Ichiro Kusumi, MD, PhD, Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo 060-8638, Japan. Email: email@example.com
Aim: The Japanese blood glucose monitoring guidance for patients receiving second-generation antipsychotics has been newly developed. We aimed to report a cross-sectional study using the baseline data of the Japanese monitoring guidance to find undiagnosed hyperglycemia systematically as a routine clinical practice and to quantify the frequency of glucose abnormalities in schizophrenia patients treated with second-generation antipsychotics.
Methods: Data for 537 patients with schizophrenia, who had not been diagnosed as having diabetes prior to baseline screening and started the monitoring between June 2008 and January 2009, were collected from medical records in 25 hospitals. Blood glucose (fasting or casual), hemoglobinA1c, serum lipids, height/weight, clinical diabetic symptoms, and family history of diabetes were assessed. Patients were classified into normal, pre-diabetic or probable diabetic type based on their values of blood glucose or hemoglobinA1c, and various background characteristics and serum lipid values were compared among the three types.
Results: Out of 537 patients, 13 (2.4%) met criteria for probable diabetic type, 51 (9.5%) for pre-diabetic type, and 473 (88.1%) for normal type. Individuals categorized as probable diabetic type had a higher body mass index and higher frequency of family history of diabetes mellitus than those with normal type.
Conclusion: Glucose abnormalities were newly detected in 11.9% of schizophrenia patients treated with second-generation antipsychotics by the baseline monitoring. To assess the detective power and usefulness of the guidance, longitudinal investigations are necessary.
SECOND-GENERATION ANTIPSYCHOTICS (SGA) have provided a clear benefit for many patients with schizophrenia in part due to their reduced propensity to cause extrapyramidal side-effects often associated with first-generation antipsychotics (FGA).1 However, SGA can induce substantial weight gain in vulnerable individuals,1,2 and these agents have been associated with an increased risk for dyslipidemia and type 2 diabetes mellitus.3 The development of diabetes mellitus within an individual schizophrenia patient can depend on the contribution of drug effects as well as the contribution of individual host factors, such as family history, the disease itself, sedentary lifestyle and unhealthy dietary habits.3 A meta-analysis comparing diabetes risk for different antipsychotics in people with schizophrenia indicated that SGA are associated with increased risk for diabetes compared with FGA.4 The potential correlations between some SGA and both obesity and diabetes is of considerable clinical concern because obesity and diabetes are important risk factors for cardiovascular disease (CVD), and the relative risk of CVD mortality is significantly greater in people with psychiatric disorders than in the general population.5 Accordingly, the US Food and Drug Administration (FDA) proposed the inclusion of the following statement in the package insert of all atypical antipsychotic drugs: ‘Patients starting on these drugs who have diabetes risk factors, such as obesity or a family history of diabetes, should have fasting blood glucose testing at the start of treatment and periodically thereafter.’6 In Japan, olanzapine and quetiapine became contraindicated in patients with diabetes mellitus or a history of diabetes mellitus after the emergency safety information (the ‘Dear Doctor’ letter) was issued in 2002,7,8 and it is instructed that other SGA should be used with caution in diabetic patients as well as in those with diabetic risk factors.9
Therefore, patients treated with SGA should receive appropriate baseline screening and ongoing monitoring to avoid cardiovascular risk factors, including obesity and diabetes, and to extend the longevity. There have been several international reviews and guidelines published to prevent metabolic adverse reactions to SGA. In Japan, four experts on psychopharmacology and diabetes mellitus recently proposed a monitoring guidance for blood glucose in patients treated with SGA based on the review of consensus guidelines5,10,11 and articles,12–18 the characteristics of Japanese patients, and the healthcare environment in Japan.19
In this study, we conducted a cross-sectional study using a baseline data of the Japanese blood glucose monitoring guidance in order to find undiagnosed hyperglycemia systematically as a routine clinical practice in schizophrenia patients treated with SGA and to clarify the metabolic profiles of those patients.
This cross-sectional study was achieved using the baseline data for patients who began to receive the Japanese monitoring guidance for blood glucose during June 2008 and January 2009. Subjects were primarily diagnosed with schizophrenia based on ICD-10 criteria, treated with at least one of the following SGA at entry as clozapine (under clinical trial for approval), risperidone, perospirone, olanzapine, quetiapine, aripiprazole and blonanserin. Participants included both in- and outpatients who started to receive a new SGA or were receiving some SGA at baseline monitoring. Individuals who had been diagnosed with diabetes mellitus by internists or received diabetes treatments prior to baseline screening, and who had seclusion or physical restraint episodes during baseline monitoring, were excluded. Selection of participants was conveniently, not consecutively achieved on each site. Data were collected from medical records that the collaborating investigators gained in usual clinical settings as far as possible. The study was conducted in the Department of Psychiatry, Hokkaido University Hospital, and at 24 associated hospitals (nine public general hospitals and 15 private psychiatric hospitals) in the Hokkaido district. The study was approved by the institutional review board of Hokkaido University Hospital.
