Skip to content

Advertisement

  • Research article
  • Open Access
  • Open Peer Review

Marginal structural models for the estimation of the risk of Diabetes Mellitus in the presence of elevated depressive symptoms and antidepressant medication use in the Women’s Health Initiative observational and clinical trial cohorts

  • 1Email author,
  • 2,
  • 2,
  • 1,
  • 2,
  • 2,
  • 1 and
  • 2
BMC Endocrine Disorders201515:56

https://doi.org/10.1186/s12902-015-0049-7

  • Received: 7 April 2015
  • Accepted: 18 September 2015
  • Published:
Open Peer Review reports

Abstract

Background

We evaluate the combined effect of the presence of elevated depressive symptoms and antidepressant medication use with respect to risk of type 2 diabetes among approximately 120,000 women enrolled in the Women’s Health Initiative (WHI), and compare several different statistical models appropriate for causal inference in non-randomized settings.

Methods

Data were analyzed for 52,326 women in the Women’s Health Initiative Clinical Trials (CT) Cohort and 68,169 women in the Observational Study (OS) Cohort after exclusions. We included follow-up to 2005, resulting in a median duration of 7.6 years of follow up after enrollment. Results from three multivariable Cox models were compared to those from marginal structural models that included time varying measures of antidepressant medication use, presence of elevated depressive symptoms and BMI, while adjusting for potential confounders including age, ethnicity, education, minutes of recreational physical activity per week, total energy intake, hormone therapy use, family history of diabetes and smoking status.

Results

Our results are consistent with previous studies examining the relationship of antidepressant medication use and risk of type 2 diabetes. All models showed a significant increase in diabetes risk for those taking antidepressants. The Cox Proportional Hazards models using baseline covariates showed the lowest increase in risk , with hazard ratios of 1.19 (95 % CI 1.06 – 1.35) and 1.14 (95 % CI 1.01 – 1.30) in the OS and CT, respectively. Hazard ratios from marginal structural models comparing antidepressant users to non-users were 1.35 (95 % CI 1.21 – 1.51) and 1.27 (95 % CI 1.13 – 1.43) in the WHI OS and CT, respectively – however, differences among estimates from traditional Cox models and marginal structural models were not statistically significant in both cohorts. One explanation suggests that time-dependent confounding was not a substantial factor in these data, however other explanations exist. Unadjusted Cox Proportional Hazards models showed that women with elevated depressive symptoms had a significant increase in diabetes risk that remained after adjustment for confounders. However, this association missed the threshold for statistical significance in propensity score adjusted and marginal structural models.

Conclusions

Results from the multiple approaches provide further evidence of an increase in risk of type 2 diabetes for those on antidepressants.

Keywords

  • Antidepressant medication
  • Depression
  • Type 2 diabetes
  • Marginal structural models
  • Propensity score

Background

Diabetes is a chronic illness with serious health consequences, such as adult blindness, non-traumatic limb amputation, renal failure and neuropathy. Previous literature has noted considerable diabetes and depression among postmenopausal women, with a prevalence rate that is approximately 12 % for each [1, 2]. Recent literature also suggests an increased risk of diabetes among those who are depressed and on antidepressant medications [36]. It is increasingly important to further investigate whether depression or antidepressant medication is influencing this association given that approximately 11 % of American women take antidepressant medication, and use is rising [7]. While the rates of use for depression treatment has remained the same, off-label use of antidepressants has increased significantly [8]. Examples of off-label use include treatment for certain types of pain, fibromyalgia, insomnia, and general unhappiness. In this analysis, we compare four statistical approaches to evaluate the combined effect of the presence of elevated depressive symptoms and antidepressant medication use on incident type 2 diabetes using data on approximately 120,000 women in the Women’s Health Initiative (WHI).

