Diabetes mellitus in patients with schizophrenia in Taiwan

Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 523 – 527 www.elsevier.com/locate/pnpbp

Diabetes mellitus in patients with schizophrenia in Taiwan Chi-Fa Hunga, Ching-Kuan Wua,b, Pao-Yen Lina,c,T a

Department of Psychiatry, Chang Gung Memorial Hospital, Kaohsiung, 123 Ta Pei Road, Niao-Sung Shiang, Kaohsiung County, 833, Taiwan b Department of Psychiatry, Jing-Ho Mental Health Yen-Chou Hospital, No.3-20 Shenshuei Rd., Shenshuei Tsuen, Yenchou Shiang, Kaohsiung County, 824, Taiwan c Department of Biology, Brandeis University, 415 South St., M/S 008, Waltham, MA 02454, USA Accepted 28 January 2005 Available online 5 March 2005

Abstract A higher prevalence of diabetes mellitus (DM) has been reported in schizophrenic patients for decades. But the risk factors for diabetes in these patients were not well understood. The aim of our study is to establish the prevalence of DM in patients with schizophrenia in Taiwan and discover the risk factors associated with it. In 246 recruited schizophrenic patients, the prevalence of DM was 9.8%, not significantly different from that of the general population in Taiwan. However, we found a significantly higher prevalence of DM in younger schizophrenic patients ( p=0.001) than in the general population, but not in older patients ( pN0.10). Our results showed old age, a longer duration of illness, obesity, and having a family history of DM were independent factors associated with DM in schizophrenia. These results suggest that schizophrenia may make young people more vulnerable to developing DM. Further large-scale, controlled studies should be done to confirm our results. D 2005 Elsevier Inc. All rights reserved. Keywords: Antipsychotic agents; Diabetes mellitus; Prevalence; Schizophrenia

1. Introduction Patients with schizophrenia have been found to have a higher mortality rate (Osby et al., 2000), and a higher prevalence of common medical disorders than the general population (Davidson, 2002; Addington et al., 2003; Subramaniam et al., 2003). These medical disorders seldom receive sufficient treatment (Cradock-O’Leary et al., 2002). Type 2 diabetes mellitus (DM), one of the most common medical diseases, has been reported to have a higher prevalence in schizophrenic patients than in reference populations (Tabata et al., 1987; Mukherjee et al., 1996;

Abbreviations: BMI, body mass index; DM, diabetes mellitus; PR, prevalence rate. T Corresponding author. Department of Biology, Brandeis University, 415 South St., M/S 008, Waltham, MA 02454, USA. E-mail address: [email protected] (P.-Y. Lin). 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2005.01.003

Dixon et al., 2000; Sernyak et al., 2002; Lamberti et al., 2003; Subramaniam et al., 2003; Taylor et al., 2003). Some studies have been conducted in Japanese people (Tabata et al., 1987), in Italian people (Mukherjee et al., 1996), and in mixed ethnic groups (Dixon et al., 2000; Sernyak et al., 2002; Lamberti et al., 2003). The prevalence rate of DM in schizophrenic patients in the above studies ranged from 8.8% (Tabata et al., 1987) to 20.9% (Subramaniam et al., 2003). The large differences across studies may reflect difference in study designs, methods of identifying DM, demographic and clinical characteristics of patients, and even the ethnic groups of the subjects. Increased age was often found to be associated with a higher risk of DM in these patients (Mukherjee et al., 1996; Dixon et al., 2000; Sernyak et al., 2002; Subramaniam et al., 2003). But, other possible risk factors for DM in schizophrenic patients were not properly examined. In this study, we aimed to establish the prevalence rate of DM in schizophrenic patients in Taiwan and examine

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differences in the clinical characteristics of schizophrenic patients with and without DM.

