Elsevier

Psychiatry Research

Volume 129, Issue 1, 30 November 2004, Pages 29-37
Psychiatry Research

Association of aggressive behavior in Korean male schizophrenic patients with polymorphisms in the serotonin transporter promoter and catecholamine-O-methyltransferase genes

https://doi.org/10.1016/j.psychres.2004.06.013Get rights and content

Abstract

The incidence of aggressive behavior in patients with schizophrenia is higher than in the general population. Among particular gene polymorphisms posited to be involved in psychiatric disorders, the catecholamine-O-methyltransferase (COMT) and serotonin transporter (5-HTTPR) genes have been the focus of recent research on aggression. In this study, we hypothesized that both the COMT and the 5-HTTPR genotypes may be dependent on and related to aggression in Korean patients with schizophrenia. The subjects were 168 unrelated male schizophrenic patients diagnosed according to DSM-IV. Among two psychiatric hospital staff and medical university students, 158 unrelated male subjects with no lifetime history of psychiatric disorders were recruited to establish the COMT and 5-HTTPR genotype distribution in the general population. All episodes of aggression from the last discharge to readmission were rated. The Total Overt Aggression Scale (OAS) score (sum of the scores of all episodes of aggression), highest OAS score (highest individual episode score, 0–16), OAS category, and OAS category score (mean score within each category) were recorded. There were statistically significant effects of COMT genotype on the mean OAS 4 (physical aggression against other people) score and the highest OAS score. The most predictive was the OAS 4 score. There was a statistically significant effect of 5-HTTPR genotype on mean total score. Thus, the COMT gene is associated with the severity of aggression and with physical aggression against other people, whereas the 5-HTTPR gene is associated with the summary score of all episodes of aggression.

Introduction

The incidence of aggressive behavior in schizophrenia has been reported to be much higher than that in the general population (Swanson et al., 1990). Steinert et al. (1999) reported that aggressive and violent behavior against the self and others frequently occurs in schizophrenia during the first 2 years of illness, and that such behavior constitutes one of the major causes of rehospitalization. The causes of aggressive behavior are various, and the role of the neurotransmitters believed to be involved in the mediation of this behavior is undoubtedly complex.

Accumulating evidence suggests that genetic factors partially determine aggressive, antisocial, and criminal behavior Cadoret et al., 1995, Brennan et al., 1996, Cairns, 1996, Tecott and Barondes, 1996, Miles and Carey, 1997. Among the particular gene polymorphisms that have been posited to be involved in aggressive behavior, the catechol-O-methyl-transferase (COMT) gene and the serotonin transporter promoter region (5-HTTPR) have been the focus of recent research attention.

Strous et al. (1997) and Lachman et al. (1998) reported a correlation between aggressive behavior in schizophrenia and the low-activity allele of the COMT gene (COMTL). The COMT gene inactivates dopamine. Enzymatic activities also are reduced by a common polymorphism at this gene. Such reduction is due to a G-to-A transition at codon 158, which results in the valine (high activity allele, COMTH) to methionine (low activity allele, COMTL) substitution forming a three- to four-fold reduction of variants in enzymatic activities (Lachman et al., 1996).

Kotler et al. (1999a) suggested in their study of a correlation between the COMT gene polymorphism and aggressive behavior that the involvement of COMT in violent behavior underlines the importance of nonserotonergic mechanisms in such conduct since serotonin is not a substrate for this enzyme. However, serotonin has frequently been suggested as a causative factor for impulsive, violent, and dangerous behavior in humans and animals Hilakivi-Clarke and Goldberg, 1993, Cases et al., 1995, Kunz et al., 1995.

Since the mid-1970s, many studies have shown that impulsive-aggression and suicidal behavior are correlated with serotonin transmission (Åsberg et al., 1976). The magnitude and duration of serotonin transmission are mainly associated with the serotonin transporter (5-HTT), which regulates the uptake of serotonin at synaptic junctions Lesch et al., 1993, Lesch et al., 1996.

