Endogenous and Antipsychotic-Related Risks for Diabetes Mellitus in Young People With Schizophrenia: A Danish Population-Based Cohort Study
Publication: American Journal of Psychiatry
Abstract
Objective:
Diabetes mellitus contributes to excessive cardiovascular deaths and reduced life expectancy in schizophrenia. This population-based cohort study investigated the endogenous risk for diabetes in antipsychotic-naive schizophrenia and evaluated the risks added by starting antipsychotic treatment in people with schizophrenia.
Method:
The study followed all people born in Denmark on or after Jan. 1, 1977, until Jan. 1, 2013 (N=2,736,510). The Danish Psychiatric Central Research Register ascertained schizophrenia diagnoses. The Danish National Prescription Registry provided data on prescriptions of antipsychotics. Diabetes was ascertained from the Danish National Patient Register and Danish National Prescription Registry. The authors estimated the endogenous and antipsychotic-related risks for diabetes by using Cox proportional hazards regression models, while accounting for potential confounders.
Results:
Of the cohort members, 14,118 (0.52%) developed diabetes, and 8,945 (0.33%) developed schizophrenia during follow-up (49,582,279 person-years). The adjusted hazard ratio for diabetes was 3.07 (95% confidence interval [CI], 1.71–5.41) in antipsychotic-naive schizophrenia compared with the general population. The risk for diabetes after starting antipsychotic treatment was significantly higher (adjusted hazard ratio, 3.64; 95% CI, 1.95–6.82) than the risk in antipsychotic-naive schizophrenia, after adjustment for family history of diabetes and other potential confounders. First-line treatment with either first-generation antipsychotics (adjusted hazard ratio, 3.06; 95% CI, 1.32–7.05) or second-generation antipsychotics (adjusted hazard ratio, 3.44; 95% CI, 1.73–6.83) increased the risk for diabetes without a statistically significant difference. Appropriate sensitivity analyses limited to type 2 diabetes corroborated these results.
Conclusions:
Schizophrenia confers a high endogenous risk for diabetes, and the risk is further increased by both first-generation and second-generation antipsychotics. Early detection and effective treatment of diabetes should be an integral part of multidisciplinary management of schizophrenia regardless of antipsychotic drug exposure.
The prevalence of diabetes mellitus is four to five times higher among people with schizophrenia than in the general population (1). Those who suffer from both diabetes and schizophrenia have a three- to fourfold higher overall mortality rate than the general population, and at least one-third of those deaths can be attributed to diabetes (2). Diabetes contributes to excessive cardiovascular deaths and more than 20 years of reduced life expectancy in people with schizophrenia (3, 4). Young people with schizophrenia, age less than 40 years, are at high risk (5) for early-onset type 2 diabetes, which is a rapidly progressing severe disease subtype with increased risks for microvascular and macrovascular complications (4, 6–8).
Studies from the preneuroleptic era (9) have reported an increased prevalence of diabetes, impaired glucose tolerance, and increased insulin resistance in people with schizophrenia (10–12). Abnormal glucose tolerance is more prevalent in antipsychotic-naive people with schizophrenia than among healthy controls, and this association is independent of the effects of body mass index and of poor health habits (13–15). Moreover, increased prevalence of diabetes among the first-degree relatives of people with schizophrenia indicates a potential genetic link between schizophrenia and diabetes (16, 17). TCF7L2 and IGF2BP2, two of the most replicated susceptibility genes for type 2 diabetes, have been associated with schizophrenia (18–20). Furthermore, linkage studies, genetic association studies, and pathway analyses have supported shared genetic risks in these two disorders (21–23).
As soon as chlorpromazine was introduced in 1952, there were several reports of its association with diabetes and impaired glucose tolerance (10). Since the introduction of second-generation antipsychotic drugs, their association with diabetes has been investigated more systematically (24–28). A meta-analysis, not including data on aripiprazole, ziprasidone, and amisulpride, indicated that second-generation antipsychotics confer more risk for diabetes in schizophrenia than do first-generation antipsychotic drugs (29). However, a longitudinal study showed that both second-generation and first-generation antipsychotics increase the risk for diabetes and that second-generation antipsychotics, as a class, confer significantly less risk for incident diabetes than first-generation antipsychotics (30). Individual first-generation and second-generation antipsychotics may differ widely in their risks for diabetes (30–32). Clozapine may confer higher risk for diabetes than other second-generation antipsychotics (31, 33). A recent meta-analysis reported the incidence of type 2 diabetes in 2–24-year-olds exposed to antipsychotics as 3.09 (95% confidence interval [CI], 2.35–3.82) per 1,000 person-years, and it also showed that the risk for early-onset type 2 diabetes was significantly higher in those who received prescriptions for second-generation antipsychotics (34). Dose-response effects (30) and several plausible biological mechanisms (21) indicate a causal association between antipsychotics and diabetes. Antagonism of central and peripheral M3, H1, 5-HT2c, other serotonergic, and adrenergic receptors may have direct diabetogenic effects, or they can increase the risk of diabetes by indirect mechanisms, such as weight gain and reduced insulin sensitivity (21, 31, 35).
There are several caveats in our current understanding of endogenous and antipsychotic-related risks of diabetes in schizophrenia. First, to our knowledge there has not been any large population-based cohort study investigating endogenous risk for diabetes in antipsychotic-naive people with schizophrenia compared with the general population. Second, population-based cohort studies focusing on the risks for early-onset diabetes in young people with schizophrenia are sparse (34). Third, despite a large volume of literature, the impact of the first-line therapeutic decision of choosing between first-generation and second-generation antipsychotics on the antipsychotic-related risk for diabetes in schizophrenia remains uncertain (29, 30). Fourth, previous studies investigating the antipsychotic-related risks for diabetes in schizophrenia have seldom been adjusted for the effects of family history of diabetes and for the dosage of other potentially diabetogenic psychotropic medications (36–38). Hence, this population-based cohort study included all young people (more than 2.7 million) born on Jan. 1, 1977, or later in Denmark, investigated endogenous risk for early-onset diabetes in antipsychotic-naive schizophrenia, and evaluated the antipsychotic-related risks in people with schizophrenia, after adjusting for the effects of potential confounders.
