Journal of Psychiatric Research xxx (2014) 1e8

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Temperament and character in remitted and symptomatic patients with schizophrenia: Modulation by the COMT Val158Met genotype Hiroaki Hori a, *, Takashi Fujii a, Noriko Yamamoto a, Toshiya Teraishi a, Miho Ota a, Junko Matsuo a, Yukiko Kinoshita a, Ikki Ishida a, Kotaro Hattori a, Mitsutoshi Okazaki b, Kunimasa Arima b, Hiroshi Kunugi a a b

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 28 August 2013 Received in revised form 9 May 2014 Accepted 9 May 2014

While research on remission in schizophrenia has gained attention, personality characteristics associated with remission in schizophrenia have been under-studied. A functional valine-to-methionine (Val158Met) polymorphism in the catechol-O-methyltransferase (COMT) gene is shown to modify clinical presentation of schizophrenia despite weak or no association with the disorder itself. Studies also report that this polymorphism can affect personality traits. We aimed to examine personality traits of remitted patients with schizophrenia as compared to symptomatic patients and healthy controls and to investigate whether the COMT Val158Met polymorphism influences their personality. Scores on the Temperament and Character Inventory were compared between 34 remitted outpatients with schizophrenia, age- and sex-matched 72 symptomatic outpatients with schizophrenia, and matched 247 healthy individuals. The effect of COMT Val158Met polymorphism on personality was examined in each group. The analysis of covariance, controlling for confounding variables, revealed that compared to healthy controls, symptomatic patients exhibited a pervasively altered personality profile whereas remitted patients showed alterations in more limited personality dimensions and demonstrated normal levels of noveltyseeking, reward dependence and cooperativeness. The two-way analysis of covariance, with genotype and sex as between-subject factors and confounders as covariates, revealed that Met carriers demonstrated significantly lower reward dependence and cooperativeness than Val homozygotes in symptomatic patients; while no significant genotype effect was found in remitted patients or in healthy individuals. These findings indicate that remitted patients with schizophrenia have a relatively adaptive personality profile compared to symptomatic patients. The COMT Val158Met polymorphism might have a modulating effect on the relationship between personality and remission. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Schizophrenia Temperament Character Remission COMT Val158Met polymorphism

1. Introduction Personality research in schizophrenia can date back to the seminal descriptions by Kraepelin (1919) and Bleuler (1950). Subsequently, a growing body of empirical research has investigated personality traits in patients with schizophrenia. Studies using selfreport questionnaires such as the NEO Five-Factor Inventory (Costa

* Corresponding author. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Tel.: þ81 42 341 2711; fax: þ81 42 346 1744. E-mail address: [email protected] (H. Hori).

and McCrae, 1992) have reported that schizophrenia is associated with a unique personality profile as indicated by high neuroticism, low extraversion and low conscientiousness (Camisa et al., 2005; Gurrera et al., 2000; Pillmann et al., 2003). More recently, researchers including our group have used the Temperament and Character Inventory (TCI; Cloninger et al, 1993), a well-established self-report questionnaire measuring a set of personality dimensions, for this purpose (Guillem et al., 2002; Hori et al., 2008; Ohi et al., 2012; Smith et al., 2008). These studies from various ethnic groups have quite consistently reported that schizophrenia is associated with low self-directedness, cooperativeness and reward dependence and high harm avoidance and selftranscendence. Such altered personality traits in schizophrenia have been shown to be associated with their symptomatology

http://dx.doi.org/10.1016/j.jpsychires.2014.05.006 0022-3956/Ó 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Hori H, et al., Temperament and character in remitted and symptomatic patients with schizophrenia: Modulation by the COMT Val158Met genotype, Journal of Psychiatric Research (2014), http://dx.doi.org/10.1016/j.jpsychires.2014.05.006

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H. Hori et al. / Journal of Psychiatric Research xxx (2014) 1e8

