J Neural Transm (2015) 122:907–914 DOI 10.1007/s00702-014-1327-7
PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - ORIGINAL ARTICLE
Possible association between DBH 19 bp insertion/deletion polymorphism and clinical symptoms in schizophrenia with tardive dyskinesia Li Hui • Mei Han • Xu Feng Huang • Min Jie Ye • Ke Zheng • Jin Cai He • Meng Han Lv • Bao Hua Zhang Jair C. Soares • Xiang Yang Zhang
•
Received: 17 July 2014 / Accepted: 15 October 2014 / Published online: 22 October 2014 Ó Springer-Verlag Wien 2014
Abstract Overactivity of dopaminergic neurotransmission is a putative mechanism of tardive dyskinesia (TD). Previous studies have found dysfunction in plasma dopamine beta-hydoxylase (DBH) in schizophrenia with TD. Moreover, DBH, whose activity and levels are strongly controlled by the DBH gene, is a key enzyme in the conversion of dopamine (DA) to norepinephrine (NE) associated with excited behavior. This study examined whether the DBH50 -insertion/deletion (Ins/Del) polymorphism was associated with excited behavior in schizophrenia with TD. The presence of the DBH50 -Ins/Del polymorphism was determined in 741 schizophrenia with TD (n = 345) and without TD (n = 396). The Abnormal Involuntary Movement Scale and Positive and Negative Syndrome Scale were used to assess the severity of TD and psychopathology of schizophrenia. There was no significant difference in the allelic and genotypic frequencies of the DBH50 -Ins/ Del polymorphism between schizophrenia with and without TD (both p [ 0.05). However, the excited symptoms score was significantly different to the DBH50 -Ins/Del
L. Hui M. J. Ye K. Zheng Institute of Wenzhou Kangning Mental Health, Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China M. Han X. F. Huang School of Medicine, IHMRI, University of Wollongong, Wollongong, NSW, Australia M. Han X. F. Huang Schizophrenia Research Institute, Sydney, NSW, Australia K. Zheng J. C. He Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
genotypic groups in schizophrenia with TD (p \ 0.05) but not in the two groups of non-TD and total patients (both p [ 0.05). The excited symptoms score was higher in TD patients with the Del/Del genotype than those with Ins alleles (p = 0.015). Our findings suggest that the DBH50 Ins/Del polymorphism may not contribute directly to the development of TD in schizophrenia, but it may be involved in the excited behavior of TD patients. Keywords Dopamine beta-hydroxylase Excited behavior Genotype Schizophrenia Tardive dyskinesia
Introduction Tardive dyskinesia (TD) is a motor syndrome consisting of involuntary, hyperkinetic, and abnormal movements, with nearly a 25–40 % incidence in schizophrenia patients on long-term antipsychotic treatment and individual conditions (McCreadie et al. 1996; van Os et al. 1997; Correll
M. H. Lv B. H. Zhang X. Y. Zhang Beijing HuiLongGuan Hospital, Peking University, Beijing, People’s Republic of China J. C. Soares X. Y. Zhang Department of Psychiatry and Behavioral Sciences, Harris County Psychiatric Center, The University of Texas Health Science Center at Houston, Houston, TX, USA X. Y. Zhang (&) Psychiatry Research Center, Beijing HuiLongGuan Hospital, Peking University, Chang-Ping District, Beijing 100096, People’s Republic of China e-mail:
[email protected]
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and Malhotra 2004; Jeste 2004; Kane 2004; Margolese et al. 2005; Tarsy and Baldessarini 2006; Remington et al. 2007; Correll and Schenk 2008; Li et al. 2009).Schizophrenia with TD currently has no well-accepted treatments and its pathophysiology is still poorly understood (Soares and McGrath 1999; Remington et al. 2007). However, familial studies, genome-wide association studies, and twoway meta-analysis have found that the development of TD has a possible genetic basis (Muller et al. 2001, 2004; Bakker et al. 2008; Aberg et al. 2010; Greenbaum et al. 2010; Syu et al. 2010; Tanaka et al. 2011). Dopamine beta-hydroxylase (DBH) is the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE) in adrenergic and noradrenergic neurons in the central neuronal system (Ishiguro et al. 1993). Previous studies found that plasma DBH activity was significantly higher in schizophrenia with TD than those without TD (Jeste et al. 1981; Wagner et al. 1982; Kaufmann et al. 1986). The overactivity of dopaminergic neurotransmission in the basal ganglia and up-regulation of DA receptors is a putative mechanism of TD because of the chronic blockade of DA D2-like receptors by antipsychotics (Casey 2000). Moreover, the DBH enzyme is under the strong control of the DBH gene (Weinshilboum 1978; Cubells et al. 