Prevalence of metabolic syndrome in bipolar patients initiating acute-phase treatment: A 6-month follow up

Authors


Jinbei Zhang, BM, Department of Psychiatry, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China. Email: jinbeizhang@gmail.com

Abstract

Aims:  To evaluate the prevalence of metabolic syndrome (MetS) and its correlates in patients with bipolar disorder (BD) during acute-phase treatment in southern China.

Methods:  This study included 148 BD patients presenting with acute mood symptoms and 65 healthy controls at entry. Sociodemographic characteristics were noted for all participants. For patients, lifestyle information (alcohol, smoking, and exercise habits) and clinical characteristics were also collected. Patients were followed up for 6 months after the commencement of pharmacological treatment. Using the Chinese Medical Association Diabetes Branch criteria, MetS prevalence rates were calculated at entry and recalculated for patients at months 1, 3, and 6.

Results:  At baseline, MetS was presented in 11.5% of the patients; overweight, 34.5%; low high-density lipoprotein cholesterol, 15.5%; hypertriglyceridemia, 29.1%; hypertension, 14.9%; and hyperglycemia, 5.4%. Compared with controls, the patients had a significantly higher prevalence of MetS and all its components except for hyperglycemia (P < 0.05). In the regression analysis, history of hypertension, presence of diabetes, and alcohol drinking were associated with MetS. During the follow-up period, rates of MetS and overweight increased gradually and stably, hypertriglyceridemia and low high-density lipoprotein cholesterol increased significantly in the first month and then remained stable, and hypertension and hyperglycemia remained stable all the time.

Conclusions:  These data show that MetS is highly prevalent in Chinese BD patients. Weight gain and dyslipidemia result from a short period of treatment. Early interventions for weight gain and dyslipidemia are warranted.

METABOLIC SYNDROME (MetS) is comprised of dyslipidemia, hypertension, hyperglycemia, and abdominal obesity.1,2 Individuals with MetS are at high risk for developing cardiovascular diseases,2,3 type 2 diabetes,4,5 and stroke.6 In addition, MetS is associated with high premature mortality. In China, the prevalence of MetS is increasing rapidly and has become one of the important public health challenges.7–9

Bipolar disorder (BD) has been associated with a number of risk factors mediating the development of MetS, such as endocrine disturbances,10–13 deregulation of the sympathetic nervous system,14,15 unhealthy lifestyle patterns,16,17 and adverse metabolic effects of psychotropic medication.18,19 In BD patients, occurrence of MetS and subsequent cardiovascular disease often lead to poor treatment compliance and deteriorated mood symptoms. Therefore, in recent years, there has been a rising concern about the prevalence of MetS in BD patients and researches involving different ethnicities have been published. The prevalence rates of MetS in BD patients reported by different studies vary considerably by geographic area, ranging approximately from 20% to 50%. Two studies from the USA involving 171 and 98 BD patients found remarkably high rates of MetS of 30% and 49%, respectively,20,21 whereas studies carried out in European countries indicated lower rates of MetS: 21.5% in a group of Norwegian patients and 22.4% in a group of Spanish patients.22,23 However, reports on the prevalence of MetS in Chinese BD patients remain scant. Only a recent study conducted on 117 Taiwanese patients found an MetS rate of 33.9%.24

So far, the cause of MetS in BD patients remains unclear. Of the risk factors, psychotropic medications have been the major focus of most research work. Since the introduction of second-generation antipsychotics (SGA) into the treatment of BD, the correlation between SGA and weight gain and the subsequent risk for dyslipidemia and/or diabetes has been established in BD patients.25,26 In addition, lithium and valproate, the two most commonly used mood stabilizers in the treatment of BD, have been reported to show detrimental effects on bodyweight and blood lipid profile. A 6-year follow-up study showed that lithium used in long-term maintenance treatment was associated with increased bodyweight.27 A cross-sectional design study conducted on valproic acid-treated BD patients, drug-free BD patients, and healthy controls showed that valproic acid treatment for BD may increase the risk for metabolic disturbances.28 Furthermore, combination treatment with SGA and mood stabilizers can result in additional risk for weight gain and associated metabolic abnormalities in BD patients. A 1-month follow-up study conducted on BD patients at acute-phase treatment showed that patients prescribed with olanzapine plus valproate showed the largest increase in weight.29 However, how and to what extent a routine treatment would contribute to the increased prevalence of MetS in BD patients remain unknown.

