Schizophrenia patients at higher risk of diabetes, hypertension and hyperlipidemia: a population-based study

RE: Revision for Manuscript: SCHRES-D-10-00183R5

Title: Schizophrenia patients at higher risk of diabetes, hypertension and hyperlipidemia: a population-based study

Chun-Hui Liao

, Chen-Shu Chang

, Wang-Ching Wei

, Shih-Ni Chang

, Chien-Chang Liao

, Hsien-Yuan Lane

, Fung-Chang Sung

*

a

Department of Psychiatry, China Medical University and Hospital, Taichung 404, Taiwan

b

Department of Public Health, China Medical University and Hospital, Taichung 404, Taiwan

c

Department of Neurology, Changhua Christian Hospital, Changhua City 500, Taiwan

d

Management Office for Health Data, China Medical University and Hospital, Taichung 404, Taiwan

Running title: metabolic problems in schizophrenia patients

*Corresponding author:

Fung-Chang Sung, PH.D., M.P.H.

Professor and Dean

China Medical University College of Public Health 91 Hsueh-Shih Road

Taichung 404, Taiwan

Telephone: 886-4-2203-5740 Fax: 886-4-2201-9901

Email: fcsung@mail.cmu.edu.tw; fcsung1008@yahoo.com

Word Counts: 250 in abstract; 2770 in main text; 4 tables

ABSTRACT

Objective: This study investigates risks of developing diabetes mellitus (DM),

hypertension, and hyperlipidemia in treating schizophrenia with first- and

second-generation antipsychotics (FGA and SGA, respectively).

Methods: We established two study sets, each consisting of patients with

schizophrenia and without schizophrenia, from the insurance claims from 1997-2000.

Study set I had 1631 patients taking FGA and 6524 non-schizophrenia controls; the

other had 1,224 patients taking SGA and 4,896 controls. Controls were selected

frequency matched with sex, age and the index year. All subjects were free of the

studied metabolic disorders at the baseline. We measured incidences of these

disorders developed by the end of 2008 in each cohort and their respective hazard

ratios (HRs) for these disorders.

Results: Schizophrenics taking FGA were older than those taking SGA. In the Cox

models, significant adjusted HRs associated with SGA were 1.82 (95% confidence

interval (CI) 1.30-2.55) for DM and 1.41 (95% CI 1.09-1.83) for hyperlipidemia. For

those on the FGA, the risk was only significant in developing DM (HR 1.32, 95% CI

1.01-1.75). The age-specific antipsychotics-associated risks for metabolic disorders

were higher in young patients than in older patients particularly for hypertension; the

HRs in 10-19 years of age were 4.52 (95% CI 1.76-11.6) associated with FGA and

3.92 (95% CI 1.83-8.39) associated with SGA.

Conclusions: Patients with schizophrenia on SGA have higher risk of developing

metabolic disorders than those on FGA, reflecting that older patients have already

experienced the risk of developing these side-effects and were free of them at the

baseline.

Key words: antipsychotics, retrospective cohort study, metabolic abnormality,

schizophrenia

1. Introduction

Schizophrenia is a significant mental illness with prevalence rates ranging 1-17

per 1000 worldwide (Chien et al., 2009; Warner and de Girolamo, 1995). Patients

with the disease are at a higher risk of mortality, with a life expectancy approximately

20% shorter than the general population (Newman and Bland, 1991). Coronary artery

disease and other cardiovascular diseases are also the major disease associated with

schizophrenia (Brown, 1997; Hennekens et al., 2005). Individuals with schizophrenia

commonly require long-term antipsychotic treatment, and have an unhealthy lifestyle

with poor diet selection. These patients are at an elevated risk of weight gain, leading

to obesity and metabolic syndrome (Bobes et al., 2007; Cohn et al., 2004; De Hert et

al., 2006; Hagg et al., 2006; Huang et al. 2009; McEvoy et al., 2005; Suvisaari et al.,