(Guillem et al., 2002; Hori et al., 2008; Ohi et al., 2012), internalized stigma (Margetic et al., 2010), medication adherence (Aukst Margeti c et al., 2011), suicidality (Albayrak et al., 2012; Aukst Margeti c et al., 2012), functioning (Eklund et al., 2004), cognition (Boeker et al., 2006; Guillem et al., 2008) and subjective quality of life (Hansson et al., 2001; Margeti c et al., 2011). One of the important treatment goals for individuals with schizophrenia is to achieve symptomatic remission. An increasing interest has been addressed to this issue since the Remission in Schizophrenia Working Group proposed the standardized criteria for symptomatic remission in schizophrenia (Andreasen et al., 2005). Using the new criteria, the view that remission is an achievable goal for individuals with schizophrenia has gained momentum (Emsley et al., 2011; Leucht et al., 2007). Studies have reported that, compared to symptomatic patients, remitted patients show more favorable characteristics including milder depressive symptoms (Brissos et al., 2011), better social (Brissos et al., 2011; Meesters et al., 2011) and cognitive (Braw et al., 2012; Hofer et al., 2011) functioning, and better subjective quality of life (Bodén et al., 2009; Brissos et al., 2011; Li et al., 2010), although some studies did not find such an association of remission with mood (Meesters et al., 2011), cognitive function (Brissos et al., 2011; Meesters et al., 2011) or subjective quality of life (Meesters et al., 2011). To our knowledge, however, no studies have examined the relationship between symptomatic remission and personality traits in schizophrenia. Given the aforementioned roles of personality in various outcomes in schizophrenia, studying personality traits in remitted patients relative to symptomatic patients may give a clue to the question as to why remission occurs in some patients and not in others. A number of studies have reported that personality traits as assessed with the TCI are influenced by genetic factors including the catechol-O-methyltransferase (COMT) gene (reviewed in Calati et al., 2011). COMT is involved in the synaptic catabolism of dopamine and other catecholamine neurotransmitters. COMT has a functional polymorphism resulting from a single amino acid substitution from valine to methionine at codon 158 (Val158Met), with the low-activity (Met) allele leading to an approximately three- to four-fold reduction in enzymatic activity compared with the highactivity (Val) allele (Lachman et al., 1996). As prefrontal dopaminergic dysfunction is one of the cardinal features of schizophrenia, an association between the COMT Val158Met polymorphism and schizophrenia has been extensively studied; however, the findings have been controversial, with several meta-analyses showing no significant association (Glatt et al., 2003; Fan et al., 2005; Munafò et al., 2005). While the reason for this lack of association is not entirely clear, animal studies have demonstrated the involvement of COMT in a diverse array of phenotypes such as aggressive behavior (Gogos et al., 1998), social interaction (Babovic et al., 2007), cognition (Babovic et al., 2008) and stress reactivity (Desbonnet et al., 2012). Correspondingly, in human studies, the COMT Val158Met polymorphism has been associated with aggression (Jones et al., 2001; Singh et al., 2012; Soyka, 2011) and a variety of neurobehavioral phenotypes of schizophrenia such as symptomatology (Goghari and Sponheim, 2008; Molero et al., 2007; Wang et al., 2010), brain/cognitive functioning (Ceaser et al., 2013; Lopez-Garcia et al., 2013; Nolan et al., 2004) and stress reactivity (Peerbooms et al., 2012; van Winkel et al., 2008). Thus, potential associations of the COMT Val158Met polymorphism with schizophrenia-linked (endo)phenotypes have been a focus of constant attention despite no significant risk for schizophrenia. With respect to the association with personality traits, the COMT Val158Met polymorphism was reported to influence personality in relatives of schizophrenia patients (Silberschmidt and Sponheim, 2008), in addition to the above-mentioned evidence in healthy