Method
Study Population
This population-based cohort study included people from the Danish Civil Registration System (39), which has recorded data on all Danish citizens since 1968. Each Danish citizen is assigned a unique 10-digit personal identification number at birth. This number is used in all Danish registries, enabling unambiguous linkage among them. The registration system provides data on gender, date of birth, date of death, date of migration, and parental identity. Our cohort included all people who were born in Denmark on or after Jan. 1, 1977. They were followed up until Jan. 1, 2013.
People With Diabetes
Information on diabetes was derived from the Danish National Patient Register (40) and the Danish National Prescription Registry (41). The Danish National Patient Register, established in 1977, collects data on all hospitalizations from nonpsychiatric hospitals, including dates of admission and discharge and discharge diagnoses, coded by the treating physicians according to the 8th revision of the International Classification of Diseases (ICD-8) (42) until the end of 1993 and the 10th revision (ICD-10) (43) thereafter. Since 1995, outpatient visits have also been recorded. We identified all hospital discharge diagnoses of diabetes. In ICD-8 these included codes 249 (insulin-dependent diabetes [type 1]) and 250 (non-insulin-dependent diabetes [type 2]). In ICD-10 these included codes E10 (brittle, juvenile, and ketoacidosis prone diabetes), E11 (adult-onset, maturity-onset, nonketotic, and stable diabetes), E12–14 (malnutrition, other specified and unspecified diabetes), H36.0 (diabetic retinopathy), and O24 (diabetes in pregnancy, childbirth, and puerperium) excluding O24.4 (gestational diabetes). Neither the ICD-8 nor ICD-10 provides specific codes for late-onset type 1 diabetes in adults or drug-induced diabetes. Because people with schizophrenia may develop type 2 diabetes at younger ages than the general population, and because the Danish registers include more frequent use of unspecified diabetes codes in people with schizophrenia, we examined the complete spectrum of ICD diabetes codes. Although using the Danish National Patient Register and Danish National Prescription Registry to identify people with diabetes has proven to yield high-quality and almost complete (44, 45) data, we cannot reliably distinguish type 1 and type 2 diabetes by using the registers (46, 47).
In addition to hospital contacts involving diabetes, we identified antidiabetic prescriptions from the Danish National Prescription Registry, because many people with diabetes are treated only in primary care. The prescription registry contains data from 1995 on all prescription drugs dispensed at all Danish pharmacies, and the information includes the Anatomical Therapeutic Chemical (ATC) classification system codes, dispensing dates, drug names, dose units, number of dose units in package, number of daily defined doses sold (48), and dispensing pharmacy codes. Antidiabetic drugs are available only by prescription in Denmark, so we identified all prescription redemptions for antidiabetic drugs (ATC code: A10). However, women with polycystic ovary syndrome may be treated with metformin (ATC code: A10BA02). Thus, to avoid inclusion of these nondiabetic people, we excluded all metformin prescriptions redeemed by women age 20 or more years in this cohort. Onset of diabetes was defined as the date of first admission with diabetes since birth or as the date of the first prescription for an antidiabetic drug since 1995 or later, whichever came first.
People With Schizophrenia
The Danish Psychiatric Central Research Register (49) was established as an electronic database in 1969 and has been recording data on all psychiatric admissions since 1969. Diagnoses in the Danish Psychiatric Central Research Register were coded in accordance with the ICD-8 (42) until the end of 1993 and ICD-10 (43) thereafter. This register includes data on all outpatient visits since 1995. We identified all hospital discharge diagnoses of schizophrenia (ICD-8: 295 [excluding 295.79] and ICD-10: F20). These diagnoses have been validated (50) and have contributed substantially to epidemiological research (49). As the data in the Danish National Prescription Registry have been complete only since 1995, we excluded all people (N=97) who developed schizophrenia before Jan. 1, 1996, to ensure that we had complete psychopharmacological data and at least 1 year of prescription use history for all people with schizophrenia after they had been diagnosed. Hence, we included all incident schizophrenia cases since Jan. 1, 1996.
Exposure to Antipsychotics
We traced all oral and depot antipsychotic prescriptions (ATC code: N05A, excluding N05AN [lithium]) since 1995 using information from the Danish National Prescription Registry (48). The prescription registry is a powerful pharmacoepidemiological tool that provides complete high-quality data on all filled prescriptions for antipsychotics prescribed by various psychiatric departments, general practitioners, or other specialists after 1995. It does not record the drugs that are dispensed within hospitals. All Danish pharmacies are obliged to register all dispensed prescriptions, and they have a high economic incentive for completeness of prescription registration because of the universal reimbursement system for prescription drugs in Denmark. Antipsychotics were subdivided into first-generation antipsychotics, second-generation antipsychotics (ATC codes: N05AD03, N05AE03–4, N05AH04, N05AL01, N05AL05, N05AX08, and N05AX13), olanzapine, aripiprazole, and clozapine (see Appendix S1 in the data supplement accompanying the online version of this article).
Covariates of Interest
We chose our covariates a priori on the basis of their availability, previous research associating them with diabetes or schizophrenia, and their influence on the prescribing pattern of antipsychotics. From the Danish National Prescription Registry, we identified other potentially diabetogenic psychotropic medications, such as tricyclic (ATC code: N06AA) and tetracyclic (ATC codes: N06AA21, N06AX03, N06AX11) antidepressants (36) and valproate (ATC code: N03AG01) (37, 38). Data on gender, urbanicity, and calendar period were derived from the Danish Civil Registration System and the Danish National Patient Register (40). Using the parental identity from the civil registration system, we identified siblings and half-siblings, and we linked them to the national patient register and prescription register to establish family history of diabetes.