2007). The prevalence of metabolic syndrome among patients with schizophrenia may

range from 24%-43% in males and 27%-52% in females. A recent population-based

period-prevalence study in Canada showed that patients with schizophrenia have an

elevated prevalence of diabetes mellitus (DM), hypertension, hyperlipidemia and

cardiovascular diseases (Bresee et al., 2010). Lin et al. (2008) even found that patients

with schizophrenia have a higher risk of stroke. Hypertension, DM and hyperlipdemia

are known risk factors of stroke. Chien et al. (2009) also found that the prevalence of

DM in patients with schizophrenia was around 7.90% in Taiwan. Central obesity,

hypertension, hyperglycemia and dyslipidemia are the core problems of metabolic

syndrome that contribute to the high prevalence of cardiovascular disease (Grundy et

al., 2004; Laaksonen et al., 2004; Mokdad et al., 2003).

The association between metabolic abnormalities and schizophrenia has reached

new developments in recent years after the use of second-generation antipsychotics

(SGA). Studies have suggested that the medication may contribute to metabolic

abnormalities, particularly the risk of diabetes (Hennekens et al., 2005; Newcommer,

2007; Scheen and De Hert, 2007; Tschoner et al., 2007). Two well-designed multi-city

clinical trials in adults (Lieberman et al., 2005) and youth (Sikich et al., 2008) with

schizophrenia revealed that olanzapine can most likely increase weight gain and

measures of other metabolic abnormalities. In a meta-analysis, Smith et al. (2008)

found that SGA are associated with slightly increased risk of diabetes, compared with

the first-generation antipsychotics (FGA). Most of these studies were limited by small

sample sizes. In a retrospective chart review study for patients with three-year

treatment exposure, De Hert et al. (2008) found a more than three-fold higher risk of

metabolism syndrome for patients started with SGA than those started with FGA.

Most studies appeared to lack of comparison with the general population in measuring

the effectiveness of medications and were limited by short follow-up time.

We conducted a 12-year follow-up, population-based cohort study to estimate the

risks of developing DM, hypertension and hyperlipidemia in schizophrenic patients

prescribed with FGA and SGA and compared them with their corresponding

non-schizophrenia controls. The results derived from this study can provide an

evidenced-based data plan for a more comprehensive approach in the long-term care

of schizophrenic patients taking into consideration the prevention of metabolic

syndrome and related cardiovascular diseases.

2. Methods

2.1. Databases of Taiwan National Health Insurance

This study used claims data of the National Health Insurance (NHI) obtained

from the National Health Research Institute (NHRI) in Taiwan from 1996 to 2008.

The Department of Health in Taiwan incorporated 13 insurance programs to launch

the universal NHI program in March 1995. This insurance program has covered 99%

of all 23 million citizens and contracted with 97% of hospitals and clinics in Taiwan

(Cheng 2009). The NHI program provides comprehensive medical services, including

outpatient and inpatient cares, Chinese medicine, dental care, childbirth, physical

therapy, preventive cares, home care, and rehabilitation for chronic mental illness.

Using the electronic claims database, the NHRI randomly selected from the insured

population to establish a representative reimbursement claims dataset of a sample of

one million insured persons in 2000. We were able to use scrambled patient

identifications to link files, including the information on patient gender, birth date,

and other demographic data. The scrambled identification system safeguards the

insured population against the violation of personal privacy and confidentiality. The

codes of health care received, codes of health care providers, and medical costs

covered by the insurance program were also available. The diagnoses were coded

using the International Classification of Diseases 9

Revision of the Clinical

Modification (ICD-9-CM).

2.2. Study samples

From the dataset, the claims data for 837,810 insured aged 10 years and above

defined in 1997 were extracted, approximately equivalent to 3.6% of all enrollees in

the insurance system. Based on this sub-dataset, patients with histories of DM

(ICD-9-CM codes 250), hypertension (ICD-9-CM codes 401-405) and/or

hyperlipidemia (ICD-9-CM codes 272.0-272.4) identified were excluded from the

study samples selection. Patients newly diagnosed with schizophrenia (ICD-9-CM

295) in 1997-2000 that were prescribed with FGA and SGA were identified and

defined separately as two treatment cohorts, the FGA cohort and SGA cohort,

respectively, in two study sets, set I and set II. For comparison, two cohorts of

non-schizophrenia controls were also established by random selection from the

insured population without the history of schizophrenia or other psychiatric illness.