2. Methods 2.1. Subjects Subjects were recruited from three private psychiatric hospitals in southern Taiwan. All of them were Taiwanese of Han origin. Patients in the chronic ward were continuously sampled, interviewed in person. Recruited subjects should meet the DSM-IV criteria for schizophrenia (American Psychiatric Association, 1994). Written informed consents were obtained from all recruited subjects after the protocol and procedures had been fully explained. We included schizophrenic patients 18 years or older who had been taking stable doses of antipsychotics for more than 4 weeks. The patients were excluded if they: (1) refused or were unable to sign informed consent, (2) had psychotic disorders caused by a general medical condition, or (3) had a history of illicit drug or alcohol abuse because it might be associated with an earlier onset of type 2 DM (Johnson et al., 2001). 2.2. Assessment Height and weight were measured for all patients and body mass index (BMI) was calculated. The following variables were registered for all patients: age, sex, body weight, height, duration of psychiatric disease, type and duration of antipsychotic therapy, and history of diabetes in first degree relatives. The data were collected either by interviewing patients directly or from the medical record. When patients were not clear about family history of DM, it was clarified by speaking with their family. Onset of the psychiatric disease was defined as the first time the patient presented symptoms consistent with his diagnosis. Obesity was defined as Taiwanese criteria, BMIR27 kg/ m2, which has been used in some studies (Lin et al., 2003; Pan et al., 2004). After the patients had fasted for a minimum of 8 h overnight, fasting venous blood sugar concentrations were measured. Blood sugar levels of subjects were tested twice with a 1-week interval. Patients were diagnosed as having DM when they had a fasting plasma glucose over 126 mg/ dl, which was newly changed by American Diabetes Association (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003). 2.3. Statistics The age-specific and overall prevalences of DM in schizophrenic patients were obtained and compared with the prevalence of DM from a population-based study in southern Taiwan (Lu et al., 1998).

The main demographic and clinical variables were compared between patients with and without DM. Unpaired Student’s t-tests were used for continuous variables, while chi-square tests for categorical variables. For variables contributing to a between-group difference, we performed a stepwise logistic regression with DM as a dependent (outcome) variable, and sex, duration of disease, family history of DM, and obesity as independent variables. Age was not included as an independent variable in the regression model because of its high correlation with duration of disease. A p value of less than 0.05 was considered statistically significant. All the statistical analyses were performed using the SPSS for Windows software (version 11.0).

3. Results 3.1. Prevalence of DM in schizophrenic patients Two hundred forty-six (136 males, 110 females) schizophrenic patients were included in this study. Their mean age was 37.9 years (S.D.=10.5). The overall prevalence of DM was 9.8% (N=24). The prevalence rate of diabetes increased with age. The highest prevalence (25%) occurred in patients aged 60 to 69. Comparing with data from people in the same age group from a survey of the general population in southern Taiwan (Lu et al., 1998), we found a significantly higher prevalence of diabetes in younger schizophrenic patients (age 20 to 49) ( pb0.001), but not in older patients (age 50 to 69) ( pN0.10). Overall, the prevalence of DM in our sample

Table 1 Age-specific prevalence of diabetes mellitus in patients with schizophrenia and general population in Taiwan Age (years)

Schizophrenia patients

General population in Taiwana

Number

Number

PR of DM, N (%)

p

PR of DM, N (%)

b20 20–29 30–39

4 54 87

0 (0.0) 2 (3.7) 6 (6.9)

341 358

4 (1.2) 7 (2.0)

40–49 50–59 60–69

69 24 8

11 (15.9) 3 (12.5) 2 (25.0)

397 244 194

26 (6.5) 33 (13.5) 50 (25.8)

Total

246

24 (9.8)

1534

120 (7.8)

b0.001b

N0.10c N0.10d

PR, prevalence rate; DM, diabetes mellitus. a Data are from Lu et al. (1998). b Schizophrenia patients vs. general population in age group 20–49, v 2 (1)=13.81. c Schizophrenia patients vs. general population in age group 50–69, v 2 (1)=0.22. d Schizophrenia patients vs. general population in age group 20–69, v 2 (1)=1.23.

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Table 2 Demographic and clinical characteristics of schizophrenic patients Non-DM (N=222)

DM (N=24)

Statistical resultsa

p

N (%) MeanFS.D.

N (%) MeanFS.D.

