RBC COMT in blood samples from siblings of probands inthese families also showed an apparent biomodal distribution.
Previous studies have suggested that the activity of erythrocyte catechol-O-methyltransferase (COMT) may be reduced in women with bipolar and particularly unipolar affective illness. More recently, increased COMT activity in both men and women with affective disorder was reported. The activity of COMT in erythrocytes was determined in 184 outpatients with primary affective disorder at the Lithium Clinic of the New York State Psychiatric Institute. COMT activity was determined by a modification of the Axelrod and Cohn method with dopamine as substrate. This change resulted in an apparent threefold increase in the values for COMT activity; however, when both methods were compared, the results correlated (r = 0.97, p less than 0.001, N = 37). We found that the values for women were not significantly lower than those for men. In addition, there was no difference between patients with affective disorder and controls. Further, no difference was demonstrated between patients diagnosed as bipolar or uni-polar. Parameters such as mood, medication, and inpatient or outpatient status had no effect on COMT activity. The results of previous studies are discussed in an attempt to reconcile the different results.
Catechol-O-methyltransferase (COMT; EC 2.1.1.6) is a physiologically important enzyme in the metabolism of catecholamine neurotransmitters and catechol drugs. Using primers derived from the known rat cDNA sequence for COMT, we have used the polymerase chain reaction to produce an amplified DNA fragment corresponding to the complete coding region of the rat gene. With this fragment as a probe, we have hybridized DNAs from two panels consisting of human/rodent and human/hamster somatic cell hybrids carrying various translocations and deletions to refine the chromosomal location of human COMT. Southern blot analysis indicates that the human COMT gene is localized to 22q11.1----q11.2, a region to which several anonymous DNA sequences, but until now, no structural genes, have been assigned.
Catechol-O-methyltransferase (COMT) cDNA clones were isolated from a human placental cDNA library using synthetic oligonucleotides as probes. All four positive clones isolated contained an open reading frame, which potentially coded for a 24.4-kD polypeptide, presumably corresponding to the cytoplasmic form of the COMT (S-COMT). In addition to the S-COMT sequences, two of the clones carried extensions in the 5' end, which potentially coded for a 50-amino-acid peptide extending the S-COMT reading frame. This sequence contained a stretch of signal sequence-like hydrophobic amino acids in its amino terminus. The deduced human COMT polypeptide had 80% similarity with the previously characterized rat COMT. Expression of one of the cDNA clones in human K-562 cells resulted in cell clones with 3- to 10-fold increased COMT activity. Cell-free translation of transcripts synthesized in vitro from one of the short cDNAs yielded a 26-kD product, similar in size to human S-COMT. Translation of transcripts from one of the long cDNAs gave 30-kD and 26-kD polypeptides, suggesting translation initiation from two different AUG initiation codons. The 30-kD protein, but not the 25-kD protein, associated with microsomal membranes in translation lysates. A potential polyadenylation signal AATTAA was detected in the 3' ends of two of the clones 265 nucleotides downstream from the COMT translation termination codon. RNA blotting on human placental RNA revealed a 1.5-kb-long COMT-specific transcript. DNA analysis suggested that human, as well as rat, canine and monkey cells have one gene for COMT.
Catechol-O-methyltransferase activity and thermal stability in the human red blood cell are controlled by a common genetic polymorphism. Approximately 25% to 30% of a randomly selected population sample is homozygous for the traits of low catechol-O-methyltransferase activity and thermolabile enzyme in the red blood cell. We tested the hypothesis that the catechol-O-methyltransferase genetic polymorphism might also control those same characteristics of the enzyme in an important human drug-metabolizing organ, the liver. Catechol-O-methyltransferase enzyme activity and thermal stability were measured in 99 hepatic biopsy samples obtained during clinically indicated surgery. The frequency distribution of heated/control ratios, a measure of enzyme thermal stability, was bimodal, with 28% of samples included in a subgroup with thermolabile enzyme. There were no sex-related differences in hepatic catechol-O-methyltransferase thermal stability. However, catechol-O-methyltransferase enzyme activity in hepatic tissue from male subjects was significantly higher than that in samples from female subjects: 61.3 +/- 20.2 units/mg protein (mean +/- SD; n = 50) versus 46.6 +/- 22.2 units/mg protein (n = 49; p = 0.0002). There was a significant correlation of hepatic catechol-O-methyltransferase activity and thermal stability in samples from both female (rs = 0.698; p = 0.0001) and male subjects (rs = 0.429; p = 0.002). Finally, when both red blood cell catechol-O-methyltransferase activity and thermal stability were measured in blood samples from 34 of these patients, there was a significant correlation between catechol-O-methyltransferase heated/control ratios and levels of enzyme activity in hepatic tissue and in red blood cell lysates. These findings indicate that the genetic polymorphism that controls catechol-O-methyltransferase activity level and thermal stability in red blood cells also controls those same properties of the enzyme in the human liver.