2011). Thus, these results suggest that the DBH gene may be the candidate gene for schizophrenia with TD. The 4.5 kilobases upstream of the 50 flank transcriptional starting site in the DBH gene on chromosome 9q34 contain a 19 nucleotide insertion–deletion polymorphism. This polymorphism is called the DBH50 -Ins/Del polymorphism. DBH50 -Del allele is associated with decreased promoter activity causing lower plasma and cerebrospinal fluid (CSF) DBH levels and activity (Cubells et al. 1998, 2000; Zabetian et al. 2001; Tang and Epstein 2007), which may result in a higher production of DA and alter the DA/NE ratio in relevant brain regions (Cubells and Zabetian 2004). Previous studies found that DA affected the cortical excitability of the human brain (Nitsche et al. 2010), and the CSF DA level was correlated with agitated and aggressive behavior in dementia (Engelborghs et al. 2008). An increased level of DA in the striatum may increase social and aggressive behavior in mice with a GluA3deficiency (Adamczyk et al. 2012). Several studies have found that DBH, DA and NE are involved in the modulation of aggressive behavior which is under genetic variation in humans and animals (Nelson and Trainor 2007; Craig and Halton 2009; Neumann et al. 2010). Furthermore, the variables of the DBH gene influence the aggressive behavior in attention-deficit/hyperactivity disorder (ADHD), tenseness in the young Chinese Han population, and hyperactivity in childhood (Barkley et al. 2006; Hess et al. 2009; Gong et al. 2010). Taken together, these results suggest that the DBH50 -Ins/Del polymorphism
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may be related to excited behavior in schizophrenia with TD. Moreover, some recent studies found that the DBH50 Ins/Del polymorphism may influence the psychopathology of schizophrenia with TD (Sun et al. 2013), cognitive function in first-episode schizophrenia (Hui et al. 2013), positive symptoms in schizophrenia (Zhou et al. 2013), and smoking severity in schizophrenic smokers (Zhang et al. 2012), which all suggest that this polymorphism should be a functional site. Therefore, the main aim of this study is to examine whether the DBH50 -Ins/Del polymorphism is associated with susceptibility to excited behavior in schizophrenia with TD.
Materials and methods Ethics statement The research protocol and informed consent were approved by the institutional review board of Beijing Huilongguan Hospital. The clinical staff explained the research protocol and procedures to the potential subjects. The description of the study was tailored to maximize the subject’s understanding using language appropriate to the subject’s level of comprehension and emotional readiness. If the subject was willing to consent to participate in the study, the researcher provided an in-depth description to the subject and their guardians. In cases where guardians were entrusted with assessing the subject’s participation, they gave their written consent on behalf of the subject. Subjects Seven hundred and forty-one schizophrenia patients (626 male, 115 female) took part in this study. Eight TD patients have been excluded due to their irregular use of antipsychotic drugs or concomitant use of other drugs. The patients were all northern Chinese Han population from Beijing Huilongguan Hospital (a Beijing city-owned psychiatric hospital) and Rongjun Hospital in Hebei Province. All patients met the following inclusion criteria: (1) age 20–75 years; (2) confirmed DSM-IV diagnosis of schizophrenia; (3) at least 5 years of illness; (4) receiving stable doses of oral antipsychotic drugs for at least 12 months before entry into the study. All patients were of the chronic type, and had been ill for an average 24.5 ± 9.4 years, with current antipsychotic treatment for an average of 40.8 ± 51.5 months. Since admission, all patients received dietetically balanced hospital meals, which were occasionally supplemented by gifts (usually fruit). Patients had the opportunity to exercise for about an hour per day. Antipsychotic drug treatment was mainly monotherapy with the most common medications consisting of
DBH and clinical symptoms in TD
clozapine, risperidone, perphenazine, sulpiride, chlorpromazine, and haloperidol. The mean daily dose of antipsychotics being in chlorpromazine equivalents was 415.1 ± 204.9 mg/days for each patient using the standard guidelines (Woods 2003). A complete medical history, physical examination, and laboratory tests were obtained from patients. Any patients with major medical illnesses were excluded. None of the patients met criteria for drug or alcohol abuse or dependence.