Given that acute-phase treatment and subsequent maintenance treatment might exacerbate the metabolic disturbances, this 6-month follow-up study aimed to evaluate the prevalence rates and correlates of MetS in acute-phase BD patients under naturalistic clinical settings. Throughout this study period, MetS was defined using modified criteria by the Chinese Medical Association Diabetes Branch (CDS), which have been widely used by Chinese clinicians recently30 and will be described hereafter.

METHODS

This was a 6-month follow-up observational study conducted from January 2008 to September 2009. The study protocol was previously reviewed and approved by the ethics committee at the Third Affiliated Hospital of Sun-Yat Sen University. All participants provided written informed consent before participating in the study.

Subjects

The patient group consisted of 148 BD patients (104 BD type I, 44 BD type II) consecutively admitted to the psychiatric department in the Third Affiliated Hospital of Sun-Yat Sen University between January 2008 and January 2009. All patients were diagnosed according to the criteria of the DSM-IV by two experienced psychiatrists and were presenting with acutely exacerbated mood symptoms at entry because of discontinuation or irregularity of medication treatment for at least 3 months. Exclusion criteria were as follows: (i) younger than 18 years or older than 65 years; (ii) severe physical illness; (iii) organic mental diseases, mental retardation or dementia; (iv) pregnancy or lactation (for women patients); (v) substance abuse within past 3 months; and (vi) medication non-compliance (confirmed by guardians and treating psychiatrists during the follow-up period).

Sixty-five healthy control subjects from the Physical Examination Center in the same hospital were also enrolled for baseline comparison. Based on clinical interview, these control subjects satisfied the criteria of having no history of major mental health problems, mental retardation, or acquired brain injury. The exclusion criteria included pregnancy, lactation, active substance abuse, or refusal to provide written informed consent before participating in the study.

Assessments

At study entry, general sociodemographic information was collected for each participant. Symptom severity of each patient was assessed using the Hamilton Depression Scale (HAMD)31 and the Bech–Rafaelsen Mania Rating Scale (BRMS).32 During the study period, all treatment decisions or changes in treatment medications, such as dose reduction, dose augmentation, or switch strategies, were made by the patients and their treating psychiatrists together. For each patient, the frequently used treatment strategy was noted.

Body mass index was calculated as weight in kilograms divided by the square of the height in meters. Blood pressure was taken using an electronic sphygmomanometer after the participants had rested for at least 5 min. Vein blood samples were collected if participants confirmed fasting for at least 10 h. Patients were followed up for 6 months and had their weight, blood pressure and vein blood retaken at months 1, 3, and 6.

MetS was defined using the CDS criteria and required fulfillment of at least three of the following five components.

  • 1 Overweight: body mass index ≥ 25 kg/m2
  • 2 Hypertriglyceridemia: ≥1.70 mmol/L or being on  lipid-lowering medication
  • 3 Low high-density lipoprotein cholesterol (HDL-C):  <0.91 mmol/L (men) and <1.01 mmol/L (women)
  • 4 Hypertension: systolic pressure ≥140 mmHg and  diastolic pressure ≥90 mmHg or on antihyperten sive medication
  • 5 High fasting glucose: ≥6.1 mmol/L or being on  antidiabetic medication.

To examine which clinical and lifestyle-related factors would facilitate the treatment-emergent MetS in BD patients after the 6-month treatment, history for hypertension, hyperlipemia, or cardiovascular diseases and current treatments for diabetes were assessed by directly interviewing the patients and confirmed by looking at medical reports. Furthermore, a family history of mental disorder and MetS-related disease were noted in a direct interview. Lifestyles were also investigated at entry. Information about smoking (yes or no) and drinking habits were obtained by directly interviewing the patients or his/her legal guardian. Patients were considered to be alcohol users if they reported drinking alcohol twice a week or more often. The exercise habits were assessed by rating vigorous exercises (walking or engaging in other strength exercises for at least 20 min) into the following four categories: absent (0 times per week), mild (1–2 times per week), moderate (3–5 times per week), and intense (>5 times per week).

Statistical analysis

Participants' characteristics are summarized as mean and SD for continuous variables and frequency and percentage for categorical variables. The unpaired Student's t-test for continuous variables and the χ2-test for categorical variables were used to examine the difference between the two groups. Fisher's exact test was used for categorical variables if the expected cell size was less than 5. Risk for variables associated with the presence of MetS in BD patients was estimated using a stepwise logistic regression analysis with MetS as the dependent variable. To reduce the bias caused by the dropouts, the last observation carried forward33,34 method was used when the prevalence of MetS in the patient group was calculated at each visit. The adopted two-tailed level of significance was 0.05. All data were analyzed using the commercial statistical package spss 13.0 (spss, Chicago, IL, USA).