These controls were frequency-matched with age, sex and index year of the cases in

the corresponding schizophrenia cohort, with a control sample size four-fold of the

corresponding schizophrenia cohort. Each study subject was followed until a

diagnosis of DM, hypertension or hyperlipidemia was made, or until the time the

subject was censored for loss to follow-up, death, or termination of insurance, or up to

31 December 2008, the end of the follow-up. We followed these cohorts as fixed

groups for this study. To ensure the validity of the diagnoses of the three major

follow-up outcomes, we identified the patients through both ICD-9-CM disease codes

and medications prescribed. Medications of FGAs and SGAs were listed in the

appendix.

2.3. Statistical analysis

Demographic factors, including age, sex, occupation, population density, and

income between each treatment cohort and the controls were compared. We

categorized the ages into four groups (10–19, 20–39, 40–59, and 60 or more years),

and occupations into three groups (white collar, blue collar and others). All the

insured were grouped into four-quartile groups from high to low based on the

population density in the areas the subjects lived. The subjects' incomes for insurance

premium estimation were classified into three groups with monthly pay of <15,000,

15,000–29,999, and >30,000 New Taiwan Dollars (1.0 USD is about 31-34 NTD).

The Chi-square test was used to examine the differences.

The sex-specific and age-specific incidence density rates of the studied disorders

were calculated for each cohort. The case cohort to the control cohort rate ratios with

95% confidence intervals (CI) were calculated by sex. Cox proportional hazard

regressions were used to measure the risk of developing DM, hypertension or

hyperlipidemia associated with schizophrenia for each study set. The hazard ratio (HR)

was presented with 95% CI, controlling for socio-demographic variables used for

adjustment in the multivariable Cox analyses. This study used the SAS statistical

package (SAS Institute Inc., Cary, NC. Version 9.1) to perform all analyses, with the

statistical adopted significance level at 0.05.

3. Results

Study set I consisted of 1631 newly diagnosed schizophrenia cases in the FGA

cohort and 6524 non-schizophrenia controls during the period of 1997-2001 (Table 1).

The corresponding sample sizes in study set II were 1,224 cases and 4,896 controls.

Cases in both schizophrenia cohorts had lower income, and higher un-employment,

low income and retired rates, and resided in less urbanized areas compared with the

respective controls. However, the two cohorts in study set I were older than the two

cohorts in study set II.

Table 2 shows that the incidence density rates of DM, hypertension and

hyperlipidemia by sex in study set II tended to be higher in the schizophrenia cohort

on SGA than in the non-schizophrenia controls. The incidence density rates of DM,

hypertension and hyperlipidemia were 1.90, 1.19 and 1.56 times higher in patients

taking SGA than in their corresponding controls, respectively. The incidence of DM

was the highest in the SGA cohort, followed by FGA cohort, control cohort I, and the

lowest in the control cohort II. The hierarchy was particularly true among female

subjects, with incidence density rates of 6.27, 5.40, 3.94 and 2.65 per 1,000

person-years, respectively. Comparing the incidences of DM, hypertension and

hyperlipidemia between the cohorts of study set I, only the incidence of

hyperlipidemia in females was significantly higher in the FGA cohort than in the

controls.

Table 3 presents the age-specific HRs of DM, hypertension and hyperlipidemia

associated with schizophrenia controlling for the socio-demographic variables. The

results indicate that younger schizophrenic patients had higher risk of developing DM

and hypertension for both study sets, and develpoing hyperlipidemia for study set II.

The HR of developing hypertension in teens with schizophrenia was even greater for

those taking FGA (HR 4.52, 95% CI 1.76-11.6) than for SGA (HR 3.92, 95% CI

1.83-8.39).