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maintained for the PANSS and 0.88 for the AIMS total scores. Genotyping The genotypes of the DBH50 -Ins/Del were identified as reported in our previous studies (Hui et al. 2012, 2013). A research assistant who was blind to the clinical status genotyped every patient twice for accuracy of genotyping. Statistical analysis
Clinical measures Each patient filled out a detailed questionnaire that recorded general information, sociodemographic characteristics, and medical and psychological conditions. Additional information was collected from available medical records and collateral data (from family and/or treating clinicians). Four experienced psychiatrists who were blind to the clinical status of the patients assessed the severity of TD using the Abnormal Involuntary Movement Scale (AIMS) (Guy 1976). Diagnosis of TD was based on the Research Diagnostic Criteria in DSM-IV, in combination with the criteria of Schooler and Kane (Schooler and Kane 1982). Tardive Dyskinesia was classified as present in a particular subject with an AIMS score of at least three (moderate degree) in any body part or with at least two (mild degree) in two or more body parts. Each item on the AIMS ranges from 0 to 4, and the total AIMS score was calculated by adding items 1–7. The patients with TD were re-evaluated for TD at least 1 month later using the AIMS and diagnosed with TD only if both evaluations consistently revealed the presence of TD. A total of 345 schizophrenia patients with TD (the average age 49.5 ± 9.0 years) were included in the study (317 male, 28 female). A total of 396 schizophrenia patients without TD (the average age 46.7 ± 9.9 years) were included in the study (309 male, 87 female). Four experienced psychiatrists, who were blind to the clinical status of patients, assessed the severity of the patients’ psychopathology using the Positive and Negative Syndrome Scale (PANSS). The PANSS is composed of positive symptoms, negative symptoms, general psychopathology, and the PANSS total score (Kay et al. 1987). A recent study has found some new consensus models including cognitive symptoms (composed of three PANSS items: P2, N5, and G11), excited symptoms (composed of four PANSS items: P4, P7, G8, and G14), and depressive symptoms (composed of three PANSS items: G2, G3, and G6) (Wallwork et al. 2012). The attending psychiatrists had been trained in the use of the AIMS and PANSS before this study was initiated. After training repeated assessments showed a correlation coefficient of greater than 0.84 was
The Hardy–Weinberg equilibrium for the genotypic distributions of the single nucleotide polymorphism (SNP) was tested with the Chi-square (v2) goodness-of-fit test. The UNPHASED program (version 3.0.13) (http://www. mrc-bsu.cam.ac.uk/personal/frank/software/unphased) was applied to analyze genotyping data in a phased-unknown model (Dudbridge 2008). Multiple logistic regression models were used to examine the relations between the DBH50 -Ins/Del polymorphism and schizophrenia with TD by adjusting for significantly different confounders including age and gender. Group differences were compared using Student t tests or one-way analysis of variance (ANOVA) for continuous variables and v2 for categorical variables in schizophrenia with and without TD. Post hoc comparisons between subgroups were made using the Fisher’s least significant difference procedure. When significant differences in the variables among three genotypic groups were found in ANOVA, the effect of the DBH50 -Ins/Del genotype on clinical symptoms was re-tested by adding these variables to the analysis model as covariates. Bonferroni corrections were applied to each test to adjust for