The WHI is a longitudinal study including repeated measurements for presence of elevated depressive symptoms, antidepressant use and self-reported diagnosis of type 2 diabetes. A previously reported analysis in the WHI [9] found that elevated depressive symptoms and antidepressant medication use resulted in increased type 2 diabetes risk. This analysis was based on Cox models that are subject to bias in the presence of time-dependent confounding [1012]. A probable mechanism that gives rise to time-dependent confounding in this context is shown in Fig. 2 (Appendix) - participants with increased BMI could be more likely to be depressed and/or on antidepressants in the future [13]. Moreover, BMI and depression/antidepressant medication use can also significantly influence future diabetes risk. Thus, an analysis based on Cox models as in the previous literature [9] to evaluate the causal relationship between presence of elevated depressive symptoms/antidepressant use (exposure) and diabetes risk (outcome) could result in biased estimates by misattributing the effects of time-dependent confounders to the exposures of interest.

In the presence of time-dependent confounding, all Cox models including those that incorporate time-varying covariates are subject to bias [1012]. Marginal structural models (MSMs) overcome limitations of Cox models - MSMs use inverse probability of treatment/exposure weighting and, given assumptions, can yield consistent and unbiased causal estimates of the effect of exposure [1012]. Other methods in this setting include propensity score adjusted models in which the probability of treatment assignment conditional on baseline covariates (or propensity score) is adjusted for as an additional covariate.

The objective of this work was to estimate the combined effect of antidepressant medication use/presence of elevated depressive symptoms on type 2 diabetes in the WHI, and to compare results obtained from MSMs and propensity score adjusted Cox models to more traditional approaches such Cox models [9, 14, 15]. The results presented in this paper go beyond a previously reported analysis of this hypothesis in the WHI [9] by comparing results from four different statistical approaches including MSMs that are recommended for causal inference in observational studies.

Methods

Women’s health initiative (WHI)

The WHI enrolled 68,132 participants into clinical trials (WHI-CT) and 93,676 participants into an observational study (WHI-OS) between 1993 and 1998 [1619]. Eligibility criteria included: postmenopausal women aged 50 to 79 years, reliable/mentally competent, and expected survival and local residency for at least three years. Medication use, presence of elevated depressive symptoms, and diabetes status were collected from participants over an average of 7.6 years of follow-up. We analyzed data with follow-up to 2005.

Study variables

Incident diabetes

Diabetes status was assessed by self-report at baseline and at each annual follow-up visit, which has been found to be a reliable indicator of diagnosed diabetes [20]. Time to diabetes was calculated as the interval between study enrollment and development of diabetes as evidenced by an annual medical history update, or censorship (death or end of study participation).

Antidepressant medication use

WHI-CT participants were instructed to bring all current prescription and nonprescription medications in original containers to clinic visits at baseline and years 1, 3, 6, and 9. WHI-OS medication data were collected at baseline and year 3. The Master Drug Data Base (MDDB: Medi-Span, Indianapolis, IN) was used to categorize the medications. Based on the MDDB classification, a binary indicator for antidepressant medication use was created. Antidepressants include the following major groups: 1) Selective serotonin reuptake inhibitors; 2) Monoamine oxidase inhibitors; 3) Tricyclic antidepressants; 4) Tetracyclics; 5) Serotonin/norepinephrine reuptake inhibitors (SNRIs); 6) Aminoketones; 7) Triazolopyridines; and 8) Dibenzoxazepine. A dichotomous indicator of antidepressant medication use was then created for each measurement period [9]. Due to sample size limitations, we did not perform analyses by class of medication.

Elevated depressive symptoms

Elevated depressive symptoms were measured using the 6-item Center for Epidemiological Studies Depression Scale (CES-D) [21]. A participant was determined to have elevated depressive symptoms if their score was 5 or higher on the CES-D. Presence of elevated depressive symptoms was available at baseline and year 3 in the WHI-OS and at baseline, year 1, and close out in the WHI-CT. Only 6 % of participants were assessed at years 3, 6, and 9. Due to high levels of missing values at year 1 and later, analysis in the CT cohort adjusted only for baseline presence of elevated depressive symptoms.