RESULTS

All participants completed the baseline assessments. Of 148 patients, 140 (94.6%) had their weight, blood pressure and vein blood retaken at month 1, 123 (83.1%) at month 3, and 113 (76.4%) at month 6. According to telephone interviews, there were two reasons for discontinuation. One was recovery determined by patients and their caregivers and subsequent refusal to continue the treatment (10 patients, 6.7%). The other was direct refusal to continue the study (25 patients, 16.9%).

The frequencies of current diagnosis in the patient group at entry were 69.6% in depression with a mean HAMD score of 29.45 (SD, 7.93), 18.2% in mania with a mean BRMS score of 18.52 (SD, 10.23), and 12.2% in mixed states with an HAMD score of 25.83 (SD, 8.6) and a mean BRMS score of 9.5 (SD, 5.4). The average duration of hospitalization was 21 days (SD, 11.5). These patients continued their maintenance treatment at the psychiatry outpatient clinic in our hospital. Of the 148 patients, 98 (66%) had been free of any psychotropic medications and 50 (34%) had taken the prescribed drugs irregularly for at least 3 months. Based on medical records of the 50 patients, divalproex, lithium, or one of the two mood stabilizers plus olanzapine or quetiapine were mostly used during the previous 3 months. The treatment duration every month ranged from 5 to 15 days.

The patient and control groups were matched for age, gender, and marital status (P = 0.823, 0.553, and 0.241, respectively). The occupational status was significantly different between these two groups (χ2 = 71.34; P < 0.001). Thirty-eight percent of our BD patients were students, 12.8% were housewives, and only 35.2% were employees. On the other hand, 81.9% of the controls were employees (Table 1).

Table 1.  Sociodemographic characteristics of patient group and control group
CharacteristicsPatient groupControl groupStatistics
n = 148n = 65t2P
  • χ2-test.

  • Student's t-test.

  • §

    § Fisher's exact test.

Sex, n (%)    
 Female78 (52.7%)31 (47.7%)0.4540.501
 Male70 (47.3%)34 (52.3%)
Age (years), mean ± SD30.93 ± 12.3630.65 ± 5.830.220.823
Marital status    
 Married68 (45.9%)33 (50.8%)0.4210.516
 Single80 (54.1%)32 (49.3%)
Occupational status, n (%)    
 Employee52 (35.2%)62 (81.9%)71.3480.000§
 Housewife19 (12.8%)1 (15%)
 Student56 (37.8%)2 (3.1)
 Retired11 (7.4%)0 (0%)
 Unemployed10 (6.8%)0 (0%)

The baseline prevalence of MetS in the patient group was 11.5%, and no significant difference was found between patients free of medication and those taking drugs irregularly (data not shown). Overweight was present in 34.5% of the patients; hypertriglyceridemia, 29.1%; low HDL-C, 15.5%; hypertension, 14.9%; and hyperglycemia, 5.4%. Compared with controls, the patients had sixfold higher prevalence rates of MetS (11.5% vs 1.6%). Except for hyperglycemia, the prevalence rates of all components of MetS in the patient group were significantly higher than those in the control group (P < 0.05). Overweight and hypertriglyceridemia were the top two metabolic abnormalities in both groups (Table 2).

Table 2.  Prevalence of metabolic syndrome and its components in patient group and control group at baseline assessment
CriterionPatient groupControl groupStatistics
n = 148n = 65χ2P
  1. BMI, body mass index; HDL-C, high-density lipoprotein cholesterol.

BMI > 2551 (34.5%)7 (10.8%)12.7920.0001
Triglycerides ≥1.70 mmol/L or being on lipid-lowering medication43 (29.1%)10 (15.4%)4.5150.039
HDL-C < 0.91 mmol/L (men) and <1.01 mmol/L (women)23 (15.5%)0 (0%)11.3240.0001
Blood pressure ≥140/90 mmHg or being on antihypertensive medication22 (14.9%)2 (3.1%)6.2770.010
Fasting glucose > 6.1 mmol/L or being on antidiabetic medication8 (5.4%)0 (0%)3.6510.110
At least three or more criteria17 (11.5%)1 (1.6%)5.7770.015

Throughout the follow-up period, the prevalence rate of MetS in the patient group increased from 11.5% to 20.9%; overweight, from 34.5% to 45.3%; hypertriglyceridemia, from 29.1% to 40.5%; low HDL-C, from 15.5% to 19.6%; and hypertension, from 14.9% to 16.2%. Hyperglycemia showed no change. With regard to the change patterns, the prevalence rates of MetS and overweight increased gradually and stably; hypertriglyceridemia and low HDL-C increased significantly in the first month and then remained stable; and hypertension and hyperglycemia remained stable all the time (Fig. 1).