multiple testing. Stepwise multivariate analysis using the PANSS symptom score with the positive result as the dependent variable was used to investigate the impact of a range of variables including gene polymorphism, gender, age, education, age of onset, duration of illness, antipsychotic types, medication, duration of antipsychotic treatment, and AIMS total score. SPSS version 17.0 was used for all statistical analysis. Data were presented as mean and standard (mean ± SD), and all p values were two tailed with the significance level set at 0.05. To ensure our study had adequate power, we have calculated the needed sample size based on the effect size ranging from 1.4 to 2.0 with at least 80 percent power and a type I error level of 0.05 (a \0.05, two sided) under logadditive model, using the Quanto software (Gauderman 2002). According to the previous studies on Chinese Han population (Zhou et al. 2013), the minor allele frequency (D allele) of patients with TD was set to be 43.0 percent. With the case–control ratio of 1:1.15 in this study, for the
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Table 1 Comparison of DBH50 -Ins/Del allelic and genotypic frequencies between TD and non-TD patients Non-TD patients (n = 396)
v2
p
286 (41.4 %)
339 (42.8 %)
0.28
0.60
Ins 404 (58.6 %) Genotypic frequencies (%)
453 (57.2 %) 0.32
0.85
Variable
TD patients (n = 345)
Allelic frequencies (%) Del
Del/Del
60 (17.4 %)
72 (18.2 %)
Ins/Del
166 (48.1 %)
195 (49.2 %)
Ins/Ins
119 (34.5 %)
129 (32.6 %)
There are no allelic or genotypic differences between TD and non-TD patients after adjusting for gender and age (p [ 0.05) DBH dopamine beta-hydroxylase, Ins/Del insertion/deletion, TD tardive dyskinesia
range of effect size of 1.4, 1.6, 1.8 and 2.0, the number of cases required for the desired power of 0.8 is 262, 135, 87 and 63, respectively. Therefore, our sample size (345 cases and 396 controls) was deemed suitable for this pilot study on the association between the DBH50 -Ins/Del polymorphism and schizophrenia with TD. The sample power was calculated using quanto software (Gauderman 2002), with known-risk allelic frequencies, a TD population prevalence of 33 %in schizophrenia (Zhang et al. 2009), and examining log-additive models. The significance level was set at a p value of 0.05.
Results The v2 goodness-of-fit test showed that the genotypic distributions of the DBH50 -Ins/Del polymorphism in schizophrenia with and without TD were consistent with the Hardy–Weinberg equilibrium (both p [ 0.05). Quanto analysis revealed that this total sample had 0.89–0.99 statistical power to detect the association of the DBH50 -Ins/ Del polymorphism in these with TD through log-additive inheritance, with a genetic effect ranging from 1.4 to 2.0 (a = 0.05, two-tailed test). The DBH50 -Ins/Del allelic and genotypic frequencies are summarized in Table 1. There were no significant differences in the DBH50 -Ins/Del allelic and genotypic distributions between patients with and without TD (v2 = 0.28, df = 1, p [ 0.05; v2 = 0.32, df = 2, p [ 0.05; OR 0.95, 95 % CI 0.77–1.16). We did not find any differences of the DBH50 -Ins/Del allelic and genotypic frequencies between two groups after adjusting for gender and age (both p [ 0.05). We examined the effects of the DBH50 -Ins/Del genetic variants on demographic and clinical variables in the patients with and without TD, respectively (Table 2). The