Age Duration of disease (years)b BMI (Body mass index)

37.25F10.37 11.60F8.24 25.46F5.15

43.75F9.82 17.88F11.55 25.75F5.75

t (244)= 2.93 t (238)= 3.38 t (244)= 0.26

0.004 0.016 0.794

Sex Male Female

128 (57.7) 94 (42.3)

8 (33.3) 16 (66.7)

v 2 (1)=5.18

0.023

Antipsychotics Traditional antipsychotics Atypical antipsychotics

109 (49.1) 113 (50.9)

13 (54.2) 11 (45.8)

v 2 (1)=0.19

0.667

DM family history No Yes

207 (93.2) 15 (6.8)

18 (75.0) 6 (25.0)

v 2 (1)=9.23

0.002

Obesity c No Yes

148 (66.7) 74 (33.3)

12 (50.0) 12 (50.0)

v 2 (1)=2.65

0.104

a b c

Degree of freedom is shown in parentheses. Data was available for 240 patients. Obesity was defined as Taiwanese criteria (Lin et al., 2003; Pan et al., 2004), BMIR27 kg/m2.

was not different from that of general population in Taiwan ( pN0.10) (Table 1). 3.2. Factors associated with DM in schizophrenic patients The demographic and clinical characteristics of schizophrenic patients are shown in Table 2. Patients with DM were significantly older ( p=0.004) and had a longer duration of disease ( p=0.016) than those without DM, while BMI was not different between patients with and without DM. Being female ( p=0.023) and having a family history of diabetes ( p=0.002) were significantly associated with DM in schizophrenic patients, though no association was found between DM and obesity, or the types of antipsychotic they were using. The duration of antipsychotic usage was not included in the analysis because it was not available for some subjects. Based on the results of these preliminary findings, we performed a stepwise logistic regression to explore the

factors contributing to DM in schizophrenics after controlling other variables. The independent variables associated with DM were obesity ( p=0.009), family history of DM ( p=0.01) and duration of disease ( p=0.001) (Table 3).

4. Discussion 4.1. Prevalence of DM in schizophrenic patients Our study found the overall prevalence of DM was 9.8% in schizophrenics. It is close to the prevalence of DM in the study of Lamberti et al. (2003) (10.8%), but much lower than that in the study in Sernyak et al. (2002) (18.7%) and Subramaniam et al. (2003) (20.9%). Since old age has been recognized as a risk factor of DM, this discrepancy might reflect the different ages of the samples in the individual studies. Our sample has a mean age of 37.9 years. The mean ages of the samples in the study of Lamberti et al. (2003),

Table 3 Summary of the statistics for the best-fit logistic regression model applied to our dataa Variables Sex BMI Obesity Family history of DM Duration of disease Constant

B 0.669 0.132 2.152 1.546 0.076 3.551

S.E.

Wald

df

p

Exp(B)

0.501 0.080 0.829 0.598 0.024 0.621

1.787 2.721 6.731 6.681 10.326 32.661

1 1 1 1 1 1

0.181 0.099 0.009 0.010 0.001 0.000

0.512 0.876 8.601 4.694 1.079 0.029

B=coefficient; S.E.=standard error of B; Wald=Wald statistics; df=degree of freedom; p=significance level; Exp(B)=odds ratio. Omnibus Test of Model Coefficients: v 2 (5)=25.63, pb0.001. a In this analysis, the dependent variable was the occurrence of DM.

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Sernyak et al. (2002), and Subramaniam et al. (2003) are 42.1, 52, and 55.5 years, respectively. Although the prevalence rate in our study (9.8%) is not adjusted for age and sex, it is higher than that of the general population (7.8%) (Lu et al., 1998), which supports the results of previous reports showing DM is more prevalent in the schizophrenic population in diverse ethnic groups (Mukherjee et al., 1996; Dixon et al., 2000; Sernyak et al., 2002; Lamberti et al., 2003; Subramaniam et al., 2003; Taylor et al., 2003). Also, we found a significant higher prevalence of DM in younger schizophrenic patients (20–49 years) than in the reference population of the same age-group, but not in older schizophrenic patients (50–69 years) (Table 1). This finding is similar to the results of the study of Subramaniam et al. (2003), which was done in chronic schizophrenic patients in Singapore. They found a higher prevalence of DM in agegroups 30–39, 40–49, and 50–59, but lower in group 60–69, compared to the age-specific reference populations. These results suggest that, at least in Asian populations, having schizophrenia makes young people more vulnerable to DM, or it causes occult dysfunctional glucose metabolism to manifest at an earlier age. The results may also be explained by the selective mortality due to diabetes-related medical complications in older schizophrenic patients with DM.

