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The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese patients with schizophrenia
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The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese patients with schizophrenia Lijuan Huo a,b, Guangya Zhang c, Xiang-Dong Du c, Qiaqiufang Jia c, Zheng-Kang Qian c, Dachun Chen d, Meihong Xiu d, Fengchun Wu a,b, Jair C. Soares e, Xingbing Huang a, Ryan M. Cassidy e, Yuping Ning a,b,⁎, Xiang Yang Zhang a,b,f,⁎⁎ a
Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China c Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu Province, China d Beijing HuilongGuan Hosptial, Beijing, China e Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA f CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences; Department of Psychology, University of Chinese Academy of Sciences, Beijing, China b
a r t i c l e
i n f o
Article history: Received 15 January 2019 Accepted 21 December 2019 Available online xxxx Keywords: Schizophrenia Diabetes Prevalence Risk factor
a b s t r a c t Diabetes is one of the most common comorbid diseases in patients with schizophrenia. The present study examined the prevalence of diabetes and its clinical correlates in a large sample of Chinese patients with schizophrenia, which has not been examined systemically. In this cross-sectional study, a total of 1189 patients (males/females = 938/251; average age: 48.51 ± 10.09 years) were recruited. Fasting blood samples were collected to diagnose diabetes. Psychiatric symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). The prevalence of diabetes was 12.53% with a significant gender difference (males: 10.87% versus females: 18.73%). Compared to patients without diabetes, those with diabetes were older, had a later age of onset, had a higher BMI, had higher positive symptom scores and had higher level of metabolic indices, including triglyceride, cholesterol and HDL cholesterol. After stepwise binary logistic regression analysis, age, BMI, and triglyceride level remained significantly associated with diabetes. This study suggests that diabetes occur with high prevalence in Chinese schizophrenia patients. In addition, age, BMI, and triglyceride level possibly are useful markers predicting an increased risk for diabetes. © 2020 Elsevier B.V. All rights reserved.
1. Introduction Diabetes mellitus is a major metabolic disorder which, if not wellcontrolled, leads to many medical sequela affecting nearly every organ system. The substantial excess risks of death among persons with type 2 diabetes (Tancredi et al., 2015) make it a public health problem worldwide; deaths attributable to diabetes account for more than five million deaths per year (IDF Diabetes Atlas Group, 2015). According to Global Report on Diabetes from WHO (2016), the prevalence of diabetes in the general population is steadily increasing - most markedly, in the world's middle-income countries. Special populations, such as patients with schizophrenia, are at even greater risk. As confirmed by several
⁎ Correspondence to: Y. Ning, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Liwan District, Guangzhou 510370, China ⁎⁎ Correspondence to: X.Y. Zhang, Institute of Psychology, Chinese Academy of Sciences; 16 Lincui Road, Chaoyang District, Beijing, 100101, China. E-mail addresses: [email protected] (Y. Ning), [email protected] (X.Y. Zhang).
recent meta-analyses, the prevalence of diabetes in schizophrenia ranges from 10% to 15%, two to three times higher than that in the general population (Stubbs et al., 2015; Schoepf et al., 2012; Vancampfort et al., 2016). The underlying mechanisms for increased co-morbidity with diabetes in schizophrenia are multifactorial. The clearest evidence demonstrates that some of the increased risks for diabetes stem from the use of antipsychotics, especially atypical antipsychotics (Smith et al., 2008; Lin and Shuldiner 2010; De Hert et al., 2012). However, even firstepisode, drug-naïve patients with schizophrenia have impaired fasting glucose, greater insulin resistance, and elevated fasting 2-h plasma glucose levels (Zhang et al., 2015). The origins of this association are not known, but one possible explanation arises from overlapping genetic risk factors between diabetes and schizophrenia (Zhang et al., 2013). Using genome-wide approaches, Hackinger et al. (2018) identified 29 genes associated with both disorders. As further evidence for this, one recent study showed that dopamine dysfunction potentially contributed to the comorbidity of schizophrenia and diabetes (Gragnoli et al., 2016). It also must be said that schizophrenia patients may engage in
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Please cite this article as: L. Huo, G. Zhang, X.-D. Du, et al., The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese patients with s..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.029
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lifestyle drivers of metabolic disease, such as sedentarism, poor diet, increased food intake, and increased smoking behavior (Heald et al., 2017). There is significant variability in the prevalence and association of diabetes with schizophrenia in different regions or ethnic populations (Stubbs et al., 2015; Vancampfort et al., 2016). In mainland China, only one study has been conducted which found that, in schizophrenia patients receiving long-term clozapine treatment, there was a 22% prevalence of diabetes (Zhang et al., 2011). This study focused on the influence of clozapine and found that it, at least in part, increased the risk of diabetes. There are many other risk factors that could also be predictive, which have yet to be explored in this population. In this study, we investigated the prevalence of diabetes and its clinical correlates in a large of sample (n = 1189) of chronic patients with schizophrenia in a Chinese Han population. The preliminary purpose of this study was to investigate whether diabetes was significantly higher in schizophrenia patients in a Chinese Han population. A secondary aim of this study was to determine factors associated with increased diabetes in individuals with schizophrenia.