BMI

BMI was available at baseline and year 3 in the WHI-OS and at baseline, years 1, 3, 6 and 9 in the WHI-CT.

Other covariates

Other variables available at baseline for inclusion in multivariable models include: age, race/ethnicity (American Indian/Alaskan Native; Asian or Pacific Islander; Black/African American; Hispanic/Latino; White; Other), education (<=high school; high school or GED; > = high school, but less than 4 years of college; 4 or more years of college), minutes of recreational physical activity per week, total energy intake, hormone therapy use (never, former, current), family history of diabetes (no, yes, don’t know) and smoking status (never smoked, past smoker, current smoker).

Statistical analysis

Analysis datasets

WHI OS: included 68,169 women after exclusions for self-reported diagnosis of diabetes at baseline or missing data on one or more of the following: baseline diabetes status, race/ethnicity, presence of elevated depressive symptoms, antidepressant medication use, BMI or women for whom the Year 3 visit occurred more than 3.5 years post enrollment (Fig. 1). 3624 (5.3 %) women reported diagnosis of type 2 diabetes during follow-up. Antidepressant use, BMI, presence of elevated depressive symptoms was available at baseline and year 3 and included in analyses.
Fig. 1
Fig. 1

Flow chart describing analytic cohort included for the investigation (N = 120,495)

WHI CT: included 52,326 women after the following exclusions - women with a self-reported diagnosis of diabetes at baseline or missing data on one or more of the following: diabetes status at baseline, race/ethnicity, baseline presence of elevated depressive symptoms, antidepressant medication use, BMI (Fig. 1). 4171 (8.0 %) women reported diagnosis of type 2 diabetes during follow-up. Antidepressant use and BMI were recorded at baseline, year 1 and year 3. Models adjusted for presence of elevated depressive symptoms at baseline because presence of elevated depressive symptoms was only measured on a small percentage (6.26 %) of women after year 1.

Statistical models

We compared results from four approaches for estimating the association between the presence of elevated depressive symptoms/antidepressant medication use with incident type 2 diabetes, in the WHI-OS and WHI-CT datasets separately. Results reported by Ma and colleagues [9] were based on multivariable Cox models as in Approach 1 and Approach 2 described below. The results from these models were compared to propensity score adjusted models (Approach 3) and MSMs (Approach 4) [2225]. The interaction of elevated depressive symptoms and antidepressant medication use was investigated in all models, but all interactions were insignificant (p > 0.26 in WHI-OS, p > 0.06 in WHI-CT).

Approach 1 is a Cox proportional hazards (PH) model including the following covariates at baseline: elevated depressive symptoms, antidepressant use, BMI, age, ethnicity, education, minutes of recreational physical activity per week, total energy intake, hormone therapy use, family history of diabetes and smoking status.

Approach 2 is a Cox model with time-varying values of elevated depressive symptoms (WHI-OS only), antidepressant medication use and BMI, and baseline values of age, ethnicity, education, minutes of recreational physical activity per week, total energy intake, hormone therapy use, family history of diabetes and smoking status.

Approach 3 is similar to Approach 2, with additional adjustment for propensity for taking antidepressants at baseline. The propensity score was calculated to predict antidepressant use at baseline (outcome) from a logistic model. Predictors included in the model were baseline measures of BMI, age, ethnicity, education, minutes of recreational physical activity per week, total energy intake, hormone therapy use, family history of diabetes and smoking status.

Approach 4 is a MSM for a time to event outcome [10]. Two separate logistic regression models were fit to calculate the probability of being on antidepressants and the probability of censoring (not observing the outcome by that point in time). The models incorporated time-varying data on the presence of elevated depressive symptoms and BMI while adjusting for baseline values of age, ethnicity, education, minutes of recreational physical activity per week, total energy intake, hormone therapy use, family history of diabetes and smoking status. These models were used to determine the stabilized Inverse Probability of Treatment (IPTW) weights. In the WHI-CT analysis, models were also adjusted for clinical site. To relax the linearity assumption, we added a quadratic function of time to the model. Model details and associated SAS code are included in the Appendix.