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DBH50 -Ins/Del genetic variants had a significant effect on the excited symptom score of PANSS in patients with TD (F = 3.24, df = 2, p = 0.04). However, the significant effect of this polymorphism on the excited symptoms score of PANSS in patients with TD did not pass the Bonferroni correction (p [ 0.05). Furthermore, the TD patients with a Del/Del genotype had significantly higher excited symptoms scores than the TD patients with Ins alleles (F = 5.92, p = 0.015). Moreover, the PANSS excited symptoms score was significantly different to the DBH50 Ins/Del genotypic groups in male schizophrenia patients with TD (p \ 0.05) but not in the two groups of male nonTD and total patients (both p [ 0.05). Male TD patients with a Del/Del genotype had significantly higher excited symptoms scores than TD patients with Ins alleles (p \ 0.05). The patients with and without TD differed significantly in gender, age, education, duration of illness, antipsychotic types, negative symptoms, PANSS total score, cognitive symptoms, depressive symptoms, and AIMS total score (all p \ 0.05). However, we did not find any differences in the negative symptoms, PANSS total score, cognitive symptoms, and depressive symptoms between the two groups after adjusting for gender, age, education, duration of illness, antipsychotic types and AIMS (all p [ 0.05). We did not find any effects of the DBH genotype on excited symptoms in the two groups of non-TD and total patients (both p [ 0.05). In addition, we did not find any significant genotypic effects for positive symptoms, negative symptoms, general psychopathology, PANSS total score, cognitive symptoms, depressive symptoms, and AIMS total score in the three groups of TD, non-TD and total patients (all p [ 0.05). Stepwise multivariate regression analysis using the PANSS excited symptoms score as a dependent variable was performed for TD patients to investigate possible independent determinants from variables including DBH50 -Ins/Del genetic variants, gender, age, education, age of onset, duration of illness, antipsychotic types, medication, duration of antipsychotic treatment, and AIMS total score (Table 3). This analysis identified DBH50 -Ins/Del genetic variants (b = 0.44, t = 2.11, p = 0.036), gender (b = 0.95, t = 3.26, p = 0.001), and medication (b = 0.001, t = 2.18, p = 0.03) as independent contributors to the excited symptoms score, which together accounted for 23.7 % of the variance in the excited symptoms score of TD patients. Further, this polymorphism accounted for 12.7 % of the variance in the excited symptoms score of TD patients.
Discussion We did not find any significant differences in the DBH50 Ins/Del polymorphism between schizophrenia patients with
8.5 ± 2.3 23.1 ± 3.7 25.2 ± 8.4 43/17 417.5 ± 189.8 32.3 ± 32.7
Education (years)
Age of onset (years)
Duration of illness (years)
Antipsychotic types (a typical/ typical)
Medication (mg/days) (CPZ equivalents)
Duration of antipsychotic treatment (ms)
154/12
4.4 ± 0.9 9.4 ± 3.5
3.5 ± 1.4
111/8
9.0 ± 4.3
3.5 ± 1.2
4.5 ± 1.3
9.7 ± 4.2
59.3 ± 13.3
23.8 ± 7.5 25.9 ± 6.3
11.4 ± 4.4
42.9 ± 50.5
405.4 ± 191.5
101/18
26.2 ± 8.7
23.4 ± 5.9
8.7 ± 2.5
49.7 ± 8.8
63/9
0.9 ± 1.3
3.9 ± 1.7
4.6 ± 2.0
8.4 ± 4.4
58.3 ± 16.3
21.9 ± 8.7 24.6 ± 6.3
11.9 ± 5.0
43.1 ± 66.4
398.1 ± 190.6
50/22
21.5 ± 8.2
23.5 ± 4.7
8.8 ± 2.4
44.9 ± 8.5
1.1 ± 1.4
3.7 ± 1.5
4.6 ± 1.7
8.9 ± 4.4
59.2 ± 16.4
21.5 ± 8.6 26.0 ± 6.6
11.7 ± 5.1
42.0 ± 49.4
433.3 ± 217.4
145/50
23.3 ± 9.6
23.5 ± 5.8
9.6 ± 7.0
46.8 ± 9.5
146/49
Ins/Del (n = 195)
0.9 ± 1.3
3.9 ± 1.8
4.8 ± 2.7
8.6 ± 4.5
58.3 ± 17.3
20.7 ± 8.8 25.9 ± 7.6
11.6 ± 5.7
38.3 ± 57.0
427.6 ± 236.1
95/34
24.1 ± 10.8
23.4 ± 5.8
8.9 ± 2.6
47.5 ± 11.2
100/29
Ins/Ins (n = 129)
4.8 ± 5.0
3.6 ± 1.4
4.8 ± 2.3
9.1 ± 4.6
61.2 ± 15.6
23.5 ± 8.0 25.5 ± 6.5
12.1 ± 5.2
38.2 ± 53.9
406.9 ± 189.7
93/39
23.2 ± 8.5
23.3 ± 4.3
8.7 ± 2.3
46.5 ± 8.8
115/17
Del/Del (n = 132)
Total patients
b
a
4.9 ± 4.9
3.6 ± 1.4
4.5 ± 1.4
9.2 ± 4.2
60.0 ± 15.7
22.8 ± 8.7 25.7 ± 6.2
11.5 ± 4.9
42.1 ± 49.0
416.9 ± 203.4