2.4. Clinical measurement The 30-item Positive and Negative Syndrome Scale (PANSS) was assessed by four independent experienced psychiatrists, who simultaneously attended a training program prior to the study. The inter-rater correlation coefficient was N0.8 for repeated assessments of the PANSS total score. 2.5. Data analysis The normality test was conducted for data of each variable using the Kolmogorov–Smirnov one-sample test. Demographic and clinical variables of the diabetic and non-diabetic groups were compared with independent t-tests for continuous variables and chi-squared test for categorical variables. A binary logistic regression analysis was performed to assess which factors were strongly associated with diabetes mellitus. All statistical analyses were performed with SPSS version 21.0. 3. Results 3.1. Demographic characteristics of patients with schizophrenia
2. Methods 2.1. Study setting and subjects The cross-sectional study was conducted at Beijing Hui-Long-Guan hospital and Hebei Rong-Jun hospital. Both of these are large public psychiatric hospitals in China. In total, 1189 Chinese inpatients between 16 and 76 years old with a DSM-IV diagnosis of schizophrenia were recruited. Diagnoses were made for each patient by two independent experienced psychiatrists, according to the Structured Clinical Interview for DSM-IV (SCID). All subjects signed written informed consent before participating in the study - this was approved by the ethics committee of Beijing Hui-Long-Guan hospital.
2.2. Demographic data collection A detailed questionnaire that recorded general information, sociodemographic characteristics, medical and psychiatric conditions were administered by research staff. Medical records and collateral resources were also used to collect additional information. The following data were collected on each patient: sex, age, education, age of onset, age of the first hospitalization, number of hospitalizations, duration of illness, antipsychotic medicines (type and dose), and smoking behavior.
2.3. Measurement of anthropometric variables, plasma glucose and lipid profile Body weight and height were measured to calculate body mass index (BMI, weight in kg/square of height in meters). Body weight was measured with an electronic scale calibrated to 0.1 kg with subjects wearing light indoor clothes. Height was measured to the nearest millimeter when subjects stood barefoot and upright. Patients were defined as obese with BMI ≥ 28, consistent with the criteria of Chinese Working Group on Obesity in China (WGOC) (Ji and Chen, 2013). Blood samples of all patients were collected between 7 and 9 a.m. after an overnight fast. According to World Health Organization diagnostic criteria for diabetes mellitus, diabetes was diagnosed as fasting hyperglycemia (≥126 mg/dL) or plasma glucose levels higher than 200 mg/dL after a 75-g Oral Glucose Tolerance Test (OGTT). Additionally, triglycerides, HDL cholesterol, and LDL cholesterol levels, apolipoprotein A1 (APOA1), and APOB were measured using in-hospital laboratory facilities.
Since some patients did not fully complete the questionnaire or clinical measures, numbers of patients varied slightly in different categories. A total of 1189 patients, with 251 females and 938 males, were included in our study. The average age of patients was 48.51 ± 10.09 years, ranging from 16 to 76 years. The average years of education was 9.08 ± 2.71 years, ranging from 0 to 19 years. The average age of illness onset was 23.88 ± 6.05 years, ranging from 1 to 19 years. Among all patients, 23.7% took typical antipsychotics, while 76.3% took atypical antipsychotics. 63.5% patients were regular smokers, with the average number of cigarettes/day being 12.31 ± 8.73. 3.2. Prevalence of diabetes mellitus and risk factors The overall prevalence of diabetes mellitus was 12.53% (149/1189) in patients with schizophrenia. 10.87% (102/938) of males and 18.73% (47/251) of females were diabetic; this difference was significant (X2 = 11.14, p = 0.001). In addition, the prevalence of obesity was 17.5% (146/834). The demographic and clinical characteristics of patients with diabetes vs. those without diabetes were compared and depicted in Table 1. Significant differences between the diabetic and non-diabetic groups were found in the following variables: age (t = 4.312, p b 0.001), sex (X2 = 11.14, p = 0.001), age of onset (t = 4.312, p = 0.01), BMI (t = −5.66, p b 0.001) and positive subscore of PANSS (t = 2.303, p = 0.021). Patients with diabetes were older, with a later onset of schizophrenia, a higher BMI and more severe positive symptoms than patients without diabetes. In addition, triglycerides (t = 6.92, p b 0.001), total cholesterol (t = 0.251, p = 0.002) and LDL cholesterol (t = 3.54, p b 0.001) levels were significantly higher in the diabetic group. Furthermore, a stepwise forward binary logistic regression was performed to identify the risk factors for diabetes, showing that older age (odd ratio = 1. 04, 95% CI = 1.01–1.07, Wald x2 = 5.1, p = 0.02), greater BMI (odd ratio = 1. 15, 95% CI = 1.07–1.23, Wald x2 = 15.52, p ≤ 0.001) and higher triglyceride level (odd ratio = 1. 32, 95% CI = 1.05–1.67, Wald x2 = 5.73, p = 0.02) were important predictors for diabetes. 4. Discussion Diabetes and its complications are major drivers of increased mortality in patients with schizophrenia. To the best of our knowledge, this is the first study reporting the prevalence and risk factors of diabetes in schizophrenia patients in a Chinese Han population. We found that 12.53% of patients with schizophrenia had concomitant diabetes.