individuals. Moreover, this polymorphism has been shown to affect schizotypal traits in nonclinical populations (Avramopoulos et al., 2002; Docherty and Sponheim, 2008; Ma et al., 2007; Schürhoff et al., 2007; Smyrnis et al., 2007). However, the possible association of this polymorphism with temperament and character has not been examined in schizophrenia patients. Assuming that the COMT Val158Met variant affects both personality traits and clinical outcome (e.g., symptomatic remission) of schizophrenia, and that personality traits can also influence the clinical outcome in schizophrenia, interaction between the Val158Met variant and personality on the outcome could be expected. The present study aimed (1) to examine temperament and character traits of remitted patients with schizophrenia as compared to those of symptomatic patients and healthy controls and (2) to investigate the possible association of the COMT Val158Met polymorphism with their temperament and character. We hypothesized that (1) remitted patients would exhibit more adaptive personality traits than symptomatic patients and (2) the Val158Met polymorphism would have differential effects on personality traits between remitted and symptomatic patients. 2. Materials and methods 2.1. Participants A total of 106 outpatients with schizophrenia (65 men and 41 women; mean age  standard deviation (S.D.): 37.5  8.4 years, range: 20e58 years) were recruited from the outpatient clinic of the National Center of Neurology and Psychiatry Hospital, Japan, which is located at the western part of Tokyo, or through advertisements in free local magazines and our website announcement. Most of the patients recruited via advertisements or website announcement were regularly attending to a nearby hospital or clinic located in the same geographical area. Consensus diagnosis by at least two psychiatrists was made for each patient according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria (American Psychiatric Association, 1994), by using the Mini-International Neuropsychiatric Interview (MINI; Otsubo et al., 2005; Sheehan et al., 1998) and through unstructured interview as well as information from medical records. To determine personality alteration in schizophrenia patients, age- and sex-matched 247 healthy individuals (141 men and 106 women; mean age  S.D.: 37.6  12.2 years, range: 20e59 years) were recruited as a healthy comparison group from the same geographical area via the free local magazines and our website announcement. With regard to the genetic part of this study, we employed broader inclusion criteria in terms of age and sex in order to recruit a larger sample of healthy subjects; this resulted in 700 healthy volunteers (184 men and 516 women; mean age  S.D.: 44.6  15.4 years, range: 18e74 years). All healthy subjects were interviewed using the MINI by a research psychiatrist, and only those who demonstrated no current Axis I psychiatric disorders were enrolled. In addition, those individuals who demonstrated one or more of the following conditions in a non-structured interview performed by an experienced psychiatrist were excluded: past or current regular contact to psychiatric services, having a history of regular use of psychotropics or substance abuse/ dependence, presenting other obvious self-reported signs of past primary psychotic and mood disorders, and having a prior medical history of central nervous system disease or severe head injury. All participants were biologically unrelated Japanese. The present experiments on our participants were conducted in accordance with the Declaration of Helsinki. After the nature of the study procedures had been fully explained, written informed consent was obtained from all participants. The study was approved by

Please cite this article in press as: Hori H, et al., Temperament and character in remitted and symptomatic patients with schizophrenia: Modulation by the COMT Val158Met genotype, Journal of Psychiatric Research (2014), http://dx.doi.org/10.1016/j.jpsychires.2014.05.006