Figure 1.

Prevalence of (a) metabolic syndrome (MetS) and (b) its components during the study period. (inline image) Low high-desnity lipoprotein cholesterol; (inline image) Hypertension; (inline image) High fasting glucose; (inline image) Hypertriglyceridemia; (inline image) Overweight.

Table 3 describes clinical, demographic and lifestyle correlates of MetS in the patients after 6 months of pharmacological treatment. The prevalence of MetS was not significantly different between sexes. Patients with MetS (35.65 ± 13.99) were significantly older than those without the syndrome (29.68 ± 11.64; t = 2.43; P = 0.016).

Table 3.  Characteristics of patients with and without metabolic syndrome (MetS) at the study endpoint
CharacteristicsWith MetSWithout MetSStatistics
n = 31n = 117t2P
  • Fisher's exact test.

  • Others, Lithium or Valproate + selective serotonin reuptake inhibitor or Lamotrigine + SGA; SGA, second-generation antipsychotics.

Age, mean (SD)35.65 ± 13.9929.68 ± 11.64t = 2.430.016
Sex, n (%)    
 Female14 (45.2%)64 (54.7%)χ2 = 0.890.421
 Male17 (54.8%)53 (45.3%)
Age at first onset, mean (years) (SD)30.90 ± 14.4625.12 ± 10.17t = 2.560.011
Duration of illness mean (years) (SD)4.74 ± 4.584.55 ± 5.53t = 0.1720.863
Duration of treatment mean (years) (SD)3.14 ± 3.042.56 ± 4.63t = 0.6600.512
History of hyperlipemia n (%)4 (12.9%)2 (1.7%)χ2 = 7.8950.018
History of coronary heart disease n (%)00  
History of hypertension n (%)4 (12.9%)2 (1.7%)χ2 = 7.8950.018
History/presence of diabetes n (%)5 (16.1%)3 (2.6%)χ2 = 8.8190.011
Family history of mental disorder3 (9.7%)27 (23.1%)χ2 = 2.7230.132
Family history of metabolic disease5 (16.1%)11 (9.4%)χ2 = 1.150.283
Smoking9 (29.0%)25 (21.4%)χ2 = 0.8140.367
Alcoholism7 (22.6%)6 (5.1%)χ2 = 9.3160.002
Frequency of physical exercise, n (%)    
 Absent17 (54.8%)58 (49.6%)χ2 = 0.3860.986
 Mild1 (3.2%)6 (5.1%)
 Moderate5 (16.1%)20 (17.1%)
 Intense8 (25.8%)33 (28.2%)
Medication combination frequently used    
 Lithium + SGA2 (6.5%)4 (3.4%)χ2 = 1.5480.691
 Valproate + SGA9 (29.0%)26 (22.2%)
 Lithium + Valproate + SGA7 (22.6%)26 (22.2%)
 Others13 (41.9%)61 (52.1%)

Patients with MetS had an older mean age at first onset (30.9 vs 25) than those without MetS (t = 2.56; P = 0.011). Significantly more patients with MetS had comorbidity for diabetes than patients without MetS (16.1% vs 2.6%; χ2 = 8.819, P = 0.011). MetS was significantly more prevalent in patients with a history of hyperlipemia or hypertension: 12.9% of patients with MetS had a history of hyperlipemia or hypertension versus 1.7% of those without (χ2 = 7.895; P = 0.018). Other clinical variables were not significantly associated with the presence of MetS.

Smoking and exercise habits were not different between patients with and those without MetS. Significantly more patients with MetS had a habit of alcohol drinking than patients without MetS (22.6% versus 5.1%; χ2 = 9.316; P = 0.002).

According to their medical records, combination treatments with mood stabilizers and SGA or selective serotonin reuptake inhibitor were used for these acute-phase patients. The antipsychotic use patterns in patients with and without MetS are also presented in Table 3. No statistically significant association between MetS and a specific treatment strategy was found in this study.

In the logistic stepwise regression analysis with MetS as the dependent variable and age, age at first onset, presence of diabetes, history of hypertension/hyperlipemia and habit of alcohol drinking as covariates, only a history of hypertension, presence of diabetes and alcohol drinking were significantly associated with MetS. Of the 131 patients without MetS before entering acute phase treatment, 19 patients had newly developed MetS at study endpoint. When only these patients were included in the logistic stepwise regression analysis, factors associated with MetS were history of hypertension and alcohol drinking.