Please cite this article as: L. Huo, G. Zhang, X.-D. Du, et al., The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese patients with s..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.029
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Table 1 Characteristics of patients with schizophrenia with or without diabetes mellitus.
Age (years) Gender Male (%) Female (%) Education (years) Age of onset (years) Hospitalization numbers BMI Obesity Smoking behavior Cigarettes/day Antipsychotic Atypical Typical Antipsychotic dose (mg/day) (chlorpromazine equivalents) PANSS Total score P subscore N subscore G subscore Cardo-metabolic Triglyceride (mmol/L) Cholesterol (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) APOA1 (g/L) APOB (g/L)
Patient with diabetes
Patient without diabetes
t or x2
P value
52.14 ± 8.94
48 ± 10.14
4.312
b0.001
102/149 (68.46%) 47/149 (37.54%) 9.18 ± 2.72 24.66 ± 5.56 4.29 ± 3.53 26.95 ± 4.36 31/75 (41.3%) 84/142 (59.2%) 10.73 ± 7.15
836/1040 (80.38%) 204/1040 (19.62%) 9.06 ± 2.71 23.77 ± 6.11 3.98 ± 2.62 24.15 ± 4.06 115/759 (15.2%) 636/991 (64.1%) 12.52 ± 8.9
11.14
0.001
0.596 2.584 0.606 −5.66 46.02 1.35 −1.477
0.551 0.01 0.544 b0.001 b0.001 0.245 0.140
107/146 (73.3%) 39/146 (26.7%) 479.93 ± 526.89
780/1018 (76.7%) 237/1018 (23.3%) 438.29 ± 384.01
0.819
0.365
0.360
0.719
62.97 13.55 22.03 27.38
61.66 12.32 22.79 26.51
1.102 2.303 −0.759 1.603
0.271 0.021 0.448 0.109
6.92 0.251 0.983 3.544 1.1 −0.581
b0.001 0.002 0.326 b0.001 0.272 0.561
2.24 4.67 1.27 2.96 1.61 0.99
± ± ± ±
± ± ± ± ± ±
19.04 6.48 8.27 8.35
1.31 1.05 0.3 0.82 0.35 0.34
Furthermore, some demographic and clinical variables were demonstrated to be the risk factors for diabetes, including older age, being female, higher BMI, and higher triglyceride level. The prevalence rate of diabetes was higher in our sample than that reported in studies performed in high-income areas of Asia, i.e. Taiwan and Japan (Chien et al., 2009; Hung et al., 2005; Okumura et al., 2010), but slightly lower than in India (15%) (Subashini et al., 2011). The differences between regions may be attributable to the discrepancies in quality of health care, policies and environments supporting healthy lifestyles, dietary habits, antipsychotics typically prescribed, and genetic risk factors for diabetes that are independent of those for schizophrenia. Differences in methodology and sample size between studies may also contribute. Given the global trend toward an obesogenic and diabetogenic lifestyle, it is not surprising that the worldwide prevalence of diabetes is on the rise (NCD Risk Factor Collaboration, 2016). In China, a large, nationally representative survey in 2013 found that the estimated overall prevalence of diabetes was about 11% (Wang et al., 2017; Xu et al., 2013). As a result, the difference in the occurrence of diabetes between the normal population and the schizophrenia may be getting smaller. Dispute remains over whether gender contributes to the risk of diabetes. Even in the normal population, various studies have found that diabetes is more common in females (Gu et al., 2003) and in males (Yang et al., 2010). Markedly higher risk of diabetes in female schizophrenia was found in the current study, which was consistent with some previous studies (Dixon et al., 2000; Chen et al., 2011; Chien et al., 2009; Vancampfort et al., 2016). There were chronic patients with schizophrenia receiving long-term antipsychotics included in these studies. We could speculate that poorer diabetes treatment and more complications among women with schizophrenia may cause the higher prevalence. Another study reported that in the first-episode schizophrenia group, male gender was associated with higher metabolic risk (Chen et al., 2016). Systematic research and cogent summary of the available data are lacking to make any clear picture of the ultimate role that gender plays in predicting the development of diabetes in schizophrenia. Agreeing with most previous literature (Annamalai et al., 2017; Li et al., 2017; Vancampfort et al., 2015), we found that the prevalence of
1.58 4.39 1.24 2.76 1.60 0.98
± ± ± ±
± ± ± ± ± ±
17.58 5.62 8.4 7.78
1 0.96 0.35 0.95 0.49 0.26
diabetes in schizophrenia increased with high BMI, or obesity. Obesity is a symptom of metabolic disease and is predictive of insulin resistance and altered blood chemistry, which in turn drives the development cardiovascular disease and diabetes. Unhealthy lifestyles (Heald et al., 2017) and antipsychotic therapy (Manu et al., 2015) are likely to be the prime drivers of obesity and then diabetes in schizophrenia. Shared genetic risk factors for both schizophrenia and metabolic disease may also contribute; for example, the fat mass and associated genes (FTO) and leptin and leptin receptor genes (LEP, LEPR) are strongly related to both metabolic syndrome and schizophrenia (Malan-Müller et al., 2016). Interestingly, our result showed that only positive symptomatology on the PANSS, rather than greater symptom burden overall or negative symptoms, was associated with diabetes in our patients. As far as we know, only one previous