The authors conducted a chart review to determine the effect of beta blockers on chronic assaultiveness in seven patients with chronic schizophrenia. Six of the patients showed improvement. Four of the seven showed a greater than 70% decrease in actual assaults.
Erythrocyte catechol-O-methyltransferase (COMT) activity was measured in normal and depressed populations before specific medication. In the groups of patients, anxiety and depression scores were evaluated by the AMDP rating scale. The authors found lower enzyme activity in patients with major depression, recurrent and bipolar disorder, depressed, but no change was found in dysthymic disorder when compared to control values. However, there was no relationship between COMT activity and age, anxiety and depression scores of patients. Furthermore, the subdivision into two subpopulations, one with normal COMT activity and another with lower COMT activity, did not make it possible to assign a role to the enzyme in the severity of depression. The enzyme could, however, be considered as a genetic marker of depressive vulnerability.
Metoprolol, a selective beta 1-adrenoreceptor blocker, was administered to two patients with intermittent explosive disorder who had not done well with previous medications, including propranolol and carbamazepine. Both patients improved dramatically, suggesting clinical and theoretical relevance.
A brief critical review of serotonin involvement in two classes of aggressive behaviour, i.e. affective and predatory aggression, is presented. Special emphasis is put on the differentiation between the role played in aggression by the two ascending serotonergic systems, the mesolimbic and the mesostriatal. It is concluded that only serotonergic neurons from the dorsal raphe nucleus forming the mesostriatal system play an inhibitory role in both classes of aggression. The mesolimbic system does not seem to be directly involved in an aggression modulation. The data suggesting that the dorsal raphe may mediate its inhibitory influence through the medial amygdala is presented and discussed. Finally some attention is given to the problem of serotonin metabolism variability (biorhythm) and its implications in behavioural studies.
Erythrocyte COMT activity was determined in 31 healthy persons (16 men, 15 women) and in 34 persons with endogenous depressive syndrome (12 men, 22 women). It was found that enzyme activity is significantly higher in healthy men than in healthy women. In the group of women with endogenous depressive syndrome COMT activity is elevated as compared with the group of healthy women (P less than 0.05). This is true of all forms of affective disease: bipolar, unipolar, and undifferentiated. High COMT activity in women with depression is apparent mainly in patients whose first and second degree relatives revealed psychiatric disturbances, particularly affective disorders. This supports the significance of the sex factor in the genetic transmission of affective disorders, and a possible involvement of COMT activity changes in the pathogenesis of such disorders in women. No correlation was found between the changes in COMT activity and the psychopathological picture of depression or the severity of endogenous depressive syndrome.
On the basis of studies carried out with a group of 47 patients with endogenous depressive illness, lower plasma activity of dopamine-beta-hydroxylase (DBH) was found as compared with a control group (31 healthy persons). Lower DBH activity particularly characterized bipolar patients. Lowest DBH activity was found in patients with a family history of psychiatric disorders, in particular, affective illness (in comparison with the control group the difference was statistically significant, P less than 0.05). It was noticed, that in a period of remission or significant improvement the enzymatic activity increases, although in some cases the level of activity is still lower than in the control group. There was a correlation between activity of the enzyme and clinical course of the illness and susceptibility to antidepressive drugs. Most of the observed phenomena are related to male patients. On the basis of these studies and data supplied by corresponding literature, concerning in particular the effects of DBH inhibitors (fusaric acid, disulfiram), the authors consider that changes in DBH activity may play a role in the pathogenesis of depression and that DBH deserves further studies, also of genetic nature.