Statistical Analyses
We calculated age-specific and gender-specific incidence rates of diabetes and their 95% CIs. In order to investigate the endogenous risk for diabetes, we used Cox proportional hazards regression models to compute the adjusted hazard ratio for diabetes in antipsychotic-naive people with schizophrenia, compared with antipsychotic-naive people without schizophrenia. Follow-up began on the date of birth and ended on the date of diabetes diagnosis, first prescription of antipsychotics, emigration, or death or on Jan. 1, 2013. The first registered diagnosis of schizophrenia during follow-up was included as a time-dependent variable. Gender, family history of diabetes, urbanicity, and exposure to valproate and tricyclic or tetracyclic antidepressants were included as covariates.
We assessed antipsychotic-related risk for diabetes by including only people with schizophrenia who were antipsychotic naive at the time of their diagnosis. We employed Cox proportional hazard regression models estimating the adjusted hazard ratio by comparing the rates of diabetes in people with schizophrenia with and without antipsychotics. Follow-up began on the date of first diagnosis of schizophrenia and ended on the date of diabetes diagnosis, emigration, or death or on Jan. 1, 2013. Age was chosen as the time scale. Our Cox regression model included gender, family history of diabetes, and urbanicity as time-independent covariates and calendar period and daily defined doses of antipsychotics, valproate, and tricyclic or tetracyclic antidepressants as time-varying covariates. Moreover, we estimated adjusted hazard ratios and their 95% CIs that compared the risks for diabetes before and after starting selected antipsychotics in people with schizophrenia. Furthermore, we performed sensitivity analyses that followed the patients until their first type 2 diabetes contact (ICD-8: 250; ICD-10: E11, O24.1) and/or oral antidiabetic drug (ATC code: A10B), ignoring any previous contacts due to type 1 diabetes or insulin prescriptions. We tested the proportional hazards assumption by repeating the Cox regression models and including the primary independent variable as one of the time-varying covariates, and we did not find any violations. All analyses were performed by using the statistical software STATA 13.1 (StataCorp, College Station, Tex.).
Results
Population Characteristics
We followed 2,736,510 young people for a total of 49,582,279 person-years. The median duration of follow-up was 18.80 years (interquartile range, 16.99 years). The maximum period of follow-up was 35.96 years; thus, the oldest person in our cohort was less than 36 years old. A total of 8,945 (0.33%) people developed schizophrenia during follow-up. The mean duration of follow-up after the diagnosis of schizophrenia was 5.07 (SD=4.24) years, and the mean duration of follow-up after the first antipsychotic drug prescription was 6.40 (SD=4.34) years. Table 1 presents the sociodemographic and clinical characteristics of our cohort. People with schizophrenia were significantly more likely to have a family history of diabetes than other people (χ2>1300, df=1, p<0.001).
| Characteristic | Without Schizophrenia (N=2,727,565) | With Schizophrenia (N=8,945) | ||
|---|---|---|---|---|
| N | % | N | % | |
| Gender | ||||
| Male | 1,384,625 | 50.8 | 5,342 | 59.7 |
| Female | 1,342,940 | 49.2 | 3,603 | 40.3 |
| Degree of urbanicity | ||||
| Copenhagena | 553,452 | 20.3 | 2,176 | 24.3 |
| Other citiesb | 254,497 | 9.3 | 944 | 10.6 |
| Townsc | 678,502 | 24.9 | 2,506 | 28.0 |
| Rural areas | 1,241,114 | 45.5 | 3,319 | 37.1 |
| Family history of diabetes | 202,500 | 7.4 | 1,537 | 17.2 |
| Incident diabetes mellitus | 13,915 | 0.5 | 203 | 2.3 |
| Exposed to antipsychotics | ||||
| First-generation antipsychotics | 34,691 | 1.3 | 5,050 | 56.5 |
| Second-generation antipsychoticsd | 26,887 | 1.0 | 6,291 | 70.3 |
| Olanzapine | 7,475 | 0.3 | 3,613 | 40.4 |
| Aripiprazole | 5,479 | 0.2 | 3,511 | 39.3 |
| Clozapine | 65 | 0.0 | 912 | 10.2 |
| Antipsychotic naivee | 2,673,114 | 98.0 | 1,154 | 12.9 |
| Exposed to antidepressantsf | 51,803 | 1.9 | 2,296 | 25.7 |
| Exposed to valproate | 12,757 | 0.5 | 524 | 5.9 |
a
Living in the capital city, Copenhagen, and its suburbs.
b
Living in other cities with more than 100,000 population.
c
Living in towns with population between 10,000 and 100,000.
d
Second-generation antipsychotic drugs excluding olanzapine, aripiprazole, and clozapine.
e
People who had not received any antipsychotic medications by the end of their follow-up.
f
Exposure to tricyclic or tetracyclic antidepressants.
Incidence of Diabetes
A total of 14,118 (0.52%) people developed diabetes in this cohort (see Figure S1 in the online data supplement ). Age-specific incidence rates of diabetes in people with and without schizophrenia are presented in Table 2 (see also Figure S2 in the supplemental data ). Gender-specific incidence rates of diabetes for men and women without schizophrenia were 0.26 (95% CI, 0.26–0.27) and 0.30 (95% CI, 0.29–0.31) per 1,000 person-years, respectively. Gender-specific incidence rates of diabetes for men and women with schizophrenia were 4.02 (95% CI, 3.35–4.83) and 4.69 (95% CI, 3.81–5.77) per 1,000 person-years, respectively.