study (Nuevo et al., 2011) provided evidence for the direct relationship between positive symptoms and the prevalence of diabetes. Nuevo et al. (2011) found that the prevalence was increased with the severity of positive symptoms. Why this may be the case is not known; more research about the relation between symptomatology of schizophrenia and diabetes is needed. Contrary to the literature, we did not find that the antipsychotic therapy, including type and dosage, differed between the diabetic and non-diabetic groups. Antipsychotic usage correlates with β-cell damage and insulin resistance, likely driving diabetes through this mechanism (though whether this is associated with altered eating habits or direct damage is not yet known). (Chen et al., 2017; Whicher et al., 2018). Zhang et al., 2011 found a 22% rate of diabetes among clozapinetreated schizophrenia patients in mainland China; notably, this was much higher than the present study. This result indirectly proved that patients using clozapine were more likely to develop diabetes. In fact, the most notable side effect of second-generation antipsychotic medications is metabolic syndrome (Rubin et al., 2015; Solmi et al., 2017). However, a meta-analysis showed that compared to a drug-naïve condition, both first and second generation antipsychotics increase the risk of metabolic abnormalities (Vancampfort et al., 2015). Several limitations of this study should be noted. First, a major limitation is the absence of healthy controls with matched age and gender. Therefore, some bias possibly occurred when comparing patients of our
Please cite this article as: L. Huo, G. Zhang, X.-D. Du, et al., The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese patients with s..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.029
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study with the general population of other studies. Second, there is imbalanced ratio of gender in our sample, with a much higher number of male patients. It may partly explain the discrepancies in prevalence rate between our results and those of other studies, as our data indicated that being female increased the chance of diabetes. Third, as a cross-sectional study, it does not prove a direct causal relationship between clinical variables and increased diabetes in patients with schizophrenia. Fourth, there are many genetic and environmental factors that may affect glycometabolism, such as genetic susceptibility, the level of brain derived neurotrophic factor, physical activity, a family history of diabetes and so on. However, these data were not collected in our study. Further large controlled prospective studies should be conducted to demonstrate the relationship between these factors and glycometabolism. In summary, the current study revealed a 12.5% prevalence of diabetes in patients with schizophrenia, suggesting that metabolic dysfunction is common in schizophrenia in the Chinese Han population. Furthermore, our study demonstrated a significantly higher rate of comorbid diabetes in female compared to male patients (10.87% vs. 18.73%), suggesting a sex difference in the rate of diabetes in schizophrenia. Our study further showed that risk factors for diabetes were old age, high BMI and triglyceride levels. Diabetes results in increased mortality and decreased quality of life. Understanding the risk factors of diabetes would provide important implications for prevention and interventions, reducing the burden of diabetes in patients with schizophrenia. Contributors Lijuan Huo and Xiang Yang Zhang were responsible for study design, statistical analysis, and manuscript preparation. Dachun Chen, Meihong Xiu, Guangya Zhang, XiangDong Du, and Fengchun Wu were responsible for recruiting the patients, performing the clinical rating and collecting the samples. Qiufang Jia, Zheng-Kang Qian, Yu-Ping Ning, Xing-Bing Huang and Jair C. Soares were involved in evolving the ideas and editing the manuscript. Lijuan Huo, Ryan M. Cassidy and Xiang Yang Zhang were involved in writing the protocol, and cowrote the paper. Fengchun Wu and Xiang-Dong Du were responsible for providing the funding for the study. All authors have contributed to and have approved the final manuscript.
Role of the funding source This study was supported by the grants from the Science and Technology Department, Guangdong Province (2016A020216004), and Guangzhou Municipal Science and Technology Project (201704020168, 201807010064), CAS Pioneer Hundred Talents Program, Key Diagnosis and treatment Program of Suzhou (LCZX201515), Suzhou Key Medical Center for Psychiatric Diseases (Szzx201509), Suzhou Key Disciplines (Szxk201515), and Suzhou Introduced Project for Clinical Medical Expert Team (SZYJTD201715). These sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Declaration of competing interest No conflict of interest was disclosed for each author. Acknowledgements The authors would like to thank Drs. Yunlong Tan, Wu Fang Zhang, Zhi Ren Wang, Bao Hua Zhang, Ling Yan Qi and Gui Gang Yang for all of their hard work and significant contributions toward the study.