Results

Table 1 presents baseline characteristics of our study population, by antidepressant medication use. Baseline characteristics by presence of elevated depressive symptoms are shown in Table 4 (Appendix). In both cohorts, the mean age was approximately 63 years old (63.6 (OS); 62.8 (CT)). Women were primarily White (86.5 % (OS); 84.4 % (CT)) and most had greater than high school education (80 % (OS); 76.4 % (CT)). Approximately 30 % of women on antidepressants had elevated depressive symptoms (28.2 % (OS); 29.8 % (CT)). A greater percentage of antidepressant medication users than non-users reported current use of hormone replacement therapy (64.9 % vs. 49.7 % (OS); 53.6 % vs. 36.3 % (CT)). Antidepressant users and non-users had approximately equal proportions that reported a family history of diabetes (30 % vs. 30.6 % (OS); 31.4 % vs. 31.6 % (CT)) or current smoking (7.2 % vs. 5.4 % (OS); 9.0 % vs. 7.2 % (CT)). Mean BMI was similar for those on antidepressants vs. not (27.91 vs. 26.70 (OS); 29.41 vs. 28.48 (CT)).
Table 1

Baseline characteristics of study participants in the Women’s Health Initiative (N = 120,495)

 

Antidepressant medication use

No

Yes

Total

No

Yes

Total

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

WHI-OS N = 68,169

WHI-CT N = 52,326

Baseline presence of elevated depressive symptomsa

  No

54923 (86.7 %)

3440 (71.8 %)

58363 (85.6 %)

42582 (86.7 %)

2238 (70.2 %)

44820 (85.7 %)

  Yes

8457 (13.3 %)

1349 (28.2 %)

9806 (14.4 %)

6557 (13.3 %)

949 (29.8 %)

7506 (14.3 %)

Agea

      

  Mean (SD)

63.7 (7.3)

62.1 (7.3)

63.6 (7.3)

62.8 (6.9)

61.77 (6.9)

62.8 (6.9)

  Median (IQR)

64.0 (11.0)

62.0 (12.0)

64.0 (11.0)

63.0 (11.0)

61.0 (11.0)

63.0 (11.0)

Ethnicitya

      

  American Indian/Alaskan Native

208 (0.3 %)

19 (0.4 %)

227 (0.3 %)

181 (0.4 %)

8 (0.3 %)

189 (0.4 %)

  Asian or Pacific Islander

2009 (3.2 %)

44 (0.9 %)

2053 (3.0 %)

1207 (2.5 %)

22 (0.7 %)

1229 (2.4 %)

  Black/African American

4037 (6.4 %)

158 (3.3 %)

4195 (6.2 %)

4266 (8.7 %)

119 (3.7 %)

4385 (8.4 %)

  Hispanic/Latino

1845 (2.9 %)

146 (3.1 %)

1991 (2.9 %)

1711 (3.5 %)

85 (2.7 %)

1796 (3.4 %)

  White

54614 (86.2 %)

4380 (91.5 %)

58994 (86.5 %)

41243 (83.9 %)

2924 (91.8 %)

44167 (84.4 %)

  Other

667 (1.1 %)

42 (0.9 %)

709 (1.0 %)

531 (1.1 %)

29 (0.9 %)

560 (1.1 %)

Education

      

  <= High school

2409 (3.8 %)

189 (4 %)

2598 (3.8 %)

2302 (4.7 %)

144 (4.5 %)

2446 (4.7 %)

  High school or GED

9765 (15.5 %)

752 (15.9 %)

10517 (15.5 %)

8991 (18.4 %)

587 (18.5 %)

9578 (18.4 %)

  > = High school, but less than 4 years of college

22587 (35.9 %)

1765 (37.2 %)

24352 (36.0 %)