Baseline measurements consisted of blood glucose (fasting or casual) or hemoglobinA1c (HbA1c), serum lipids (total and high-density lipoprotein [HDL] cholesterol, triglycerides), height/weight for body mass index (BMI), clinical diabetic symptoms, and personal/family history of diabetes. According to the Japanese monitoring guidance, patients were classified into normal type, pre-diabetic type or probable diabetic type (Fig. 1). If a patient had two or three blood glucose measurements (e.g. fasting blood glucose and HbA1c) at one visit, he/she was categorized as a type based on the worst result. We compared various background characteristics and serum lipid values among the three types based on blood glucose measurement.
Values are expressed as means ± SD. In this study, HbA1c is expressed as the National Glycohemoglobin Standardization Program (NGSP) value instead of the Japan Diabetes Society (JDS) value. The correlation between the values is as follows: NGSP value = JDS value + 0.4.20anova was used to compare the three classified types for the following variables: age, total or HDL cholesterol, number of clinical signs for diabetes, and number of antipsychotics. The Wilcoxon/Kruskal–Wallis test was utilized for BMI and triglycerides. All post hoc comparisons were Bonferroni corrected. Categorical demographic variables were compared among groups using the χ2-test, and included sex and family history of diabetes. Significance was defined as P < 0.05/2 = 0.025.
Figure 2 illustrates the process of subject selection. A total of 555 schizophrenia patients treated with SGA were selected, who began to receive the Japanese blood glucose monitoring guidance during the study period. Eighteen patients were excluded because of being diagnosed as having diabetes or receiving diabetes treatment. In total, 537 patients (249 male and 288 female), including 291 inpatients and 246 outpatients, remained for analysis. The mean age of patients was 48.3 (±16.0) years, and they had been ill for a mean of 22.1 (±15.0) years. The frequency of patients with a family history of diabetes was 11.5%. Patients received a mean of 1.7 (±0.9) antipsychotics, including FGA. The number of patients receiving each SGA at baseline, including polypharmacy, is shown in Table 1. Coadministration of additional antipsychotics was not excluded.
Only half of the patients had a normal BMI (51.0%), and 33.6% of the patients were overweight (BMI > 25). The mean BMI was 23.3 (±4.4). Lipid abnormalities were also prevalent: 19.0% of patients had elevated total cholesterol (>220 mg dL−1), 22.0% had elevated triglycerides (>150 mg dL−1) and 17.8% had low HDL cholesterol (<40 mg dL−1). Clinical diabetic symptoms, such as dry mouth, polyposia, massive consumption of soft drinks, polyuria, and pollakiuria, were present in 16.6% of patients.
In the total sample, 473 (88.1%) were classified into normal type, 51 (9.5%) into pre-diabetic type, and 13 (2.4%) into probable diabetic type (Fig. 2). Glucose abnormality (pre-diabetic and probable diabetic type) was newly detected in 64 patients (11.9%). Demographic and clinical characteristics in the three classified types are shown in Table 2. Both BMI and the frequency of family history of diabetes were significantly higher in the probable diabetic type than in the normal type [χ2 = 8.64, d.f. = 2, P = 0.013 for BMI; χ2 = 12.7, d.f. = 4, P = 0.013 for the frequency of family history of diabetes]. Age was also significantly higher in the pre-diabetic type than in the normal type [F(2,534) = 6.09, P = 0.0024], but there was no significant difference between probable diabetic type and normal type. Triglycerides were numerically higher in the probable diabetic and pre-diabetic type than in the normal type, but this was not statistically significant [χ2 = 5.49, d.f. = 2, P = 0.064]. There were no significant differences in total or HDL cholesterol, or the numbers of clinical diabetic symptoms or antipsychotics among the three types [F(2,524) = 0.80, P = 0.92 for total cholesterol; F(2,464) = 0.70, P = 0.50 for HDL cholesterol; F(2,527) = 0.46, P = 0.63 for the number of clinical diabetic symptoms; F(2,533) = 1.35, P = 0.26 for the number of antipsychotics].