A significant decrease in catechol-O-methyltransferase (COMT) activity of erythrocytes was found in both male and female schizophrenic patients, as well as in male patients with schizophreniform psychosis. Among control subjects, a sex difference in COMT activity of erythrocytes was found, with males showing significantly higher activity than females. It is suggested that a genetically determined deficiency of catecholamine degradative enzymes in the central nervous system or, alternatively, influences of nongenetic hormonal factors could be implicated in the findings of altered erythrocyte COMT activity reported.
Previous studies have shown that the activity of human red cell catechol-O-methyltransferase (RBC COMT) is significantly correlated in sibs, that the population distribution is bimodal, and that RBC COMT from individuals with low activity is more thermolabile than that from individuals with high activity.
These observations and additional data from family studies are consistent with the hypothesis that RBC COMT activity is controlled by two alleles at an autosomal locus [Weinshilboum and Raymond, 1977], giving rise to genotypes with different but overlapping activity distributions.
In the present study, this hypothesis has been explored with various types of analyses. Given the assumption of Hardy-Weinberg genotype frequencies, we find that the population distribution of RBC COMT activity is explained much better by codominant or “intermediate” inheritance than by either dominant or recessive inheritance.
The intermediate genetic model has also been used to analyze the data of Scanlon et al [1979] on thermal inactivation of RBC COMT in a random sample of blood donors. Hypothesis tests based on this analysis confirm the conclusion of Scanlon et al that individuals with different COMT genotypes differ in the thermostability of their RBC COMT.
Using the RBC COMT activities of low-activity probands and their parents, we have derived the expected distribution of activity among the proband's sibs on the assumption of three genotypes in Hardy-Weinberg equilibrium in the population. The fit of this expected distribution to that observed is excellent, supporting the genetic model.
There is an extensive literature describing a central serotonin deficit in alcoholic, impulsive, violent offenders and fire setters. In the present study, we investigated biochemical concomitants of impulsivity and aggressiveness, and the physiological consequences of reduced central serotonin turnover.
Forty-three impulsive and 15 nonimpulsive alcoholic offenders and 21 healthy volunteers were studied in the forensic psychiatry ward of a university psychiatric department. The subjects underwent lumbar punctures and oral glucose and aspartame challenges, and their diurnal activity rhythm was measured with physical activity monitors. Discriminant function analyses were used to investigate psychophysiological and biochemical concomitants of aggressive and impulsive behaviors.
Alcoholic, impulsive offenders with antisocial personality disorder had low mean cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and corticotropin levels and high mean CSF testosterone concentrations. Compared with healthy volunteers, they showed increased physical activity during the daytime. Alcoholic, impulsive offenders with intermittent explosive disorder had a low mean CSF 5-HIAA concentration and blood glucose nadir after an oral glucose challenge, and desynchronized diurnal activity rhythm. Healthy volunteers had mean CSF 5-HIAA concentrations that were intermediate between those of alcoholic, impulsive and nonimpulsive offenders. Alcoholic, nonimpulsive offenders had a significantly higher mean CSF 5-HIAA concentration than all the other groups, including healthy volunteers.
In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence.
The purpose of this study was to examine the relationship between behavior and serotonin by using a nonhuman primate model of aggression and impulse control.
During a routine capture and medical examination, 26 adolescent male rhesus macaques (Macaca mulatta) were selected as subjects from a free-ranging population of 4,500 rhesus monkeys inhabiting a 475-acre sea island. Physiological data were obtained from 22-23 of the subjects. Blood and CSF samples were obtained, and each subject was fitted with a radio transmitter collar for rapid location. The subjects were released into their social groups, and quantitative behavioral observations were made over a 3-month period.
CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations were inversely correlated with "escalated" aggression, i.e., a measure of more intense or severe aggression as defined by the ratio of chases and physical assaults to all aggressive acts. CSF 5-HIAA concentrations were significantly lower in those subjects who showed evidence of physical wounding than in subjects with no wounds. Low CSF 5-HIAA concentrations were also correlated with greater risk-taking as determined by an analysis of leaping behaviors in the forest canopy. The ratio of long leaps (leaps that traversed the longest distances at dangerous heights) to all leaps was negatively correlated with CSF 5-HIAA concentrations.