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The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese patients with schizophrenia Lijuan Huo a,b, Guangya Zhang c, Xiang-Dong Du c, Qiaqiufang Jia c, Zheng-Kang Qian c, Dachun Chen d, Meihong Xiu d, Fengchun Wu a,b, Jair C. Soares e, Xingbing Huang a, Ryan M. Cassidy e, Yuping Ning a,b,⁎, Xiang Yang Zhang a,b,f,⁎⁎ a
Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China c Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu Province, China d Beijing HuilongGuan Hosptial, Beijing, China e Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA f CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences; Department of Psychology, University of Chinese Academy of Sciences, Beijing, China b
a r t i c l e
i n f o
Article history: Received 15 January 2019 Accepted 21 December 2019 Available online xxxx Keywords: Schizophrenia Diabetes Prevalence Risk factor
a b s t r a c t Diabetes is one of the most common comorbid diseases in patients with schizophrenia. The present study examined the prevalence of diabetes and its clinical correlates in a large sample of Chinese patients with schizophrenia, which has not been examined systemically. In this cross-sectional study, a total of 1189 patients (males/females = 938/251; average age: 48.51 ± 10.09 years) were recruited. Fasting blood samples were collected to diagnose diabetes. Psychiatric symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). The prevalence of diabetes was 12.53% with a significant gender difference (males: 10.87% versus females: 18.73%). Compared to patients without diabetes, those with diabetes were older, had a later age of onset, had a higher BMI, had higher positive symptom scores and had higher level of metabolic indices, including triglyceride, cholesterol and HDL cholesterol. After stepwise binary logistic regression analysis, age, BMI, and triglyceride level remained significantly associated with diabetes. This study suggests that diabetes occur with high prevalence in Chinese schizophrenia patients. In addition, age, BMI, and triglyceride level possibly are useful markers predicting an increased risk for diabetes. © 2020 Elsevier B.V. All rights reserved.
1. Introduction Diabetes mellitus is a major metabolic disorder which, if not wellcontrolled, leads to many medical sequela affecting nearly every organ system. The substantial excess risks of death among persons with type 2 diabetes (Tancredi et al., 2015) make it a public health problem worldwide; deaths attributable to diabetes account for more than five million deaths per year (IDF Diabetes Atlas Group, 2015). According to Global Report on Diabetes from WHO (2016), the prevalence of diabetes in the general population is steadily increasing - most markedly, in the world's middle-income countries. Special populations, such as patients with schizophrenia, are at even greater risk. As confirmed by several
⁎ Correspondence to: Y. Ning, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Liwan District, Guangzhou 510370, China ⁎⁎ Correspondence to: X.Y. Zhang, Institute of Psychology, Chinese Academy of Sciences; 16 Lincui Road, Chaoyang District, Beijing, 100101, China. E-mail addresses: [email protected] (Y. Ning), [email protected] (X.Y. Zhang).
recent meta-analyses, the prevalence of diabetes in schizophrenia ranges from 10% to 15%, two to three times higher than that in the general population (Stubbs et al., 2015; Schoepf et al., 2012; Vancampfort et al., 2016). The underlying mechanisms for increased co-morbidity with diabetes in schizophrenia are multifactorial. The clearest evidence demonstrates that some of the increased risks for diabetes stem from the use of antipsychotics, especially atypical antipsychotics (Smith et al., 2008; Lin and Shuldiner 2010; De Hert et al., 2012). However, even firstepisode, drug-naïve patients with schizophrenia have impaired fasting glucose, greater insulin resistance, and elevated fasting 2-h plasma glucose levels (Zhang et al., 2015). The origins of this association are not known, but one possible explanation arises from overlapping genetic risk factors between diabetes and schizophrenia (Zhang et al., 2013). Using genome-wide approaches, Hackinger et al. (2018) identified 29 genes associated with both disorders. As further evidence for this, one recent study showed that dopamine dysfunction potentially contributed to the comorbidity of schizophrenia and diabetes (Gragnoli et al., 2016). It also must be said that schizophrenia patients may engage in
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Please cite this article as: L. Huo, G. Zhang, X.-D. Du, et al., The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese patients with s..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.029
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lifestyle drivers of metabolic disease, such as sedentarism, poor diet, increased food intake, and increased smoking behavior (Heald et al., 2017). There is significant variability in the prevalence and association of diabetes with schizophrenia in different regions or ethnic populations (Stubbs et al., 2015; Vancampfort et al., 2016). In mainland China, only one study has been conducted which found that, in schizophrenia patients receiving long-term clozapine treatment, there was a 22% prevalence of diabetes (Zhang et al., 2011). This study focused on the influence of clozapine and found that it, at least in part, increased the risk of diabetes. There are many other risk factors that could also be predictive, which have yet to be explored in this population. In this study, we investigated the prevalence of diabetes and its clinical correlates in a large of sample (n = 1189) of chronic patients with schizophrenia in a Chinese Han population. The preliminary purpose of this study was to investigate whether diabetes was significantly higher in schizophrenia patients in a Chinese Han population. A secondary aim of this study was to determine factors associated with increased diabetes in individuals with schizophrenia.