H. Hori et al. / Journal of Psychiatric Research xxx (2014) 1e8

the ethics committee of the National Center of Neurology and Psychiatry, Japan. 2.2. Assessments Schizophrenic symptoms were assessed by a research psychiatrist in each patient, using the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987); this yields positive, negative, and general psychopathology subscale scores. Daily doses of antipsychotics, including depot antipsychotics, were converted to chlorpromazine equivalents using guidelines (American Psychiatric Association, 1997; Inagaki et al., 1999). The TCI (Cloninger et al., 1993) is a 240-item (including 14 items which are not analyzed) self-report questionnaire; each item requires a true/false answer. The term temperament refers to automatic emotional reactions to subjective experiences that may be genetically transmitted and therefore stable over time. Four dimensions of temperament are distinguished: novelty seeking, harm avoidance, reward dependence and persistence. The term character refers to concepts pertaining to the individual, focusing on personal differences in intentions, decisions and values. Three dimensions of character are distinguished: self-directedness, cooperativeness and self-transcendence. The Japanese version (Kijima et al., 1996) of TCI was used in the present study. The internal consistency reliability as measured by Cronbach’s a for novelty seeking, harm avoidance, reward dependence, persistence, self-directedness, cooperativeness and self-transcendence in the present sample was 0.60, 0.86, 0.67, 0.56, 0.82, 0.77 and 0.79 (respectively) for healthy controls and 0.52, 0.82, 0.63, 0.57, 0.83, 0.76 and 0.85 (respectively) for schizophrenia patients, indicating overall comparable levels of internal consistency reliability between patients and controls. Furthermore, the pattern of high internal consistency reliability for character dimensions relative to some temperament dimensions was similar to the one reported in previous studies from other countries (Brändström et al., 1998; Kose et al., 2009; Pélissolo and Lépine, 2000; Richter et al., 1999; Sung et al., 2002). 2.3. Remission criteria Symptomatic remission of schizophrenia was defined according to the criteria proposed by Remission in Schizophrenia Working Group (Andreasen et al., 2005). Specifically, remission was determined based on a score of 3 or less on all of the following 8 PANSS items: P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory behavior), N1 (blunted affect), N4 (social withdrawal), N6 (lack of spontaneity), G5 (mannerisms/posturing), and G9 (unusual thought content). In addition, patients were required to be clinically stable for a period of at least 6 months to be considered as in remission. Thirty-four schizophrenia patients met the remission criteria (here referred to as “remitted patients”). As a non-remitted counterpart, 72 age- and sex-matched schizophrenia patients who did not fulfill the remission criteria (“symptomatic patients”) were recruited. TCI scores were compared among the two patient groups and healthy controls. 2.4. Genotyping Genomic DNA was prepared from venous blood according to standard procedures. Rs4680 (Val158Met) was genotyped using the TaqMan 50 -exonuclease allelic discrimination assay (assay ID: C__25746809_50). The thermal cycling conditions for polymerase chain reaction were as follows: 1 cycle at 95  C for 10 min followed by 50 cycles of 92  C for 15 s and 60  C for 1 min. The allele-specific fluorescence was measured with ABI PRISM 7900 Sequence