Adolescent male rhesus macaques with low CSF 5-HIAA concentrations are at risk for 1) exhibiting more violent forms of aggressive behavior and 2) loss of impulse control as evidenced by greater risk taking during movement through the forest canopy.
The findings of a series of studies by the authors support the idea that most impulsive offenders who have a tendency to behave aggressively while intoxicated have a low brain serotonin turnover rate. The impulsive violent offenders with the lowest CSF 5-HIAA concentrations have diurnal activity rhythm disturbances, and are also prone to hypoglycemia after an oral glucose challenge. Low CSF 5-HIAA combined with hyoglycemic tendency also predicts future violence under the influence of alcohol. Sons of alcoholic fathers, who have committed violent crimes, have very low CSF 5-HIAA concentrations. Vagal tone does not correlate significantly with CSF 5-HIAA but correlates with enhanced insulin secretion, which is most prominent in subjects with intermittent explosive disorder. A polymorphism of tryptophan hydroxylase (TPH) gene is associated with low CSF 5-HIAA and a history of suicide attempts.
The effects of denervation of central noradrenergic system on the desipramine-induced enhancement of aggressive behavior were examined in long-term isolated mice. Consistent with previous reports, desipramine (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice. Pretreatment of isolated mice with DSP-4, a selective noradrenaline neurotoxin, significantly attenuated the enhancing effect of desipramine on aggressive behavior without affecting the basal aggressive responses. This effect appeared concomitant with decrease of noradrenaline levels in the cortex, hippocampus, cerebellum and hypothalamus (78%, 75%, 57%, and 17%, respectively). DSP-4 did not significantly affect dopamine or 5-HT levels in these regions. These results suggest that noradrenergic terminals originating mainly from the locus coeruleus play an important role in the desipramine enhancement of aggressive behavior, but not in the basal aggressive behavior of isolated mice.
Velo-cardio-facial (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phenotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group of clinicians using homogeneous clinical criteria independent of the deletion status. Cell lines of these patients were established and the deletion status evaluated for three loci within the commonly deleted region at 22q11.2 using fluorescence in situ hybridization (FISH). In 81% of the patients all three loci were hemizygous. In one patient we observed a smaller interstitial deletion than that defined by the three loci. The phenotype of this patient was not different from that observed in patients with larger deletions.
Human soluble (S) and membrane-bound (MB) catechol O-methyltransferase (COMT, EC 2.1.1.6) enzymes have been expressed at sufficiently high levels in Escherichia coli and in baculovirus-infected insect cells to allow kinetic characterization of the enzyme forms. The use of tight-binding inhibitors such as entacapone enabled the estimation of actual enzyme concentrations and, thereby, comparison of velocity parameters, substrate selectivity, and regioselectivity of the methylation of both enzyme forms. Kinetics of the methylation reaction of dopamine, (-)-noradrenaline, L-dopa, and 3,4-dihydroxybenzoic acid was studied in detail. Here, the catalytic number (Vmax) of S-COMT was somewhat higher than that of MB-COMT for all four substrates. The Km values varied considerably, depending on both substrate and enzyme form. S-COMT showed about 15 times higher Km values for catecholamines than MB-COMT. The distinctive difference between the enzyme forms was also the higher affinity of MB-COMT for the coenzyme S-adenosyl-L-methionine (AdoMet). The average dissociation constants Ks were 3.4 and 20.2 microM for MB-COMT and S-COMT, respectively. Comparison between the kinetic results and the atomic structure of S-COMT is presented, and a revised mechanism for the reaction cycle is discussed. Two recently published human COMT cDNA sequences differed in the position of S-COMT amino acid 108, the residue being either Val-108 [Lundström et al. (1991) DNA Cell. Biol. 10, 181-189] or Met-108 [Bertocci et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 1416-1420].(ABSTRACT TRUNCATED AT 250 WORDS)
Velo-cardio-facial syndrome (VCFS) is a common genetic disorder among individuals with cleft palate and is associated with hemizygous deletions in human chromosome 22q11. Toward the molecular definition of the deletions, we constructed a physical map of 22q11 in the form of overlapping YACs. The physical map covers > 9 cM of genetic distance, estimated to span 5 Mb of DNA, and contains a total of 64 markers. Eleven highly polymorphic short tandem-repeat polymorphic (STRP) markers were placed on the physical map, and 10 of these were unambiguously ordered. The 11 polymorphic markers were used to type the DNA from a total of 61 VCFS patients and 49 unaffected relatives. Comparison of levels of heterozygosity of these markers in VCFS patients and their unaffected relatives revealed that four of these markers are commonly hemizygous among VCFS patients. To confirm these results and to define further the breakpoints in VCFS patients, 15 VCFS individuals and their unaffected parents were genotyped for the 11 STRP markers. Haplotypes generated from this study revealed that 82% of the patients have deletions that can be defined by the STRP markers. The results revealed that all patients who have a deletion share a common proximal breakpoint, while there are two distinct distal breakpoints. Markers D22S941 and D22S944 appear to be consistently hemizygous in patients with deletions. Both of these markers are located on a single nonchimeric YAC that is 400 kb long. The results also show that the parental origin of the deleted chromosome does not have any effect on the phenotypic manifestation.