Family history of DM was found to be a strong risk factor before and after controlling other variables. Being female was associated with DM in schizophrenics, but it was not an independent risk factor after controlling other variables. It can be explained by the high degree of correlation between sex and family history of DM, as well as BMI. We did not observe the association between atypical antipsychotics and DM in these patients. This association has been reported in many studies (Koller et al., 2001; Jin et al., 2002; Koller and Doraiswamy, 2002). Usage of clozapine and olanzapine posed a higher risk for DM than other atypical antipsychotics (Jin et al., 2004). Although the risk of atypical antipsychotics might not be large, there is a significant effect. Sernyak et al. (2002) found patients receiving atypical antipsychotics were only 9% more likely to have diabetes than those who received traditional antipsychotics from a database of almost 40,000 patients. The sample size is small in our study, so the power is not large enough to detect the difference. However, since we did not have baseline blood sugar data, we could not determine whether different antipsychotic medications were associated with new onset DM or the exacerbation of preexisting DM. 4.3. Limitations of this study

4.2. Risk factors associated with DM in schizophrenic patients Several risk factors of type 2 DM have been recognized: positive family history, non-Caucasian ethnicity, older age, obesity, low level of physical activity, hypertension, and dyslipidemia (American Diabetes Association, 2001). We examined the risk factors associated with DM in schizophrenic patients by comparing the characteristics between schizophrenic patients with and without DM. Schizophrenic patients with DM are significantly older and have a longer duration of disease than those without DM. Age is significantly correlated with duration of disease (Pearson correlation efficient=0.509, pb0.05). After controlling other variables, duration of disease (or age) is still an independent risk factor for DM in these patients. This is consistent with general risk factors for DM. Obesity, which causes insulin resistance, is a wellestablished risk factor for diabetes in the general population. However, the percentage of subjects with obesity or BMI was not different between DM and non-DM cases in our study, a finding similar to that reported by Subramaniam et al. (2003). Most of our and their patients had been residents in psychiatric hospitals for a long period, and their longterm use of antipsychotic medication, similar lifestyles and similar diets might obliterate the effect of adiposity on DM. However, in the analysis by logistic regression, obesity is still an independent risk factor of DM in schizophrenic patients, which indicates the effect of obesity on DM can be confounded by other variables, such as sex and age.

This study has certain limitations. First, it is a crosssectional study design, so the observed associations should not be interpreted as causal relations. Also, it lacks cholesterol and triglyceride data, thus limiting exploring the relation between hyperlipidemia and diabetes in schizophrenia. Moreover, insulin data is not available in our study, so it is hard for us to explore the pathophysiology of impaired glucose metabolism in these patients. The duration of antipsychotics use and hospitalization was not available for some patients, thus preventing our examining the relation among life style, medication and diabetes. Our sample is small and limited to institutional patients, hence the results cannot be generalized to schizophrenic patients in the greater population. Our results should therefore be interpreted carefully and should be confirmed by further large-scale, controlled studies.

5. Conclusions This study found an overall DM prevalence of 9.8% in schizophrenic patients. Compared to the general population, we found a higher prevalence rate of DM in younger schizophrenics, a group of people who could be easily neglected in medical efforts to prevent DM. Increased age, longer duration of disease, obesity, and a family history of diabetes were risk factors for diabetes in schizophrenia. When treating schizophrenic patients, especially those bearing these factors, physicians should be vigilant for

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early symptoms of DM and monitor blood sugar levels regularly.

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