2.4. Clinical measurement The 30-item Positive and Negative Syndrome Scale (PANSS) was assessed by four independent experienced psychiatrists, who simultaneously attended a training program prior to the study. The inter-rater correlation coefficient was N0.8 for repeated assessments of the PANSS total score. 2.5. Data analysis The normality test was conducted for data of each variable using the Kolmogorov–Smirnov one-sample test. Demographic and clinical variables of the diabetic and non-diabetic groups were compared with independent t-tests for continuous variables and chi-squared test for categorical variables. A binary logistic regression analysis was performed to assess which factors were strongly associated with diabetes mellitus. All statistical analyses were performed with SPSS version 21.0. 3. Results 3.1. Demographic characteristics of patients with schizophrenia
2. Methods 2.1. Study setting and subjects The cross-sectional study was conducted at Beijing Hui-Long-Guan hospital and Hebei Rong-Jun hospital. Both of these are large public psychiatric hospitals in China. In total, 1189 Chinese inpatients between 16 and 76 years old with a DSM-IV diagnosis of schizophrenia were recruited. Diagnoses were made for each patient by two independent experienced psychiatrists, according to the Structured Clinical Interview for DSM-IV (SCID). All subjects signed written informed consent before participating in the study - this was approved by the ethics committee of Beijing Hui-Long-Guan hospital.
2.2. Demographic data collection A detailed questionnaire that recorded general information, sociodemographic characteristics, medical and psychiatric conditions were administered by research staff. Medical records and collateral resources were also used to collect additional information. The following data were collected on each patient: sex, age, education, age of onset, age of the first hospitalization, number of hospitalizations, duration of illness, antipsychotic medicines (type and dose), and smoking behavior.
2.3. Measurement of anthropometric variables, plasma glucose and lipid profile Body weight and height were measured to calculate body mass index (BMI, weight in kg/square of height in meters). Body weight was measured with an electronic scale calibrated to 0.1 kg with subjects wearing light indoor clothes. Height was measured to the nearest millimeter when subjects stood barefoot and upright. Patients were defined as obese with BMI ≥ 28, consistent with the criteria of Chinese Working Group on Obesity in China (WGOC) (Ji and Chen, 2013). Blood samples of all patients were collected between 7 and 9 a.m. after an overnight fast. According to World Health Organization diagnostic criteria for diabetes mellitus, diabetes was diagnosed as fasting hyperglycemia (≥126 mg/dL) or plasma glucose levels higher than 200 mg/dL after a 75-g Oral Glucose Tolerance Test (OGTT). Additionally, triglycerides, HDL cholesterol, and LDL cholesterol levels, apolipoprotein A1 (APOA1), and APOB were measured using in-hospital laboratory facilities.
Since some patients did not fully complete the questionnaire or clinical measures, numbers of patients varied slightly in different categories. A total of 1189 patients, with 251 females and 938 males, were included in our study. The average age of patients was 48.51 ± 10.09 years, ranging from 16 to 76 years. The average years of education was 9.08 ± 2.71 years, ranging from 0 to 19 years. The average age of illness onset was 23.88 ± 6.05 years, ranging from 1 to 19 years. Among all patients, 23.7% took typical antipsychotics, while 76.3% took atypical antipsychotics. 63.5% patients were regular smokers, with the average number of cigarettes/day being 12.31 ± 8.73. 3.2. Prevalence of diabetes mellitus and risk factors The overall prevalence of diabetes mellitus was 12.53% (149/1189) in patients with schizophrenia. 10.87% (102/938) of males and 18.73% (47/251) of females were diabetic; this difference was significant (X2 = 11.14, p = 0.001). In addition, the prevalence of obesity was 17.5% (146/834). The demographic and clinical characteristics of patients with diabetes vs. those without diabetes were compared and depicted in Table 1. Significant differences between the diabetic and non-diabetic groups were found in the following variables: age (t = 4.312, p b 0.001), sex (X2 = 11.14, p = 0.001), age of onset (t = 4.312, p = 0.01), BMI (t = −5.66, p b 0.001) and positive subscore of PANSS (t = 2.303, p = 0.021). Patients with diabetes were older, with a later onset of schizophrenia, a higher BMI and more severe positive symptoms than patients without diabetes. In addition, triglycerides (t = 6.92, p b 0.001), total cholesterol (t = 0.251, p = 0.002) and LDL cholesterol (t = 3.54, p b 0.001) levels were significantly higher in the diabetic group. Furthermore, a stepwise forward binary logistic regression was performed to identify the risk factors for diabetes, showing that older age (odd ratio = 1. 04, 95% CI = 1.01–1.07, Wald x2 = 5.1, p = 0.02), greater BMI (odd ratio = 1. 15, 95% CI = 1.07–1.23, Wald x2 = 15.52, p ≤ 0.001) and higher triglyceride level (odd ratio = 1. 32, 95% CI = 1.05–1.67, Wald x2 = 5.73, p = 0.02) were important predictors for diabetes. 4. Discussion Diabetes and its complications are major drivers of increased mortality in patients with schizophrenia. To the best of our knowledge, this is the first study reporting the prevalence and risk factors of diabetes in schizophrenia patients in a Chinese Han population. We found that 12.53% of patients with schizophrenia had concomitant diabetes.