Involvement of genetic factors in the pathogenesis of schizophrenia spectrum disorders has been indicated in twin, adoption, and familial aggregation studies; the pivotal role played by the dopamine transporter in dopaminergic neurotransmission makes it a candidate gene for these disorders. Detection of close linkage between a dopamine transporter marker and schizophrenia spectrum disorders would strongly support the existence of causal relationships between genetic mutations at the dopamine transporter locus and the disease phenotype.
The authors assessed the linkage between this gene and schizophrenia spectrum disorders by using polymorphic dopamine transporter gene markers in 156 subjects from 16 multiplex pedigrees with schizophrenia as well as schizophreniform, schizoaffective, and schizotypal disorders and mood-incongruent psychotic depression.
Complete (theta = 0.0) linkage to the schizophrenia spectrum was excluded under both dominant and recessive models.
These results indicate that allelic variants at the dopamine transporter locus do not provide major genetic contributions to the etiology of schizophrenia and related disorders in these pedigrees.
The goal of this study was to define precisely the involvement of the dopamine D1, D2, and D4 receptor genes in the etiology of schizophrenia. A linkage analysis using the lod score method was performed in 37 families originating from France (n = 14) and from the Island of La Réunion in the Indian Ocean (n = 23). No evidence of linkage between schizophrenia and genetic markers located at these loci was found. A simulation study was carried out to gauge the significance of these results. The conclusions of a nonparametric linkage test (i.e., the affected pedigree member method) were equally negative. For each genetic marker, an allelic association with the disease was also sought: 80 unrelated patients and 80 healthy control subjects were tested, and no significant association was found. These results, which are in agreement with those obtained by other groups, do not support the involvement of the dopamine D1, D2, and D4 receptor genes in the pathogenesis of schizophrenia.
Human genomic DNA fragments containing catechol O-methyltransferase (COMT) sequences were isolated and the exon-intron structure analysed by sequencing, PCR and comparing to the human COMT cDNA sequences. The gene contains six exons, of which exons 1 and 2 are noncoding. MB-ATG and S-ATG codons, responsible for the initiation of translation of the membrane-bound (MB) and soluble (S) forms of the enzyme, are located in exon 3. Two distinct COMT-specific transcripts, 1.3 kb and 1.5 kb, were detected in various human tissues and cell lines. Different quantities of the shorter COMT-specific mRNA in the tissues studied suggest a tissue-specific regulation of the COMT gene at transcriptional level. Mapping of the 5' ends of the COMT mRNAs showed that transcription initiates at multiple sites in two separate DNA regions, which are preceded by functional promoter sequences. The proximal promoter (P1), located between the two translation initiation codons and extending approximately 200 bp upstream of the MB-ATG initiation codon, apparently gives rise to the 1.3-kb S-COMT mRNA (S-mRNA). The distal promoter (P2) is located in a DNA fragment in front of and partly overlapping the transcription-start region of the 1.5-kb transcript, suggesting that it controls the expression of this MB-mRNA. Similarities between the rat and human COMT gene promoters are analyzed.