| Group and Age | Person-Years | Incident Diabetes | Incidence Ratea | Difference From People Without Schizophrenia | |
|---|---|---|---|---|---|
| People without schizophrenia (N=2,727,565) | Person-Years (millions) | N | Rate | 95% CI | |
| 0–9 years | 23.66 | 3,449 | 0.15 | 0.14–0.15 | |
| 10–14 years | 9.16 | 2,654 | 0.29 | 0.28–0.30 | |
| 15–19 years | 7.34 | 2,462 | 0.33 | 0.32–0.35 | |
| 20–24 years | 5.15 | 1,776 | 0.35 | 0.33–0.36 | |
| 25–29 years | 2.98 | 2,100 | 0.70 | 0.67–0.75 | |
| 30–36 years | 1.24 | 1,474 | 1.18 | 1.12–1.25 | |
| 0–36 years | 49.53 | 13,915 | 0.28 | 0.28–0.29 | |
| People with schizophrenia (N=8,945) | Person-Years | N | Rate | 95%CI | Mid-pb |
| 0–9 years | 29.12 | 0 | 0.00 | — | 0.99 |
| 10–14 years | 269.44 | 0 | 0.00 | — | 0.93 |
| 15–19 years | 4,824.17 | 13 | 2.69 | 1.56–4.64 | <0.001 |
| 20–24 years | 16,263.53 | 59 | 3.63 | 2.81–4.68 | <0.001 |
| 25–29 years | 16,941.88 | 75 | 4.43 | 3.53–5.55 | <0.001 |
| 30–36 years | 8,987.59 | 56 | 6.23 | 4.80–8.10 | <0.001 |
| 0–36 years | 47,315.73 | 203 | 4.29 | 3.74–4.92 | <0.001 |
a
Incidence rate of diabetes mellitus per 1,000 person-years.
b
Two-sided exact test.
Endogenous Risk for Diabetes
Among the people who were not exposed to any antipsychotics, 12,976 (0.5%) without schizophrenia and 11 (0.9%) with schizophrenia developed incident diabetes during our follow-up. Table 3 presents the incidence rates and the adjusted hazard ratios for diabetes in antipsychotic-naive people with schizophrenia. Family history of diabetes significantly increased the risk of diabetes (adjusted hazard ratio, 3.96; 95% CI, 3.82–4.11). People with schizophrenia had a higher incidence rate of diabetes, and they had an approximately threefold higher risk of diabetes (adjusted hazard ratio, 3.07; 95% CI, 1.71–5.41), compared with people without schizophrenia, after adjustment for the effects of potential confounders, including family history of diabetes.
| Group | Incidence Ratea | 95% CIa | Adjusted Hazard Ratio | 95% CI | Number Needed to Harmb | 95% CIb | p |
|---|---|---|---|---|---|---|---|
| Follow-up censored at first antipsychotic prescriptionc | |||||||
| People without schizophrenia (N=2,736,510)d | 0.27 | 0.27–0.28 | 1.00e | — | — | — | |
| People with schizophrenia (N=4,322) | 1.84 | 1.05–5.15 | |||||
| Model 1f | 2.92 | 1.66–5.15 | 1,931 | 894–5,614 | <0.001 | ||
| Model 2g | 3.07 | 1.71–5.41 | 1,791 | 841–5,219 | <0.001 | ||
| No use of antipsychotics during the entire follow-uph | |||||||
| People without schizophrenia (N=2,673,114) | 0.27 | 0.27–0.28 | 1.00e | — | — | — | |
| People with schizophrenia (N=1,154) | 2.18 | 1.09–4.36 | |||||
| Model 1f | 3.18 | 1.59–6.36 | 1,700 | 692–6,280 | 0.001 | ||
| Model 2g | 2.98 | 1.49–5.95 | 1,872 | 749–7,562 | 0.002 |
a
Incidence rate of diabetes mellitus per 1,000 person-years.
b
Number needed to harm in person-years.
c
Data were censored at the earliest date among the following: date of diagnosis of diabetes, date of the start of any antipsychotic medication, date of death, date of emigration from Denmark, and date at the end of follow-up on Jan. 1, 2013.
d
Based on the assumption that the people with schizophrenia were at risk for diabetes after the diagnosis of schizophrenia, analyses were carried out with the reference group (people without schizophrenia) and antipsychotic-naive people with schizophrenia before the diagnosis of schizophrenia.
e
Reference value.
f
Adjusted for the effects of gender, family history of diabetes, and urbanicity.
g
Adjusted for the effects of gender, family history of diabetes, urbanicity, exposure to valproate, and exposure to tricyclic or tetracyclic antidepressants.
h
Endogenous risk for diabetes in people with schizophrenia who remained antipsychotic naive until the end of follow-up was evaluated with reference to people without schizophrenia, who had not been exposed to any antipsychotics. Mean duration of follow-up after the diagnosis of schizophrenia was 3.18 (SD=3.53) years in people with schizophrenia who remained antipsychotic naive until the end of follow-up.
Antipsychotic-Related Risks
A total of 4,322 (48.3%) people with schizophrenia were antipsychotic naive at the time of their diagnosis, and the remaining 4,623 (51.7%) had received an antipsychotic drug before schizophrenia was diagnosed. A total of 83 (1.9%) people with schizophrenia who were antipsychotic naive at diagnosis developed diabetes during follow-up. Gender-specific incidence rates of diabetes for antipsychotic-treated men and women with schizophrenia were 4.22 (95% CI, 3.17–5.62), and 3.33 (95% CI, 2.23–4.96) per 1,000 person-years, respectively. Table 4 presents the incidence rates and the adjusted hazard ratios for diabetes in people with schizophrenia, comparing their risks before and after they started treatment with selected antipsychotics. The rate for diabetes significantly increased by more than threefold (adjusted hazard ratio, 3.64; 95% CI, 1.95–6.82) in people with schizophrenia after starting any antipsychotic, compared with their rate before receiving antipsychotics, when the analysis accounted for the effects of potential confounders, including family history of diabetes.