Please cite this article as: L. Huo, G. Zhang, X.-D. Du, et al., The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese patients with s..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.029
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Table 1 Characteristics of patients with schizophrenia with or without diabetes mellitus.
Age (years) Gender Male (%) Female (%) Education (years) Age of onset (years) Hospitalization numbers BMI Obesity Smoking behavior Cigarettes/day Antipsychotic Atypical Typical Antipsychotic dose (mg/day) (chlorpromazine equivalents) PANSS Total score P subscore N subscore G subscore Cardo-metabolic Triglyceride (mmol/L) Cholesterol (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) APOA1 (g/L) APOB (g/L)
Patient with diabetes
Patient without diabetes
t or x2
P value
52.14 ± 8.94
48 ± 10.14
4.312
b0.001
102/149 (68.46%) 47/149 (37.54%) 9.18 ± 2.72 24.66 ± 5.56 4.29 ± 3.53 26.95 ± 4.36 31/75 (41.3%) 84/142 (59.2%) 10.73 ± 7.15
836/1040 (80.38%) 204/1040 (19.62%) 9.06 ± 2.71 23.77 ± 6.11 3.98 ± 2.62 24.15 ± 4.06 115/759 (15.2%) 636/991 (64.1%) 12.52 ± 8.9
11.14
0.001
0.596 2.584 0.606 −5.66 46.02 1.35 −1.477
0.551 0.01 0.544 b0.001 b0.001 0.245 0.140
107/146 (73.3%) 39/146 (26.7%) 479.93 ± 526.89
780/1018 (76.7%) 237/1018 (23.3%) 438.29 ± 384.01
0.819
0.365
0.360
0.719
62.97 13.55 22.03 27.38
61.66 12.32 22.79 26.51
1.102 2.303 −0.759 1.603
0.271 0.021 0.448 0.109
6.92 0.251 0.983 3.544 1.1 −0.581
b0.001 0.002 0.326 b0.001 0.272 0.561
2.24 4.67 1.27 2.96 1.61 0.99
± ± ± ±
± ± ± ± ± ±
19.04 6.48 8.27 8.35
1.31 1.05 0.3 0.82 0.35 0.34
Furthermore, some demographic and clinical variables were demonstrated to be the risk factors for diabetes, including older age, being female, higher BMI, and higher triglyceride level. The prevalence rate of diabetes was higher in our sample than that reported in studies performed in high-income areas of Asia, i.e. Taiwan and Japan (Chien et al., 2009; Hung et al., 2005; Okumura et al., 2010), but slightly lower than in India (15%) (Subashini et al., 2011). The differences between regions may be attributable to the discrepancies in quality of health care, policies and environments supporting healthy lifestyles, dietary habits, antipsychotics typically prescribed, and genetic risk factors for diabetes that are independent of those for schizophrenia. Differences in methodology and sample size between studies may also contribute. Given the global trend toward an obesogenic and diabetogenic lifestyle, it is not surprising that the worldwide prevalence of diabetes is on the rise (NCD Risk Factor Collaboration, 2016). In China, a large, nationally representative survey in 2013 found that the estimated overall prevalence of diabetes was about 11% (Wang et al., 2017; Xu et al., 2013). As a result, the difference in the occurrence of diabetes between the normal population and the schizophrenia may be getting smaller. Dispute remains over whether gender contributes to the risk of diabetes. Even in the normal population, various studies have found that diabetes is more common in females (Gu et al., 2003) and in males (Yang et al., 2010). Markedly higher risk of diabetes in female schizophrenia was found in the current study, which was consistent with some previous studies (Dixon et al., 2000; Chen et al., 2011; Chien et al., 2009; Vancampfort et al., 2016). There were chronic patients with schizophrenia receiving long-term antipsychotics included in these studies. We could speculate that poorer diabetes treatment and more complications among women with schizophrenia may cause the higher prevalence. Another study reported that in the first-episode schizophrenia group, male gender was associated with higher metabolic risk (Chen et al., 2016). Systematic research and cogent summary of the available data are lacking to make any clear picture of the ultimate role that gender plays in predicting the development of diabetes in schizophrenia. Agreeing with most previous literature (Annamalai et al., 2017; Li et al., 2017; Vancampfort et al., 2015), we found that the prevalence of
1.58 4.39 1.24 2.76 1.60 0.98
± ± ± ±
± ± ± ± ± ±
17.58 5.62 8.4 7.78
1 0.96 0.35 0.95 0.49 0.26
diabetes in schizophrenia increased with high BMI, or obesity. Obesity is a symptom of metabolic disease and is predictive of insulin resistance and altered blood chemistry, which in turn drives the development cardiovascular disease and diabetes. Unhealthy lifestyles (Heald et al., 2017) and antipsychotic therapy (Manu et al., 2015) are likely to be the prime drivers of obesity and then diabetes in schizophrenia. Shared genetic risk factors for both schizophrenia and metabolic disease may also contribute; for example, the fat mass and associated genes (FTO) and leptin and leptin receptor genes (LEP, LEPR) are strongly related to both metabolic syndrome and schizophrenia (Malan-Müller et al., 2016). Interestingly, our result showed that only positive symptomatology on the PANSS, rather than greater symptom burden overall or negative symptoms, was associated with diabetes in our patients. As far as we know, only one previous study (Nuevo et al., 