DISCUSSION

To our knowledge, this is the first follow-up study in China to specially investigate the prevalence of metabolic abnormalities in a group of acute-phase BD patients using the CDS criteria. Because almost all previously reported MetS prevalence in the Chinese general population were based on either the National Cholesterol Educational Program Adult Treatment Program III criteria35 or the definition of the International Diabetes Federation (IDF), 36 we also enrolled a group of control subjects matched for age, gender and marital status from another department in the same hospital for comparison.

In the present study, the patient group had a significantly higher baseline prevalence of MetS, as well as most of its components, than the matched control group. Furthermore, the 11.5% prevalence rate in our patient group was definitely higher than the 6.8% prevalence rate in the general population from southern China, which was calculated according to the IDF criteria.36 The IDF criteria and our CDS criteria have been proven with good accordance.30 Thus, BD patients are at higher risk for MetS even when they are less exposed to psychotropic medication(s). Intriguingly, the baseline prevalence of MetS in our patient group is much lower than the 30.4% prevalence rates reported in another Asian group of acute-phase patients.37 Ethnicity, lifestyle, sample composition, and/or criteria used may account for the difference.

The baseline prevalence pattern of metabolic abnormalities in our patient group is quite different from that seen in a group of acute-phase BD patients from Korea. Our patient group had a much lower prevalence of MetS and its components than Korean patients. Overweight was the most common abnormality in our patients whereas hyperglycemia was the most common one in Korean patients.37 The difference in the extent of MetS prevalence may be due to sample composition, ethnicity, and criteria used. However, further work is needed to clarify which component is more associated with BD itself because both hyperglycemia and obesity could be manifestations of endocrine disturbances that most BD patients might endorse.

During the 6-month follow-up period, the prevalence rate of overweight kept increasing from 34.5% to 45.3%. Our result is partially consistent with a previous finding conducted on a group of Korean acute-phase BD patients, which found that BD patients showed weight gain even during a short period of acute treatment.29 However, the extent of increase of overweight prevalence in our study is much lower. Our data, as well as those from Korea, suggest that the propensity for weight change is different among patients in naturalistic clinical settings and inherent factors (such as genetic diathesis, depression, etc.) may contribute to the difference.

The similar change patterns of prevalence rates of hypertriglyceridemia and low HDL-C indicate that abnormalities in lipid profile are more likely to be induced in acute-phase treatment. Close monitoring of lipid profile and early intervention may help to decrease the MetS prevalence developed in acute and maintenance treatment.

Intriguingly, prevalence rates of hypertension and hyperglycemia remained stable throughout the follow-up period. This observation suggests that hypertension and hyperglycemia may not be attributed to psychotropic medication directly but to the development of overweight and dyslipidemia in BD patients.

In this study, BD patients with a history of hypertension or with diabetes had an increased risk for developing MetS. Hypertension and hyperglycemia are two classic features of MetS. Our data suggest that strategies to optimize medication algorithms should be incorporated in the treatment of these patients to prevent the development of MetS.

Alcohol drinking is associated with increased lipogenesis and decreased lipolysis in hepatocytes, eventually leading to fatty liver and dyslipidemia. In our study, alcohol seemed to facilitate treatment-emerged MetS in BD patients. Further work is needed to clarify the interaction between alcohol and psychotropic medication.

In the present study, we did not find a relation between the presence of MetS and a specific antipsychotic use pattern. Similar combination treatment strategies used for these acute-phase patients may contribute to this observation. It is necessary to carry out further investigations before drawing a conclusion for the polypharmacy effect on MetS.

Our study had some limitations. First, the follow-up period was relatively short as MetS is also associated with long-term pharmacological treatment. Second, selection bias is inevitable because our patients consisted mainly of those from southern China. Such a sample may not be representative for Chinese patients with BD in general.

In conclusion, our results show the high baseline prevalence of MetS in Chinese BD patients presenting with acute mood episodes. Close monitoring and early intervention, especially with regard to weight and blood lipid profile, would help decrease MetS prevalence in BD patients.

ACKNOWLEDGMENTS

This study was supported by the Science and Technology Plan Project (#2006B36008011) and the Medical Research Foundation of Guangdong Province (A2003219). The authors would like to gratefully acknowledge the contributions of all of the doctors, nurses, technicians, and patients that participated in this study. The authors declare no conflict of interest.

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