| Antipsychotic Status | Incidence Ratea | 95% CIa | Adjusted Hazard Ratiob | 95% CIb | Number Needed to Harmc | 95% CIc | p |
|---|---|---|---|---|---|---|---|
| Risk with starting any antipsychotic | |||||||
| Before starting any antipsychotic (N=4,322)d | 1.69 | 0.94–3.05 | 1.00e | — | — | — | |
| After starting any antipsychotic (N=3,168) | 3.93 | 3.12–4.95 | 3.64 | 1.95–6.82 | 226 | 103–625 | <0.001 |
| After first-line treatment with first-generation antipsychotic (N=450) | 3.92 | 2.23–6.91 | 3.06 | 1.32–7.05 | 289 | 99–1853 | 0.009 |
| After first-line treatment with second-generation antipsychotic other than olanzapine and clozapine (N=1,708) | 3.50 | 2.42–5.07 | 3.82 | 1.81–8.09 | 211 | 85–733 | <0.001 |
| After first-line treatment with second-generation antipsychotic other than clozapine (N=2,311) | 3.36 | 2.48–4.57 | 3.44 | 1.73–6.83 | 244 | 103–813 | <0.001 |
| Risk with starting olanzapine | |||||||
| Before starting olanzapine (N=7,652)f | 3.82 | 3.16–4.63 | 1.00e | — | — | — | |
| After starting olanzapine (N=2,115) | 5.13 | 4.01–6.55 | 1.88 | 1.36–2.59 | 300 | 166–731 | <0.001 |
| Risk with starting aripiprazole | |||||||
| Before starting aripiprazole (N=8,358)g | 3.70 | 3.11–4.41 | 1.00e | — | — | — | |
| After starting aripiprazole (N=2,719) | 5.32 | 4.13–6.87 | 2.35 | 1.70–3.26 | 202 | 121–389 | <0.001 |
| Risk with starting clozapine | |||||||
| Before starting clozapine (N=8,890)h | 3.78 | 3.24–4.41 | 1.00e | — | — | — | |
| After starting clozapine (N=862) | 8.81 | 6.44–12.06 | 3.98 | 2.77–5.73 | 90 | 57–151 | <0.001 |
a
Incidence rate of diabetes mellitus per 1,000 person-years.
b
Adjusted hazard ratios were estimated by Cox proportional hazard regression models. These models included gender, family history of diabetes, and urbanicity as time-independent covariates and calendar period and defined daily doses of antipsychotics, valproate, and tricyclic or tetracyclic antidepressants as time-dependent covariates.
c
Number needed to harm in person-years.
d
People with schizophrenia who were antipsychotic naive at the time of diagnosis of schizophrenia.
e
Reference value.
f
People with schizophrenia who had received olanzapine before their diagnosis of schizophrenia were excluded from this analysis.
g
People with schizophrenia who had received aripiprazole before their diagnosis of schizophrenia were excluded from this analysis.
h
People with schizophrenia who had received clozapine before their diagnosis of schizophrenia were excluded from this analysis.
First-Line Treatment With First-Generation or Second-Generation Antipsychotics
Compared with the people with schizophrenia who remained antipsychotic naive until the end of follow-up, those with schizophrenia who received monotherapy with either first-generation antipsychotics (adjusted hazard ratio, 3.06; 95% CI, 1.32–7.05) or second-generation antipsychotics (except clozapine) (adjusted hazard ratio, 3.44; 95% CI, 1.73–6.83) as their first-line treatment had significantly higher antipsychotic-related rates for diabetes after adjustment for the effects of potential confounders, including family history of diabetes. The first-line therapeutic decision of choosing between first-generation and second-generation antipsychotics did not make a statistically significant difference (χ2=0.13, df=1, p=0.72) in the rate for diabetes in people with schizophrenia. We repeated these analyses after excluding olanzapine from the class of second-generation antipsychotics and confirmed the earlier findings.
Risks Associated With Selected Antipsychotics
Starting either olanzapine (adjusted hazard ratio, 1.88; 95% CI, 1.36–2.59) or aripiprazole (adjusted hazard ratio, 2.35; 95% CI, 1.70–3.26) significantly increased the rate of diabetes by almost twofold in people with schizophrenia, after adjustment for the effects of potential confounders. We repeated these analyses including the duration of antipsychotic treatment before the start of either olanzapine (adjusted hazard ratio, 1.91; 95% CI, 1.37–2.65) or aripiprazole (adjusted hazard ratio, 1.69; 95% CI, 1.19–2.39) in the models and confirmed the earlier findings. Among 861 (9.6%) people with schizophrenia who received clozapine after their diagnosis, 39 (0.4%) developed incident diabetes after starting clozapine. Treatment with clozapine significantly increased the rate of diabetes by nearly fourfold (adjusted hazard ratio, 3.98; 95% CI, 2.77–5.73) in people with schizophrenia, compared with people with schizophrenia not receiving clozapine, when the analysis accounted for the potential confounders, including the family history of diabetes (see Appendix S5 in the online data supplement ).
Sensitivity Analyses
We conducted sensitivity analyses limited to potential type 2 diabetes diagnoses in this cohort (N=5,488, 0.20%) and confirmed the earlier findings of a higher rate of diabetes in antipsychotic-naive people with schizophrenia compared with the general population (adjusted hazard ratio, 4.71; 95% CI, 2.60–8.51) and an increased rate of diabetes after the start of any antipsychotic drug in people with schizophrenia (adjusted hazard ratio, 3.79; 95% CI, 1.97–7.26) without statistically significant differences between first-generation and second-generation antipsychotics (χ2=0.04, df=1, p=0.85) (see Appendixes S2, S3, and S5 in the online data supplement ). We performed more sensitivity analyses after excluding 19 people who developed diabetes more than 12 months after the last prescription for any antipsychotic, to distinguish direct antipsychotic effects from the potential effects of antipsychotic-related weight gain. The results of this sensitivity analysis also corroborated our earlier findings. The antipsychotic-related risk for diabetes after starting any antipsychotic was significantly higher (adjusted hazard ratio, 3.28; 95% CI, 1.74–6.17) than the risk in people with schizophrenia not treated with antipsychotics, and the first-line therapeutic decision of treatment with either first-generation or second-generation antipsychotic monotherapy did not make a statistically significant difference (χ2=0.78, df=1, p=0.38). Moreover, we performed sensitivity analyses by including women ages 20 or more years receiving treatment only with metformin (N=8,551). We confirmed our findings of endogenous risk of diabetes in antipsychotic-naive schizophrenia (adjusted hazard ratio, 2.10; 95% CI, 1.30–3.38) and increased rate of diabetes after the start of any antipsychotic drug in people with schizophrenia (adjusted hazard ratio, 3.56; 95% CI, 2.09–6.06) without a statistically significant difference (χ2=2.03, df=1, p=0.15) between the first-line therapeutic decision of treatment with either first-generation antipsychotics (adjusted hazard ratio, 4.27; 95% CI, 2.21–8.27) or second-generation antipsychotics (adjusted hazard ratio, 2.98; 95% CI, 1.67–5.32) monotherapy.