19110 (39.1 %)

1236 (39.0 %)

20346 (39.1 %)

  4 or more years of college

28152 (44.7 %)

2036 (42.9 %)

30188 (44.6 %)

18426 (37.7 %)

1199 (37.9 %)

19625 (37.7 %)

BMIa

      

  Mean (SD)

26.7 (5.5)

27.9 (6.0)

26.8 (5.5)

28.5 (5.6)

29.4 (6.0)

28.5 (5.7)

  Median (IQR)

25.6 (6.3)

26.7 (7.2)

25.7 (6.4)

27.6 (7.2)

28.4 (8.0)

27.6 (7.2)

Minutes of recreational physical activity per weeka

  Mean (SD)

206.9 (186.2)

172.1 (174.8)

204.5 (185.6)

163.2 (169.0)

138.9 (159.2)

161.7 (168.5)

  Median (IQR)

165.0 (225.0)

135.0 (212.5)

165.0 (225.0)

125.0 (215.0)

85.0 (195.0)

120.0 (215.0)

Total energy intake (kcal/day)a

  Mean (SD)

1533.1 (599.9)

1615.1 (640.4)

1538.8 (603.2)

1716.7 (679.5)

1819.7 (711.9)

1723.0 (682.0)

  Median (IQR)

1461.3 (730.1)

1533.2 (765.8)

1465.4 (733.4)

1618.3 (832.5)

1716.3 (870.8)

1623.7 (833.7)

Hormone replacement therapy usea

  Never

18423 (29.6 %)

738 (15.7 %)

19161 (28.6 %)

17793 (37.9 %)

662 (21.6 %)

18455 (36.9 %)

  Former

12885 (20.7 %)

914 (19.4 %)

13799 (20.6 %)

12122 (25.8 %)

760 (24.8 %)

12882 (25.7 %)

  Current

30931 (49.7 %)

3055 (64.9 %)

33986 (50.8 %)

17057 (36.3 %)

1644 (53.6 %)

18701 (37.4 %)

Family history of diabetes

  No

41656 (66.0 %)

3114 (65.2 %)

44770 (65.9 %)

31282 (63.9 %)

2022 (63.7 %)

33304 (63.9 %)

  Yes

18923 (30.0 %)

1463 (30.6 %)

20386 (30.0 %)

15378 (31.4 %)

1004 (31.6 %)

16382 (31.4 %)

  Don’t know

2569 (4.1 %)

198 (4.1 %)

2767 (4.1 %)

2280 (4.7 %)

147 (4.6 %)

2427 (4.7 %)

Smoking statusa

      

  Never smoked

32614 (52.0 %)

2188 (46.2 %)

34802 (51.6 %)

25547 (52.5 %)

1429 (45.2 %)

26976 (52.1 %)

  Past smoker

26685 (42.6 %)

2207 (46.6 %)

28892 (42.9 %)

19615 (40.3 %)

1445 (45.7 %)

21060 (40.6 %)

  Current smoker

3370 (5.4 %)

339 (7.2 %)

3709 (5.5 %)

3495 (7.2 %)

285 (9.0 %)

3780 (7.3 %)

Reported diagnosis of diabetes by end of follow-upa

  No

60077 (94.8 %)

4468 (93.3 %)

64545 (94.7 %)

45269 (92.1 %)

2886 (90.6 %)

48155 (92.0 %)

  Yes

3303 (5.2 %)

321 (6.7 %)

3624 (5.3 %)

3870 (7.9 %)

301 (9.4 %)

4171 (8.0 %)

Years from enrollment to developing diabetesa

  Mean (SD)

7.7 (1.5)

7.6 (1.5)

7.7 (1.5)

8.0 (1.7)

7.9 (1.7)

8.0 (1.7)

  Median (IQR)

7.9 (2.0)

7.9 (2.0)

7.9 (2.0)

8.0 (1.7)

8.00 (1.9)

8.0 (1.8)

aP – value of <0.002 or lower

OS cohort

Elevated depressive symptoms

An unadjusted model including only baseline values of antidepressant medication use and presence of elevated depressive symptoms showed a significant increase in diabetes risk for those with elevated depressive symptoms (HR 1.34; 95 % CI: 1.23-1.45). Approaches 1 and 2 that adjust for other confounders also resulted in a statistically significant association between the presence of elevated depressive symptoms and increased risk of diabetes – however, this association did not remain statistically significant in propensity score adjusted models and MSMs.