In the mid-1990s, Heils et al. (1996) discovered a 44-base-paired (bp) insertion/depletion polymorphism (5-HTTPR) in the 5′ promoter region of the 5-HTT gene. The 44-bp deletion promoter (S-allele) is less active than the 44-bp insertion promoter (L-allele), resulting in low-level serotonin uptake (Heils et al., 1995). Danielle et al. (2001) hypothesized that the Lgenotype would lead to a depletion of extraneuronal serotonin and increase the risk of aggression in Alzheimer's disease. Robert et al. (2001) reported that cases of Alzheimer's disease with psychotic features and aggression were significantly associated with the 5-HTTPR L/L genotype and increased L allele frequency (Robert et al., 2001). In this study, we hypothesized that both the COMT and 5-HTTPR genotypes might be related to aggressive behavior in Korean schizophrenia patients.

Section snippets

Methods

Unrelated male patients with a diagnosis of schizophrenia (n=168) according to DSM-IV criteria (American Psychiatric Association, 1994) were studied. Diagnoses were made on the basis of semistructured interviews (Endicott and Spitzer, 1978) and supplementary information. The patients were recruited from two psychiatric hospitals. Patients with drug-induced aggressive behavior or a history of alcohol and substance abuse were excluded. The goals of the research and the procedures were explained

Demographic and clinical data

Table 1, Table 2 present demographic data for the subjects. There were no significant differences with regard to age, duration of illness, duration from the latest discharge to readmission, frequency of admission, frequency of outpatient department visits for counseling concerning aggression, education, and marital state across genotypes.

COMT polymorphism

Of the 168 schizophrenic patients, 91 (54.2%) were the COMTH/COMTH type, 64 (38%) were the COMTH/COMTL type, and 13 (7.8%) were the COMTL/COMTL type. The

Discussion

In this study, there was no significant difference in the COMT and 5-HTTPR polymorphisms between the schizophrenia and control groups. This observation is similar to other studies that also reported no association of the COMT and 5-HTTPR polymorphisms with schizophrenia Bonnet-Brilhault et al., 1997, Rao et al., 1998, Tsai et al., 2000, De Chaldee et al., 2001. However, Ohmori et al. (1998) found that the COMTL allele appeared to be associated with susceptibility to schizophrenia. Park et al.

Acknowledgements

The authors thank Dr. H.M. Lachman and Dr. R.D. Strous for help in the preparation of this manuscript.

References (60)

  • M. Kunz et al.

    Serotonin in violent patients with schizophrenia

    Psychiatry Research

    (1995)
  • J.H. Lee et al.

    Possible association between serotonin transporter promoter region polymorphism and impulsivity in Koreas

    Psychiatry Research

    (2003)
  • H. Moore et al.

    The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia

    Biological Psychiatry

    (1999)
  • O. Ohmori et al.

    Association study of a functional study of a functional catechol-O-methyltransferase gene polymorphism in Japanese schizophrenics

    Neuroscience Letters

    (1998)
  • T.W. Park et al.

    Functional catechol-O-methyltransferase gene polymorphism and susceptibility to schizophrenia

    European Neuropsychopharmacology

    (2002)
  • G. Philippu et al.

    Catechol-O-methyltransferase of erythrocytes in patients with endogenous psychoses

    Psychiatry Research

    (1981)
  • R. Plutchik et al.

    A self-report measure of violence risk, II

    Comprehensive Psychiatry

    (1990)
  • M.J. Russ et al.

    Analysis of catechol-O-methyltransferase and 5-hydroxytryptamine transporter polymorphism in patients at risk for suicide

    Psychiatry Research

    (2000)
  • R.D. Strous et al.

    Analysis of functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for associations with aggressive and antisocial behaviour

    Psychiatry Research

    (1997)
  • L.H. Tecott et al.

    Genes and aggressiveness: behavioral genetics

    Current Biology

    (1996)
  • S.J. Tsai et al.

    Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response

    Schizophrenia Research

    (2000)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (1994)
  • M. Åsberg et al.

    5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor?

    Archives of General Psychiatry

    (1976)
  • P.A. Brennan et al.