Discussion
This nation-wide population-based cohort study reveals an increased endogenous risk for diabetes in antipsychotic-naive people with schizophrenia compared with people without schizophrenia. It confirms the antipsychotic-related risks for diabetes in people with schizophrenia after adjusting for potential confounders, including family history of diabetes. Moreover, it adds evidence that first-line treatments with first-generation and second-generation antipsychotics do not significantly differ on their antipsychotic-related risks for diabetes. Furthermore, it documents that the antipsychotic-related rate of diabetes in people with schizophrenia who have received other antipsychotics further increases fourfold after they start taking clozapine. The strengths of this study include the largest sample size to date, the longest follow-up, the antipsychotic-naive status of the people with schizophrenia, the focus on early-onset diabetes in young people, and statistical adjustments for the effects of family history of diabetes and other potentially diabetogenic medications.
An important limitation of our study is that we could not reliably distinguish between type 1 and type 2 diabetes. Misclassification of diabetes type is likely, and a complete classification is not possible on the basis of the information available in Danish national registers (47, 51). We can only distinguish between type 1 and type 2 diabetes on the basis of ICD codes and insulin-only therapy, which potentially indicates type 1 diabetes. Moreover, people with schizophrenia are often diagnosed with ICD-10 codes for unspecified diabetes. However, sensitivity analyses limited to potential type 2 diabetes corroborated our findings. A substantial proportion of incident diabetes in young people with schizophrenia is expected to be early-onset type 2 diabetes (52). Early-onset type 2 diabetes can be a distinct, severe, rapidly progressing disease phenotype (4, 7, 8). This may limit generalizability of our findings to older people with schizophrenia, but it may emphasize their clinical importance. Besides, the possibility of increased surveillance of people with schizophrenia by the health services, and consequent surveillance bias, may explain the increased incidence of diabetes in antipsychotic-naive schizophrenia. However, prior evidence suggests that the proportion of undiagnosed diabetes may be higher among people with schizophrenia than in the general population (53, 54). Moreover, studying a relatively homogeneous and predominantly Caucasian population from a single country may limit generalizability of our findings, but this should strengthen their internal validity (55). Other limitations of this study include the lack of data on other potential confounders, such as obesity, dyslipidemia, smoking, other substance abuse, diet, and sedentary lifestyle; the lack of data on drugs dispensed within hospitals in the Danish National Prescription Registry; and the grouping of diverse antipsychotics together during our analyses. Controlling for all potential confounders is not possible in register-based research (56), and such residual confounding could have influenced our results.
A high prevalence of endogenous diabetes in antipsychotic-naive people with schizophrenia was reported in a different Danish cohort (31, 33), and our findings confirm a higher incidence of endogenous diabetes in young people with schizophrenia. In our study, young people with schizophrenia were significantly more likely to have a family history of diabetes. This finding indicates familial aggregation and genetic overlap of these two disorders. A recent population-based cross-sectional study from Australia reported that people with psychosis are at increased risk of diabetes if they have a family history of diabetes or if they do not have a family history of diabetes but are taking antipsychotics (57). Our results, adjusted for family history of diabetes, clarify this misconception and establish that people with schizophrenia are at increased risk for diabetes regardless of their family history of diabetes and their antipsychotic drug exposure.
Previous studies have reported that second-generation antipsychotics as a class confer more risk for diabetes than first-generation antipsychotics (29). However, evidence to the contrary also exists (30). Our findings add important evidence to this debate. Similarly, aripiprazole has been reported to either lower (31) or increase (58) the risk for diabetes in schizophrenia. Our findings do not support a protective effect of aripiprazole but document its association with diabetes risk. There is a possibility that aripiprazole and first-generation antipsychotics might have been prescribed more often for diabetes-prone people with schizophrenia, and such channeling bias might have influenced pertinent findings. Similarly, olanzapine might have been prescribed more often for people perceived to be less prone for diabetes by their treating clinicians, and this could have underestimated the associated risks. To address the diabetogenic potential of olanzapine, a three-phase algorithm for antipsychotic treatment that limits use of olanzapine to only a second-line antipsychotic agent has been proposed (33). First-line treatment with second-generation antipsychotics including olanzapine did not differ significantly from first-generation antipsychotics on their risks for diabetes in this cohort. Olanzapine has not been a second-line antipsychotic in many countries, including Denmark at the time of this cohort, and it is currently recommended as a first-line antipsychotic for schizophrenia by many national (59) and international (60) guidelines. Our findings do not add evidence to change the prevailing guidelines regarding prescription of olanzapine in schizophrenia. However, they confirm the substantial increase in diabetes risk from starting clozapine treatment for people with schizophrenia.
Shared genetic factors, negative symptoms, substance abuse, and unhealthy lifestyle in schizophrenia may contribute to its endogenous risk for diabetes. Future studies should focus on underlying biological mechanisms connecting these two disorders and on potential preventive interventions. Further studies investigating antipsychotic-related risks of individual antipsychotics and of their polypharmacy (30, 61) for diabetes in people with schizophrenia are warranted. Antipsychotic-related risk for diabetes is often discussed as one of the many factors in the therapeutic decision-making process of choosing an antipsychotic agent in psychiatric clinics. Combined endogenous and antipsychotic-related risks for diabetes in schizophrenia mandate more attention. Psychiatric services should either develop specific protocols or closely collaborate with primary care facilities to screen for diabetes among people with schizophrenia in the community. Promoting a healthy lifestyle, early detection by regular, at least yearly, screening, and effective treatment of diabetes should be integral parts of multidisciplinary management of schizophrenia.