Table 2. Patient background characteristics in the classified type
type (n = 473)
type (n = 51)
type (n = 13)
P < 0.005,
P < 0.025 vs Normal.
Case number obtained data in parenthesis.
BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; HDL, high-density lipoprotein.
A cross-sectional study using the baseline data of the Japanese blood glucose monitoring guidance for 537 patients at multi-local sites showed that the probable diabetic type was present at 2.4% (n = 13) and the pre-diabetic type at 9.5% (n = 51) in schizophrenia patients receiving SGA. One must take into account that all patients in this study had never been diagnosed with diabetes prior to baseline screening, so cases classified as having the probable diabetic type were newly detected. Strictly speaking, it is unclear whether patients classified as probable diabetic type actually have diabetes mellitus, but if these patients are assumed to have the disease, 2.4% met criteria for diabetes. This result is much lower than the data from another Japanese cross-sectional study by Okumura et al.,21 suggesting that the overall prevalence of diabetes was 8.6% in schizophrenia patients treated with SGA (72%) and FGA (28%). In their study, however, definition of diabetes was not based on clinical measurements, such as plasma glucose and HbA1c, but on doctor diagnosis of diabetes. On the other hand, using an oral glucose tolerance test, van Winkel et al.22 showed a mean annual incidence of diabetes of 3.15% in schizophrenia patients treated with antipsychotics (90% SGA and 10% FGA), although the test is probably not a realistic method for screening patients with schizophrenia in mental health-care settings.
In the comparison of background characteristics, such as age, family history of diabetes mellitus and BMI among the three types, the BMI values for the probable diabetic type were significantly higher than those for the normal type. Several studies on general populations indicate that obesity is a critical risk factor for glucose abnormality,3 thus it is also important to monitor and manage obesity in patients treated with SGA. The percentage of patients with a family history of diabetes mellitus was also significantly higher for the probable diabetic type than the normal type. Regarding serum lipid values among patients within the three classified types, there were no differences in total or HDL cholesterol. Although no statistical significance was found, serum triglyceride levels were numerically higher in pre-diabetic and probable diabetic types than in the normal type. It has been suggested that elevated triglyceride levels appear to precipitate or exacerbate diabetes.23 Our present findings suggest the same possibility as in general populations that increased triglyceride levels may be a warning for developing diabetes as well as other risk factors, such as higher age, increased bodyweight, and family history of diabetes. As lipid dysregulation during treatment of schizophrenia is not a class effect of all atypical antipsychotic drugs,24 psychiatrists should appropriately integrate plans for regularly monitoring both lipid and glucose levels to avoid the morbidity and mortality associated with CVD. Recently, Sugawara et al.25 reported that patients with schizophrenia or schizoaffective disorder in Japan had high prevalence of metabolic syndrome compared to the general population. Therefore, metabolic syndrome in schizophrenia patients should be carefully monitored to minimize the risks. On the other hand, the number of clinical signs for diabetes did not differ among the three types, which suggests that subjective signs and symptoms for diabetes are frequently challenging to disentangle from adverse effects of antipsychotic medication.
This is the first cross-sectional study using a baseline data of the Japanese monitoring guidance for blood glucose in patients treated with SGA. Clearly, schizophrenia patients treated with SGA should be considered at very high risk of developing diabetes, therefore the use of a monitoring guidance for blood glucose should be encouraged in this high-risk population. Moreover, this kind of screening instrument should be routine clinical practice in all psychiatric settings. A retrospective cohort study using data from a large managed care database in the USA26 suggests that baseline glucose monitoring in patients treated with SGA remains low (21.8%), even after the American Diabetic Association guidelines5 were issued. Twelve-week glucose testing was lower (17.9%) than baseline testing. Thus, further investigations are necessary to achieve the monitoring guidelines, such as 6-month and 12-month follow up, after baseline measurement as outlined in the Japanese monitoring guidance for blood glucose. Upon 1-year follow up, it will be noteworthy to detect how many patients progress from normal type to pre-diabetic type or from pre-diabetic type to probable diabetic type.