Psychiatric disorders have been reported in over 10% of patients with velo-cardio-facial syndrome (VCFS) in long-term follow-up. To further explore the behavioral and psychiatric findings associated with VCFS in adulthood, detailed clinical histories of two patients--one with VCFS who developed a psychotic illness, and one with schizophrenia who was found to have dysmorphological features associated with VCFS--are described in the current report. The observed overlap of physical and psychiatric symptoms in these two patients suggests that VCFS and psychotic disorders may share a pathogenetic mechanism. This could be consistent with a contiguous gene model for VCFS and psychosis, suggesting chromosome 22q11 as a possible candidate region for genetic studies of schizophrenia.
The neuromodulator serotonin (5-hydroxytryptamine, 5-HT) has been associated with mood disorders such as depression, anxiety, and impulsive violence. To define the contribution of 5-HT receptor subtypes to behavior, mutant mice lacking the 5-HT1B receptor were generated by homologous recombination. These mice did not exhibit any obvious developmental or behavioral defects. However, the hyperlocomotor effect of the 5-HT1A/1B agonist RU24969 was absent in mutant mice, indicating that this effect is mediated by 5-HT1B receptors. Moreover, when confronted with an intruder, mutant mice attacked the intruder faster and more intensely than did wild-type mice, suggesting the participation of 5-HT1B receptors in aggressive behavior.
The level of catechol O-methyltransferase (COMT) activity and COMT thermal stability in human tissue are controlled by a common genetic polymorphism. We studied individual hepatic biopsy samples shown previously to have phenotypically high, low or intermediate COMT activities and thermal stabilities to test the hypothesis that the molecular mass (M(r)) and/or isoelectric point (pI) of the enzyme might differ in tissue from subjects with different presumed genotypes for the COMT genetic polymorphism. COMT was partially purified from each hepatic tissue sample by sequential ion exchange and gel filtration chromatography, and photoaffinity labelling was performed with [3H-methyl]-S-adenosyl-L-methionine ([3H-methyl]-Ado-Met), the methyl donor for the COMT enzymatic reaction. Two-dimensional sodium dodecylsulfate polyacrylamide gel electrophoresis (2-D SDS-PAGE) analysis of individual samples consistently showed the presence of three [3H-methyl]-Ado-Met photoaffinity labelled proteins with pI values of 5.4, 5.5 and 5.7, all three of which had M(r) values of approximately 27.1 kDa. The same pattern was observed in all samples irrespective of COMT phenotype. Western blot analysis of 2-D SDS-PAGE gels performed with rabbit polyclonal antibodies to partially purified human kidney COMT showed a pattern similar to that found during photoaffinity labelling. Once again, the same pattern was found in all samples irrespective of COMT phenotype. Therefore, neither photoaffinity labelling nor Western blot analysis revealed differences in either M(r) or pI of cytoplasmic COMT in hepatic tissue from subjects selected on the basis of different phenotypic expression of the COMT genetic polymorphism.
Catechol-O-methyltransferase (COMT) inactivates catecholamines and catechol drugs such as L-DOPA. A common genetic polymorphism in humans is associated with a three-to-four-fold variation in COMT enzyme activity and is also associated with individual variation in COMT thermal instability. We now show that this is due to G-->A transition at codon 158 of the COMT gene that results in a valine to methionine substitution. The two alleles can be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme Nla III. The identification of a gentic marker associated with significant alterations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnormalities in catecholamine neurotransmission are believed to occur, including mood disorders, schizophrenia, obsessive compulsive disorder, alcohol and substance abuse, and attention deficit hyperactivity disorder. In addition, this polymorphism may have pharmacogenetic significance in that it will help make it possible to identify patients who display altered metabolism of catechol drugs.
Velo-cardio-facial-syndrome (VCFS) is a common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploin-sufficiency of a gene(s) within 22q11. One candidate that has been mapped to this region is catechol-O-methyltransferase (COMT). We recently identified a polymorphism in the COMT gene that leads to a valine-->methionine substitution at amino acid 158 of the membrane-bound form of the enzyme. Homozygosity for COMT158met leads to a 3-4-fold reduction in enzymatic activity, compared with homozygotes for COMT158val. We now report that in a population of patients with VCFS, there is an apparent association between the low-activity allele, COMT158met, and the development of bipolar spectrum disorder, and in particular, a rapid-cycling form.
Human cate-chol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders
- Lachman