Acknowledgments
The authors thank Thomas Munk Laursen and Aske Astrup, Aarhus University, for advice on statistical analyses.
Footnote
Funded by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 279227. The funding organization did not play any role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, and preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. This study was approved by the Danish Data Protection Agency and the Danish Health and Medicines authority.
Supplementary Material
File (appi.ajp.2016.16040442.ds001.pdf)
- View/Download
- 1.30 MB
References
1.
De Hert M, Correll CU, Bobes J, et al: Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry 2011; 10:52–77
2.
Ribe AR, Laursen TM, Sandbaek A, et al: Long-term mortality of persons with severe mental illness and diabetes: a population-based cohort study in Denmark. Psychol Med 2014; 44:3097–3107
3.
Tiihonen J, Lönnqvist J, Wahlbeck K, et al: 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009; 374:620–627
4.
Song SH, Hardisty CA: Early-onset Type 2 diabetes mellitus: an increasing phenomenon of elevated cardiovascular risk. Expert Rev Cardiovasc Ther 2008; 6:315–322
5.
Cohen D, Dekker JJ, Peen J, Gispen-de Wied CC. Prevalence of diabetes mellitus in chronic schizophrenic inpatients in relation to long-term antipsychotic treatment. Eur Neuropsychopharmacol 2006; 16:187–194
6.
Lean ME, Pajonk FG: Patients on atypical antipsychotic drugs: another high-risk group for type 2 diabetes. Diabetes Care 2003; 26:1597–1605
7.
Wilmot E, Idris I: Early onset type 2 diabetes: risk factors, clinical impact and management. Ther Adv Chronic Dis 2014; 5:234–244
8.
Narasimhan S, Weinstock RS: Youth-onset type 2 diabetes mellitus: lessons learned from the TODAY study. Mayo Clin Proc 2014; 89:806–816
9.
Maudsley H: The Pathology of Mind, 3rd ed. London, Macmillan and Co, 1879
10.
Kohen D: Diabetes mellitus and schizophrenia: historical perspective. Br J Psychiatry Suppl 2004; 47:S64–S66
11.
Hiles BW: Hyperglycemia and glycosuria following chlorpromazine therapy (letter). JAMA 1956; 162:1651
12.
Charatan FB, Bartlett NG: The effect of chlorpromazine (Largactil) on glucose tolerance. J Ment Sci 1955; 101:351–353
13.
Kirkpatrick B, Miller BJ, Garcia-Rizo C, et al: Is abnormal glucose tolerance in antipsychotic-naive patients with nonaffective psychosis confounded by poor health habits? Schizophr Bull 2012; 38:280–284
14.
Ryan MC, Collins P, Thakore JH: Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry 2003; 160:284–289
15.
Saddichha S, Manjunatha N, Ameen S, et al: Diabetes and schizophrenia—effect of disease or drug? Results from a randomized, double-blind, controlled prospective study in first-episode schizophrenia. Acta Psychiatr Scand 2008; 117:342–347
16.
Fernandez-Egea E, Miller B, Bernardo M, et al: Parental history of type 2 diabetes in patients with nonaffective psychosis. Schizophr Res 2008; 98:302–306
17.
Mukherjee S, Schnur DB, Reddy R: Family history of type 2 diabetes in schizophrenic patients (letter). Lancet 1989; 1:495
18.
Hansen T, Ingason A, Djurovic S, et al: At-risk variant in TCF7L2 for type II diabetes increases risk of schizophrenia. Biol Psychiatry 2011; 70:59–63
19.
Irvin MR, Wiener HW, Perry RP, et al: Genetic risk factors for type 2 diabetes with pharmacologic intervention in African-American patients with schizophrenia or schizoaffective disorder. Schizophr Res 2009; 114:50–56
20.
Zhang X, Hui L, Liu Y, et al: The type 2 diabetes mellitus susceptibility gene IGF2BP2 is associated with schizophrenia in a Han Chinese population. J Clin Psychiatry 2013; 74:e287–e292
21.
Bellivier F: Schizophrenia, antipsychotics and diabetes: genetic aspects. Eur Psychiatry 2005; 20(Suppl 4):S335–S339
22.
Lin PI, Shuldiner AR: Rethinking the genetic basis for comorbidity of schizophrenia and type 2 diabetes. Schizophr Res 2010; 123:234–243
23.
Liu Y, Li Z, Zhang M, et al: Exploring the pathogenetic association between schizophrenia and type 2 diabetes mellitus diseases based on pathway analysis. BMC Med Genomics 2013; 6(suppl 1):S17
24.
Leslie DL, Rosenheck RA: Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry 2004; 161:1709–1711
25.
Baker RA, Pikalov A, Tran QV, et al: Atypical antipsychotic drugs and diabetes mellitus in the US Food and Drug Administration Adverse Event database: a systematic Bayesian signal detection analysis. Psychopharmacol Bull 2009; 42:11–31
26.
Cohen D: Atypical antipsychotics and new onset diabetes mellitus. An overview of the literature. Pharmacopsychiatry 2004; 37:1–11
27.
Newcomer JW: Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19(suppl 1):1–93
28.
De Hert M, Detraux J, van Winkel R, et al: Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 2011; 8:114–126
29.
Smith M, Hopkins D, Peveler RC, et al: First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis. Br J Psychiatry 2008; 192:406–411
30.
Kessing LV, Thomsen AF, Mogensen UB, et al: Treatment with antipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry 2010; 197:266–271
31.
Nielsen J, Skadhede S, Correll CU: Antipsychotics associated with the development of type 2 diabetes in antipsychotic-naïve schizophrenia patients. Neuropsychopharmacology 2010; 35:1997–2004
32.