Table 4 shows that, in the multivariable Cox proportional hazard analyses,

schizophrenic patients taking FGA had a significant association with developing

diabetes (HR 1.32, 95% CI 1.01-1.755). The effects seemed greater with patients

taking SGA for developing DM (HR 1.82, 95% CI 1.30-2.55), hypertension (HR 1.14,

(95% CI 0.97-1.34), and hyperlipidemia (HR 1.41, 95% CI 1.09-1.83). The over all

risks of developing DM, hypertension and hyperlipidemia increased with age (p for

trend < 0.0001). There were strong relationships among these three disorders.

4. Discussion

Schizophrenia has been associated with metabolic abnormalities such as DM.

Previous prevalence studies estimated the ratios of DM among those with

schizophrenia to be 1.5 to 2-fold higher than in the general population (Bresee et al.,

2010; Chien et al., 2009; Mukherjee et al., 1996). Factors associated with the

increased incidence of diabetes among schizophrenic patients are obesity, genetic

factors, lifestyle factors, and medication effects (Dixon et al., 2000; Mukherjee et al.,

1989; Thakore et al., 2002). Although the study design could not control and adjust all

these potential confounding factors, we also found that the occurrence of DM is

higher among schizophrenic patients than those without schizophrenia, from our

insurance claims data. The schizophrenia association is stronger for DM than for

hypertension and hyperlipidemia. Antipsychotics are associated with the increased

risk for metabolic abnormalities.

This is the first nature course study using a population-based retrospective cohort

design to measure the risk of metabolic abnormalities in schizophrenic patients

between taking typical and atypical antipsychotics, using the general population as

controls. The major findings in our present study indicate that, compared with the

non-schizophrenia controls, schizophrenic patients prescribed with SGA had a higher

risk of developing DM, hypertension, and hyperlipidemia after adjusting for

demographic factors and comorbidities. We further analyzed whether schizophrenic

patients prescribed with FGA also had higher risks for these effects. Interestingly,

schizophrenic patients taking FGA were older, with 12.5% of patients aged 60 and

above; whereas only 3.1% of patients prescribed with the SGA were aged 60 and

above. This is why the incidence rates of hypertension were higher in the study set I

cohorts than in the study set II cohorts. Additional analysis was focused on comparing

the incidence of developing DM, hypertension, and hyperlipidemia for patients taking

specific SGA. Most patients (as high as 65.3%) were prescribed with risperidone (data

not shown). However, quetiapine had higher risk than risperidone associated with

developing DM (9.3 vs. 5.7 per 1000 person-years), hypertension (23.6 vs. 17.4 per

1000 person-years) and hyperlipidemia (9.0 vs. 6.9 per 1000 person-years). Clozapine

also had high risk in association with DM (6.8 per 1000 person-years) and

hyperlipidemia (14.2 per 1000 person-years).

Studies have also found a higher prevalence of hypertension in schizophrenic

patients than in controls (Dixon et al., 1999; Nasrallah et al., 2006; Osborn et al.,

2008). This study found a moderate risk of developing hypertension in schizophrenic

patients after adjusting for socioeconomic status and comorbidities. Our definition of

hypertension developed in the follow-up period was based on the antihypertensive

drug therapy and treatment for hypertension in patients with schizophrenia. The

hypertension risk might be underestimated. Schizophrenia-related hypertension has

been associated with body weight gain and metabolic syndrome because of the

sedentary life style in patients. (Goff et al., 2005; Nasrallah et al., 2006; Susce et al.

2005).

Our study also showed a higher risk of developing hyperlipidemia associated

with schizophrenia. Obesity in people with an unhealthy lifestyle with reduced

physical activity and poor diet selection is more common in schizophrenic patients

than in the general population, and this could also be related with hyperlipidemia.

Studies on both adults and children have indicated the important role of antipsychotics

in the risk for obesity and DM in schizophrenic patients (Hennekens et al., 2005;

Newcommer, 2007; Scheen and De Hert, 2007; Tschoner et al., 2007) The findings

could be underestimated because of inequalities in recognizing and managing

cholesterol in schizophrenic patients (Hippisley-Cox et al., 2007).