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Detection Systems (Applied Biosystems, Foster City, CA). Ambiguous genotype data were excluded from the analysis based on visual inspection of scatterplots, which resulted in genotyping call rate of 98.4%. 2.5. Statistical analysis Averages are reported as means  S.D. For demographic and clinical characteristics, categorical variables were compared using the c2 test or Fisher’s exact test where appropriate. Pearson’s correlation was used to determine the relationship between continuous demographic variables and the 7 TCI dimensions. The t-test was used to examine differences in means between two groups. The analysis of variance (ANOVA) was used to examine differences between three groups. Deviations of genotype distributions from HardyeWeinberg equilibrium were assessed using the c2 test for goodness of fit. The one-way multivariate analysis of covariance (MANCOVA), with group (i.e., remitted patients, symptomatic patients and healthy controls) as the fixed factor and potentially confounding factors as covariates, was performed to compare the 7 TCI dimensions among the three groups, which was followed by post-hoc pairwise comparisons with Bonferroni correction. Relationships between the COMT Val158Met polymorphism and TCI scores were examined separately for remitted patients (n ¼ 34), symptomatic patients (n ¼ 72) and healthy individuals (n ¼ 700). As evidence suggests a role of sex in the effect of the Val158Met genotype on personality traits (Amstadter et al., 2012; Chen et al., 2011), we performed the two-way MANCOVA with genotype and sex as fixed factors and age and education as covariates in order to examine main effects of genotype and sex and genotype-by-sex interaction on the 7 TCI dimensions. These multivariate analyses were rerun without the covariates in order to test whether the results were robust to their exclusion. Statistical significance was set at two-tailed p < 0.05 unless otherwise specified. Significance level was set at more conservative p < 0.0071 (i.e., 0.05/7) in simultaneous analyses of the 7 TCI dimensions to correct for multiple testing (this correction was not applied, however, when examining relationships between demographic variables and TCI scores, as it was intended to control for potentially confounding effects of such variables on the main analyses). Analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 21.0 (SPSS Japan, Tokyo). 3. Results Demographic characteristics and clinical variables for remitted patients, symptomatic patients and healthy controls are shown in Table 1. Age and sex distributions were matched among the three groups, whereas education level was significantly higher in controls than in the two patient groups. As expected, schizophrenic symptoms as assessed with the PANSS were significantly more severe in symptomatic patients than in remitted counterparts. Relationships between demographics (i.e., age, sex and education) and TCI dimensions were examined for each of the three groups. Age was significantly correlated with novelty seeking in remitted patients (r ¼ 0.37, p ¼ 0.002) and with persistence (r ¼ 0.15, p ¼ 0.017), self-directedness (r ¼ 0.13, p ¼ 0.047) and self-transcendence (r ¼ 0.17, p ¼ 0.007) in healthy controls. Significant sex differences were found in healthy controls for reward dependence (t ¼ 2.8, p ¼ 0.005; greater in women), persistence (t ¼ 3.5, p < 0.001; greater in men) and self-transcendence (t ¼ 2.3, p ¼ 0.020; greater in women). Education level was significantly correlated with persistence (r ¼ 0.34, p < 0.001) and selfdirectedness (r ¼ 0.17, p ¼ 0.008) in healthy controls. Given this,

Please cite this article in press as: Hori H, et al., Temperament and character in remitted and symptomatic patients with schizophrenia: Modulation by the COMT Val158Met genotype, Journal of Psychiatric Research (2014), http://dx.doi.org/10.1016/j.jpsychires.2014.05.006

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H. Hori et al. / Journal of Psychiatric Research xxx (2014) 1e8

Table 1 Demographic and clinical variables of remitted schizophrenia patients, symptomatic schizophrenia patients and matched healthy controls. Characteristics

Age, years: mean  S.D. Sex, women: n (%) Education, years: mean  S.D. Age at onset, years: mean  S.D. Duration of illness, years: mean  S.D. Number of past hospitalizations: mean  S.D.a Lifetime ECT: yes, n (%) Medication dosage, bmg/day: mean  S.D. PANSS positive score: mean  S.D. PANSS negative score: mean  S.D. PANSS general psychopathology score: mean  S.D.

Schizophrenia patients (n ¼ 106) Remitted (n ¼ 34)

Symptomatic (n ¼ 72)

36.9  8.1 13 (38.2) 14.1  2.6 22.9  7.1 13.8  7.0 1.7  2.2 1 (2.9) 459.8  467.5 9.3  2.2 11.0  3.6 22.4  6.7

37.9  8.6 28 (38.9) 13.8  2.2 23.8  6.4 13.7  9.5 1.4  1.8 6 (8.3) 593.9  495.6 15.0  5.9 19.5  6.1 31.0  8.3

Healthy controls (n ¼ 247)

Statistics

p

37.6  12.2 106 (42.9) 15.8  2.8 NA NA NA NA NA NA NA NA

F(2,350) ¼ 0.09 c2(2) ¼ 0.55 F(2,350) ¼ 19.5 t ¼ 0.59 t ¼ 0.03 t ¼ 0.64 Fisher’s exact t ¼ 1.3 t ¼ 7.1 t ¼ 8.9 t ¼ 5.3

0.91 0.76

Temperament and character in remitted and symptomatic patients with schizophrenia: modulation by the COMT Val158Met genotype.

While research on remission in schizophrenia has gained attention, personality characteristics associated with remission in schizophrenia have been un...
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