280/81
24.7 ± 9.3
23.5 ± 5.4
9.1 ± 5.5
48.2 ± 9.4
300/61
Ins/Del (n = 361)
4.8 ± 5.1
3.7 ± 1.6
4.7 ± 2.1
9.1 ± 4.4
59.7 ± 15.9
22.2 ± 8.3 25.9 ± 7.0
11.5 ± 5.1
40.5 ± 53.9
417.0 ± 215.7
196/52
25.1 ± 9.9
23.4 ± 5.9
8.8 ± 2.5
48.5 ± 10.2
211/37
Ins/Ins (n = 248)
TD patients who had a Del/Del genotype have significantly higher excited symptoms scores than those TD patients who were Ins alleles (Ins/Del and Ins/Ins genotype) (F = 5.92, p = 0.015)
There was a significant genotypic effect on the excited symptoms in TD patients (F = 3.24, p = 0.04; p \ 0.05 after Bonferroni correction)
* p \ 0.05
TD tardive dyskinesia, CPZ chlorpromazine, PANSS the positive and negative syndrome scale, AIMS abnormal involuntary movement scale
9.4 ± 3.8
Depressive symptoms
AIMS total score
5.0 ± 2.7 3.4 ± 0.9
Excited symptomsb
9.5 ± 3.8
59.9 ± 15.0
59.7 ± 13.1 10.0 ± 4.6
Total score
Cognitive symptoms
24.4 ± 8.5 25.3 ± 5.6
12.4 ± 5.5 25.5 ± 6.7 26.7 ± 6.6
Positive symptoms
11.3 ± 4.7
42.3 ± 48.7
397.8 ± 184.5
135/31
26.3 ± 8.7
23.4 ± 4.8
8.4 ± 2.6
49.7 ± 9.2
Negative symptoms General psychopathology
PANSS score
52/8 48.3 ± 9.0
Age (years)
Del/Del (n = 72)
Ins/Ins (n = 119)
Del/Del (n = 60)
Ins/Del (n = 166)
Non-TD patients
TD patientsa
Gender (male/female)
Variable
Table 2 Demographic and PANSS analysis divided with regard to DBH50 -Ins/Del genotypes in TD, non-TD and total patients
DBH and clinical symptoms in TD 911
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Table 3 Stepwise multivariate regression model of the clinical and DBH50 -Ins/Del polymorphism determinants of the excited symptoms in TD patients Variables
b
t (sig)
DBH50 -Ins/Del polymorphism
0.44
2.11 (0.036)*
Gender
0.95
3.26 (0.001)**
Age Education
1.00 0.07
1.86 (0.64) 1.41 (0.16)
Age of onset
0.02
0.41 (0.68)
Duration of illness
0.09
1.66 (0.10)
Antipsychotic types(atypical/typical)
0.07
1.40 (0.16)
Medication (CPZ equivalents)
0.001
2.18 (0.03)*
Duration of antipsychotic treatment
-0.02
-0.040 (0.69)
AIMS total score
-0.05
-0.89 (0.37)
0
DBH5 -Ins/Del polymorphism was transformed into continuous variables: Del/Del = 1, genotype with Ins allele = 0 TD tardive dyskinesia, CPZ chlorpromazine, AIMS abnormal involuntary movement scale * p \ 0.05, ** p \ 0.01
and without TD. However, TD patients with a Del/Del genotype may have more excited symptoms than those with Ins alleles. Our finding that the DBH50 -Ins/Del polymorphism was not involved in the development of TD in schizophrenia is consistent with previous studies (Zhou et al. 2013; Sun et al. 2013). However, several earlier studies found that there was higher DBH activity in schizophrenia with TD than those without TD (Jeste et al. 1981; Wagner et al. 1982; Kaufmann et al. 1986). DBH enzyme activity was strongly controlled by the DBH50 -Ins/Del polymorphism (Cubells et al. 2000; Zabetian et al. 2001; Tang and Epstein 2007), suggesting that the DBH50 -Ins/Del polymorphism could be involved in the etiology of schizophrenia with TD. The above divergent results may be due to the following reasons. First, the DBH50 -Ins/Del polymorphism may not influence DBH activity in schizophrenia with TD in the Chinese Han population. Second, other functional polymorphisms of this gene or regulatory regions could contribute to DBH activity in schizophrenia with TD. Third, other factors could influence this enzyme activity in schizophrenia with TD, such as DBH and other gene interactions, DBH and environment interactions, and DBH haplotype of analysis. Therefore, further studies are still required. This is the first report showing that TD patients with the DBH50 -Del/Del genotype have more excited behavior than those with Ins alleles but not in non-TD patients. The underlying mechanism that is responsible for the DBH50 Del/Del genotype’s influence on the excited behavior could reflect a lower transcriptional activity of the DBH50 -Del/ Del genotype, resulting in a higher production of DA and