This study has some limitations. First, the data were collected from medical records that the collaborating investigators obtained in routine clinical settings, which might impact the results. There were many missing data in this study, which should result in a lower detection rate of diabetes in the schizophrenia patients treated with SGA. Second, the data were not consecutively collected at multiple sites located in the Hokkaido district, thus we did not correctly determine the prevalence of diabetes in schizophrenia patients receiving SGA in Japan. Third, baseline data of the Japanese monitoring guidance for blood glucose should be obtained when some SGA are newly started, but in this study all data were not necessarily so. Moreover, the duration of treatment with SGA until blood examination and the dose of antipsychotics were not checked. Fourth, the number of patients who refused to be monitored using this guidance is not known. Fifth, it is possible that other psychotropics, such as valproate or antidepressants, may affect the results. In this study, co-administered drugs besides antipsychotics were not checked. Sixth, this study failed to compare with the results in schizophrenia patients treated with FGA. A meta-analysis of Leucht et al.1 indicated that weight gains induced by SGA and low-potency FGA were not significantly different in schizophrenia patients. Thus, it should be necessary to use a monitoring guidance for blood glucose in schizophrenia patients treated with not only SGA but also FGA. Finally, lack of other cardiovascular risk factors, such as hypertension and smoking, may be another limitation in order to avoid cardiovascular or cerebrovascular diseases and to extend the longevity in schizophrenia patients. Given these possible sources of bias, the results need to be interpreted with caution.
In conclusion, the cross-sectional study using a baseline data of the Japanese monitoring guidance suggests that glucose abnormalities were newly detected in 11.9% of schizophrenia patients treated with SGA by the baseline monitoring. To assess the detective power and usefulness of the guidance, longitudinal investigations are necessary.
The authors would like to express appreciation to the collaborating investigators as follows: Ishikane T, Inoue S, Kohsaka M, Mieda H, Honda R at Ishikane Hospital, Sapporo; Kurokawa Y at the Department of Psychiatry, Iwamizawa Municipal General Hospital, Iwamizawa; Tsuchida S, Iwata Y at Kutchan-Kosei General Hospital, Kutchan; Oka I at Keiseikai Hospital, Sapporo; Mizuno O at Obara Hospital, Sapporo; Suzuki T, Shinohara K, Kakegawa Y at Sapporo Suzuki Hospital, Sapporo; Matsubara R at Sapporo Hanazono Hospital, Sapporo; Sugawara Y, Sugawara M, Chiba Y, Mitsuda T at San-ai Hospital, Noboribetsu: Yamada J, Shinya M, Morita N at Kei-ai Hospital, Noboribetsu; Kameyama R, Sasagawa Y, Takamaru Y, Chiaki T, Yamanaka H at the Department of Psychiatry, Otaru Municipal Second Hospital, Otaru; Nakajo T, Niwa Y, Miyaji T at the Department of Psychiatry, Kushiro City General Hospital, Kushiro; Kawai T, Sugiyama S, Noguchi M, Yasuda M, Yamamoto S at the Department of Psychiatry, Sapporo City General Hospital, Sapporo; Shimizu Y, Takada H, Hoshika T, Honma J, Mito N at the Department of Psychiatry, Muroran General Hospital, Muroran; Iwata K, Kitaichi Y at the Department of Psychiatry, Wakkanai City Hospital, Wakkanai; Miyamoto K, Ikeda T at Soen Hospital, Sapporo; Kaji N, Fujiwara Y at the Department of Psychiatry, Takikawa Municipal Hospital, Takikawa; Sawayama H, Oshibe H at Teine Hospital, Sapporo; Okazaki D, Jin K, Takeshige H, Hirota M at Hokkaido Koyogaoka Hospital, Abashiri; Takeuchi T, Tsuchiya K, Tochigi A at Midorigaoka Hospital, Tomakomai; Ishizaki T, Kudo S, Nakae S, Nakayama M, Nitta I, Watanabe S, Utsui H at Nakae Hospital, Sapporo; Ito Y, Sato M, Takada K, Tsukamoto N at Watanabe Hospital, Hakodate; Niide Y, Nakajima Y at the Department of Psychiatry, Yakumo General Hospital, Yakumo; Sasaki K, Yamada K at Honda Memorial Hospital, Eniwa; Inoue T, Kako Y, Kitagawa N, Tanaka T, Nakato Y, Fujii Y at the Department of Psychiatry, Hokkaido University Hospital, Sapporo.
The authors have no direct financial support relevant to this study. Dr Kusumi receives honoraria from Astellas and Eli Lilly, and is an advisory board member of Dainippon Sumitomo Pharma. Dr Kadowaki is a consultant of Eli Lilly. Dr Koyama receives honoraria from Astellas and Eli Lilly, and a research grant from Dainippon Sumitomo Pharma and Astellas. The other authors declare that they have no conflict of interest.