    Assessing the role of genetics in crime using adoption cohorts

    Ciba Foundation Symposium

    (1996)
  • R.J. Cadoret et al.

    Genetic-environmental interaction in the genesis of aggressivity and conduct disorders

    Archives of General Psychiatry

    (1995)
  • R.B. Cairns

    Aggression from a development perspective: genes, environments and interactions

    Ciba Foundation Symposium

    (1996)
  • O. Cases et al.

    Aggressive behavior and altered amount of brain serotonin and norepinephrine in mice lacking MAOA

    Science

    (1995)
  • D.A. Collier et al.

    A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders

    Molecular Psychiatry

    (1996)
  • P. Cortet et al.

    Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene

    Molecular Psychiatry

    (2001)
  • L.S. Danielle et al.

    The 5-HTTPRS/L Polymorphism and Aggressive Behavior in Alzheimer Disease

    Archives of Neurol

    (2001)
  • Cited by (66)

    • Depressive symptoms in schizophrenia and dopamine and serotonin gene polymorphisms

      2017, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      Contrary to that, there were findings of no association between this COMT polymorphism and clinical symptomatology of schizophrenia (Strous et al., 2006; Tovilla-Zarate et al., 2013). SERT insertion/deletion (indel) promoter polymorphism has rarely been associated with schizophrenia (Bayle et al., 2003; Carlström et al., 2012; Han et al., 2004; Ikeda et al., 2006; Konneker et al., 2010; Lee et al., 2009; Peitl et al., 2015) while its association with symptom domains has mostly been negative (Bergen et al., 2009; Konneker et al., 2010; Serretti et al., 2002). However, there have been some reports of a LL genotype being associated with positive symptoms of schizophrenia (Malhotra et al., 1998).

    • Behavioral genetics and criminal responsibility at the courtroom

      2014, Forensic Science International
      Citation Excerpt :

      These studies also included heterogeneous samples, some showing correlations between S allele expression and impulsive aggression and some not. For example, Han et al. [46] reported a correlation in patients with psychotic disorders, while Nolan et al. [15] did not find such correlations, Courtet et al. [47] found and Zalsman et al. [48], Baca-Garcia et al. [49], and Zalsman et al. [50] did not find correlations in suicide attempters, Sukonick et al. [51] and Sweet et al. [52] found, while Assal et al. [53], Ha et al. [54], and Prichard et al. [55] did not find correlations in patients with Alzheimer's disease, Beitchman et al. [37] found and Davidge et al. [36] did not find a correlation in children with history of aggressive behavior, and finally Zalsman et al. [48] did not find any correlation in adolescents with violent suicidal behavior. This correlation between S allele and aggression/impulsivity has been reported in cocaine dependents [41], adolescents with drug use [39], adolescents with aggressive and/or delinquent behavior [56], offenders, people with conduct disorders or violent behaviors [42,56,57], and male adoptees [38], always in small samples, but these results should await confirmation in larger samples.

    • The COMT Met158 allele and violence in schizophrenia: A meta-analysis

      2012, Schizophrenia Research
      Citation Excerpt :

      A common functional single nucleotide polymorphism (SNP) in the COMT gene at codon 108/158, Val158Met (rs4680), generates a valine (Val)-to‐methionine(Met) substitution and results in a fourfold reduction in COMT enzyme activity in the Met/Met homozygotes (Lotta et al., 1995), and increased dopamine levels in the prefrontal cortex. Several studies have shown a strong association between the Met allele and risk for violence in schizophrenia (Han et al., 2004, 2006; Hong et al., 2008; Kotler et al., 1999; Lachman et al., 1998; Strous et al., 1997; Strous et al., 2003; Tosato et al., 2011). In contrast, Jones et al. (2001) reported that Val/Val genotype was associated with greater risk for violence in patients with schizophrenia; others have found the association to be inconsistent (Liou et al., 2001; Koen et al., 2004; Zammit et al., 2004; Kim et al., 2008; Gu et al., 2009).

    View all citing articles on Scopus
    View full text