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an altered balance between DA and NE in the relevant brain regions (Cubells and Zabetian 2004). Several previous studies showed the association between DA and excited behavior in humans or animals (Engelborghs et al. 2008; Nitsche et al. 2010, Adamczyk et al. 2012). Moreover, studies found that the variables of the DBH gene influence the excited relevant behavior in ADHD, childhood and the young Chinese Han population (Barkley et al. 2006; Hess et al. 2009; Gong et al. 2010). Therefore, the DBH50 -Ins/Del polymorphism may contribute to excited behavior in TD patients through its influences on DBH activity or levels by modulating DA production. This present study has several limitations. First, the relatively small sample size and few female schizophrenia patients with TD (n = 28) may influence the accuracy of these results. A replication study on the association between excited symptoms and the DBH gene Ins/Del polymorphism should be conducted. Second, only one polymorphism was studied as limited resources enabled us to test only one of the single nucleotide polymorphisms (SNPs) in the DBH gene. Moreover, other functional SNPs that influence DBH activity and levels in plasma and CSF could have been genotyped to obtain more comprehensive information. For example, the DBH50 1021C/T polymorphism, which is widely considered as functional and accounts for 30–50 % of the variance of DBH activity across various populations (Cubells et al. 2000; Zabetian et al. 2001), could be examined, and DBH haplotype analyses could be applied to disclose the DBH effect on excited behavior in TD patients in a follow-up study. Third, hidden population stratification and/or the unmatched gender of our samples could be confounding factors. However, the Chinese in the Beijing area are ethnically relatively homogenous. Moreover, no gender differences in the allelic and genotypic frequencies of the DBH50 -Ins/Del polymorphism were observed in either the TD or non-TD patients. A replication study with genomic controls or a family-based population study would help to address this limitation. Fourth, the cumulative antipsychotics were not a covariate in the TD analyses because we did not record the information of TD patients taking the previous antipsychotics, which could influence the result of this study. Finally, a misclassification of genotypes is possible in spite of our quality controls, but such misclassification would typically bias the results towards no effect. In summary, we have found that the DBH50 -Ins/Del polymorphism may not play a role in the susceptibility to TD in schizophrenia. However, we have found that the DBH50 -Ins/Del polymorphism is associated with excited behavior in TD patients, suggesting that the DBH50 -Ins/Del polymorphism may be involved in excited behavior in TD patients.
DBH and clinical symptoms in TD Acknowledgments This study was funded by grants from the Beijing Municipal Natural Science Foundation (7132063 and 7072035), National Natural Science Foundation of China (81371477), NARSAD Independent Investigator Grant (20314), the National Key Technology R&D Program in the 11th Five Year Plan of China (2009BAI77B06), and the Wenzhou Municipal Sci-Tech Bureau Program (H20100021). These sources had no further role in study design, data collection and analysis, decision to publish, or preparation of the article. Conflict of interest No conflict of interest was disclosed for each author.
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