Sex and age differences associated with schizophrenia and the risk of DM,

hypertension and hyperlipidemia deserve attention. Previous studies have found

women with schizophrenia are at a higher risk for metabolic syndrome (Pilote et al.,

2007; Saari et al., 2005; Suvisaari et al., 2007). We also found in the sex-specific

analysis that the schizophrenia cohort of SGA are at a greater risk than the

non-schizophrenia controls for these three disorders. The incident DM was even

greater for females than for males (6.29 vs. 4.32 per 1,000 person-years) in the

schizophrenia cohort taking SGA. On the other hand, in the SGA cohort, males were

at a slightly greater risk than females in developing hypertension and hyperlipidemia.

Since our findings were from an observational study and limited by some unavailable

data, further studies are needed to examine the sex-specific issues in schizophrenic

patients.

Obesity and older age are highly related to DM, hypertension and hyperlipidemia,

(Flegal et al., 2002). However, studies regarding schizophrenia with age-specific

analysis found that younger patients had higher incidences of developing these

metabolic comorbidities (Kato et al., 2005; Suvisaari et al., 2007). Bresee et al. (2010)

also found that the adjusted risk of DM in schizophrenic patients was greater in

women than in men for all age groups, with the greatest risk in women ages 20-29

(aOR 2.49; 95% CI: 1.78–3.49). Our age-specific analysis also demonstrated, the

hazards of developing DM and hypertension or hyperlipidemia in schizophrenic

patients taking either FGA or SGA were significantly elevated in the 20-39 year old

group, but not in the older age group. The patients on FGA aged 10-19 had the highest

risk of developing hypertension among all age groups in this study. Our findings

reflect the greater vulnerability of younger patients in developing DM, hypertension

and hyperlipidemia. Patients on FGA in the oldest group had a 33% less risk

compared with their controls. It is likely that the older patients have already gone

through the age of developing these metabolic disorders and free of them at the

baseline. The elevated risk for younger patients and the protective effect of age

deserve further investigation.

The longitudinal design is the strength of the present study, which aims to

evaluate the relationship between schizophrenia with antipsychotics and DM,

hypertension, and hyperlipidemia using population-based data. The technique to

define both exposure and outcomes by using medication prescriptions, instead of only

clinical diagnoses, is the other strength. We only included patients who have received

the FGA or SGA therapy in the two schizophrenia cohorts. The sample size and the

power for measuring the risk of DM, hypertension and hyperlipidemia were

accordingly reduced. However, we were still able to observe the effects of

schizophrenia associated with developing the three disorders. Another limitation of

this study is that we were unable to measure the lifestyle association with the outcome

because the information was unavailable in the claims data. However, we were able to

use socio-demographic factors to control for as major covariates in the risk

estimation.

5. Conclusions

This population-based study demonstrates that patients taking antipsychotics

have an elevated risk of developing DM, hypertension and hyperlipidemia. These

three disorders may occur among patients early in the life, indicating impact of

schizophrenia is greater for younger patients than for older patients. In our study, the

selected samples were newly diagnosed and under medication with antipsychotics.

Risk estimations directed at the effects of medications in relation to sex and age are of

particularly important. Results derived from this study are of potential value in

planning comprehensive care plans for schizophrenic patients who are more

susceptible to developing hypertension and metabolic disorders leading to

cardiovascular disorders. In addition to pharmacotherapy, providing patients with

psychological intervention and family interventions to establish a healthy life style is

necessary.

Appendix. Antipsychotics are available for patients in the National Health

Insurance program of Taiwan

First-generation antipsychotics:

Haloperidol, Flupentixol, Sulpiride, Chlorpromazine, trifluoperazine, Thioridazine

HCl, Chloroprothixene HCl, Thiothixene, Clothiapine, Loxapine, Droperidol, and

Pimozide.

Second-generation antipsychotics :

Aripiprazole, Paliperidone

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