2011) provided evidence for the direct relationship between positive symptoms and the prevalence of diabetes. Nuevo et al. (2011) found that the prevalence was increased with the severity of positive symptoms. Why this may be the case is not known; more research about the relation between symptomatology of schizophrenia and diabetes is needed. Contrary to the literature, we did not find that the antipsychotic therapy, including type and dosage, differed between the diabetic and non-diabetic groups. Antipsychotic usage correlates with β-cell damage and insulin resistance, likely driving diabetes through this mechanism (though whether this is associated with altered eating habits or direct damage is not yet known). (Chen et al., 2017; Whicher et al., 2018). Zhang et al., 2011 found a 22% rate of diabetes among clozapinetreated schizophrenia patients in mainland China; notably, this was much higher than the present study. This result indirectly proved that patients using clozapine were more likely to develop diabetes. In fact, the most notable side effect of second-generation antipsychotic medications is metabolic syndrome (Rubin et al., 2015; Solmi et al., 2017). However, a meta-analysis showed that compared to a drug-naïve condition, both first and second generation antipsychotics increase the risk of metabolic abnormalities (Vancampfort et al., 2015). Several limitations of this study should be noted. First, a major limitation is the absence of healthy controls with matched age and gender. Therefore, some bias possibly occurred when comparing patients of our
Please cite this article as: L. Huo, G. Zhang, X.-D. Du, et al., The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese patients with s..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.029
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study with the general population of other studies. Second, there is imbalanced ratio of gender in our sample, with a much higher number of male patients. It may partly explain the discrepancies in prevalence rate between our results and those of other studies, as our data indicated that being female increased the chance of diabetes. Third, as a cross-sectional study, it does not prove a direct causal relationship between clinical variables and increased diabetes in patients with schizophrenia. Fourth, there are many genetic and environmental factors that may affect glycometabolism, such as genetic susceptibility, the level of brain derived neurotrophic factor, physical activity, a family history of diabetes and so on. However, these data were not collected in our study. Further large controlled prospective studies should be conducted to demonstrate the relationship between these factors and glycometabolism. In summary, the current study revealed a 12.5% prevalence of diabetes in patients with schizophrenia, suggesting that metabolic dysfunction is common in schizophrenia in the Chinese Han population. Furthermore, our study demonstrated a significantly higher rate of comorbid diabetes in female compared to male patients (10.87% vs. 18.73%), suggesting a sex difference in the rate of diabetes in schizophrenia. Our study further showed that risk factors for diabetes were old age, high BMI and triglyceride levels. Diabetes results in increased mortality and decreased quality of life. Understanding the risk factors of diabetes would provide important implications for prevention and interventions, reducing the burden of diabetes in patients with schizophrenia. Contributors Lijuan Huo and Xiang Yang Zhang were responsible for study design, statistical analysis, and manuscript preparation. Dachun Chen, Meihong Xiu, Guangya Zhang, XiangDong Du, and Fengchun Wu were responsible for recruiting the patients, performing the clinical rating and collecting the samples. Qiufang Jia, Zheng-Kang Qian, Yu-Ping Ning, Xing-Bing Huang and Jair C. Soares were involved in evolving the ideas and editing the manuscript. Lijuan Huo, Ryan M. Cassidy and Xiang Yang Zhang were involved in writing the protocol, and cowrote the paper. Fengchun Wu and Xiang-Dong Du were responsible for providing the funding for the study. All authors have contributed to and have approved the final manuscript.
Role of the funding source This study was supported by the grants from the Science and Technology Department, Guangdong Province (2016A020216004), and Guangzhou Municipal Science and Technology Project (201704020168, 201807010064), CAS Pioneer Hundred Talents Program, Key Diagnosis and treatment Program of Suzhou (LCZX201515), Suzhou Key Medical Center for Psychiatric Diseases (Szzx201509), Suzhou Key Disciplines (Szxk201515), and Suzhou Introduced Project for Clinical Medical Expert Team (SZYJTD201715). These sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Declaration of competing interest No conflict of interest was disclosed for each author. Acknowledgements The authors would like to thank Drs. Yunlong Tan, Wu Fang Zhang, Zhi Ren Wang, Bao Hua Zhang, Ling Yan Qi and Gui Gang Yang for all of their hard work and significant contributions toward the study.
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