Yood MU, DeLorenze G, Quesenberry CP Jr, et al: The incidence of diabetes in atypical antipsychotic users differs according to agent—results from a multisite epidemiologic study. Pharmacoepidemiol Drug Saf 2009; 18:791–799
33.
Cohen D, De Hert M: Endogenic and iatrogenic diabetes mellitus in drug-naïve schizophrenia: the role of olanzapine and its place in the psychopharmacological treatment algorithm. Neuropsychopharmacology 2011; 36:2368–2369
34.
Galling B, Roldán A, Nielsen RE, et al: Type 2 diabetes mellitus in youth exposed to antipsychotics: a systematic review and meta-analysis. JAMA Psychiatry 2016; 73:247–259
35.
Weston-Green K, Huang XF, Deng C: Second generation antipsychotic-induced type 2 diabetes: a role for the muscarinic M3 receptor. CNS Drugs 2013; 27:1069–1080
36.
Andersohn F, Schade R, Suissa S, et al: Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry 2009; 166:591–598
37.
Davis S. Diabetogenic drugs: treating chronic conditions to minimise new onset diabetes. S Afr Pharm J 2010; 77:22–33
38.
Abitbol R, Rej S, Segal M, Looper KJ. Diabetes mellitus onset in geriatric patients: does long-term atypical antipsychotic exposure increase risk? Psychogeriatrics 2015; 5:43–50
39.
Pedersen CB: The Danish Civil Registration System. Scand J Public Health 2011; 39(suppl):22–25
40.
Lynge E, Sandegaard JL, Rebolj M: The Danish National Patient Register. Scand J Public Health 2011; 39(suppl):30–33
41.
Kildemoes HW, Sørensen HT, Hallas J: The Danish National Prescription Registry. Scand J Public Health 2011; 39(suppl):38–41
42.
WHO: Manual of the International Classification of Diseases, Eighth Revision (ICD-8). Geneva, Switzerland, World Health Organization, 1967
43.
WHO: The ICD-10 Classification of Mental and Behavioural Disorders—Diagnostic Criteria for Research. Geneva, Switzerland, World Health Organization, 1992
44.
Nielsen GL, Sørensen HT, Pedersen AB, et al: Analyses of data quality in registries concerning diabetes mellitus—a comparison between a population based hospital discharge and an insulin prescription registry. J Med Syst 1996; 20:1–10
45.
Green A, Sortsø C, Jensen PB, et al: Validation of the Danish National Diabetes Register. Clin Epidemiol 2014; 7:5–15
46.
Elks ML, Sawyer JW Jr: Misunderstanding in the classification of diabetes mellitus. What’s in a name? West J Med 1993; 159:44–49
47.
Carstensen B, Kristensen JK, Ottosen P, et al: The Danish National Diabetes Register: trends in incidence, prevalence and mortality. Diabetologia 2008; 51:2187–2196
48.
WHO: Guidelines for ATC Classification and DDD Assignment, 2015. Oslo, WHO Collaborating Centre for Drug Statistics Methodology, 2014
49.
Mors O, Perto GP, Mortensen PB: The Danish Psychiatric Central Research Register. Scand J Public Health 2011; 39(suppl):54–57
50.
Uggerby P, Østergaard SD, Røge R, et al: The validity of the schizophrenia diagnosis in the Danish Psychiatric Central Research Register is good. Dan Med J 2013; 60:A4578
51.
Kioumourtzoglou MA, Rotem RS, Seals RM, et al: Diabetes mellitus, obesity, and diagnosis of amyotrophic lateral sclerosis: a population-based study. JAMA Neurol 2015; 72:905–911
52.
Song SH: Complication characteristics between young-onset type 2 versus type 1 diabetes in a UK population. BMJ Open Diabetes Res Care 2015; 3:e000044
53.
Nasrallah HA, Meyer JM, Goff DC, et al: Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. Schizophr Res 2006; 86:15–22
54.
Ward M, Druss B: The epidemiology of diabetes in psychotic disorders. Lancet Psychiatry 2015; 2:431–451
55.
Katon W, Pedersen HS, Ribe AR, et al: Effect of depression and diabetes mellitus on the risk for dementia: a national population-based cohort study. JAMA Psychiatry 2015; 72:612–619
56.
Olsen J: Register-based research: some methodological considerations. Scand J Public Health 2011; 39:225–229
57.
Foley DL, Mackinnon A, Morgan VA, et al: Effect of age, family history of diabetes, and antipsychotic drug treatment on risk of diabetes in people with psychosis: a population-based cross-sectional study. Lancet Psychiatry 2015; 2:1092–1098
58.
Rubin DM, Kreider AR, Matone M, et al: Risk for incident diabetes mellitus following initiation of second-generation antipsychotics among Medicaid-enrolled youths. JAMA Pediatr 2015; 169:e150285
59.
National Institute for Health and Care Excellence (NICE): Psychosis and Schizophrenia in Adults: Treatment and Management: Clinical Guideline 178. National Collaborating Centre for Mental Health, 2014 (https://www.nice.org.uk/guidance/cg178/evidence/full-guideline-490503565)
60.
Taylor D, Paton C, Kapur S: The Maudsley Prescribing Guidelines in Psychiatry, 12th ed. Oxford, UK, John Wiley & Sons, 2015
61.
Correll CU, Frederickson AM, Kane JM, et al: Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res 2007; 89:91–100
Information & Authors
Information
Published In
History
Received: 18 April 2016
Revision received: 5 September 2016
Accepted: 3 November 2016
Published online: 20 January 2017
Published in print: July 01, 2017
Keywords
Authors
Competing Interests
Dr. Cohen serves on the Lundbeck Advisory Board. Dr. Gasse received an unrestricted research grant from Eli Lilly and was in a research collaboration with LA-SER Analytica. All other authors report no financial relationships with commercial interests.
Funding Information
European Community's Seventh Framework Programme (FP7/2007-2013): n°279227
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
View Options
View options
PDF/EPUB
View PDF/EPUBLogin options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).