Antidepressant medication use

All models showed a consistent, statistically significant increase in diabetes risk for those exposed to antidepressant medications vs. those who were not (Table 2). Approach 1 using baseline measures only yielded a HR of 1.19 (95 % CI 1.06 – 1.35). Approach 2 and Approach 3 using time-varying antidepressant medication use, presence of elevated depressive symptoms and BMI, yielded almost identical results for antidepressant medication use [Approach 2: 1.31 (95 % CI 1.18 – 1.46); Approach 3: 1.32 (95 % CI 1.19 – 1.47)]. There were no significant differences in the HRs estimated for the presence of elevated depressive symptoms between Approaches 2 and 3. The results from MSMs (Approach 4) were almost identical to Approaches 2 and 3 –the HR (CI) for antidepressant medication use was 1.35 (95 % CI 1.21 – 1.51). In this application, the MSM approach yielded similar results to the traditional extended Cox model.
Table 2

Hazard ratios for presence of elevated depressive symptoms and antidepressant use with respect to incident diabetes risk

 

Unadjusted Cox PH model

Approach 1a

Approach 2a

Approach 3a

Approach 4a

 

Cox PH Model (baseline antidepressant medication use and baseline presence of elevated depressive symptoms)

Cox PH Models (baseline values of all predictors)

Cox Models (time varying antidepressant medication use, presence of elevated depressive symptoms, and BMI; baseline values for other covariates)

Cox Models (time varying antidepressant medication use, presence of elevated depressive symptoms, and BMI; adjusted for propensity score and baseline values for other covariates)

Marginal Structural Models (time varying antidepressant medication use, presence of elevated depressive symptoms, and BMI; baseline values for other covariates)

Predictor

HR (95 % CI)

HR (95 % CI)

HR (95 % CI)

HR (95 % CI)

HR (95 % CI)

 

Observational Cohort (OS) (N = 68,169)

  Antidepressant medication use up to year 3

1.26

1.19

1.31

1.32

1.35

(1.12–1.41)

(1.06–1.35)

(1.18–1.46)

(1.19–1.47)

(1.21–1.51)

  Presence of elevated depressive symptoms

1.34

1.11

1.12

1.09

1.10

(1.23–1.45)

(1.02–1.21)

(1.03–1.23)

(1.00–1.19)

(1.00–1.20)

 

Clinical Trial (CT) (N = 52,326)

  Antidepressant medication use up to year 3

1.17

1.14

1.26

1.25

1.27

(1.04–1.31)

(1.01–1.30)

(1.12–1.41)

(1.12–1.40)

(1.13–1.43)

  Presence of elevated depressive symptoms

1.31

1.13

1.12

1.09

1.10

(1.21–1.42)

(1.04–1.23)

(1.03–1.22)

(0.996–1.18)

(1.00–1.20)

aModels adjusted for baseline values of age, ethnicity, education, minutes of recreational physical activity per week, total energy intake, hormone therapy use, family history of diabetes and smoking status

CT cohort

Elevated depressive symptoms

As in the WHI-OS, the unadjusted model showed a significant increase in diabetes risk for those with elevated depressive symptoms. While this association was statistically significant in Approaches 1 and 2, it did not remain so in the propensity score adjusted model (Approach 3) and the MSM (Approach 4).

Antidepressant medication use

As in the WHI OS, all models in the WHI-CT showed a consistent, statistically significant increase in diabetes risk for those exposed to antidepressant medications vs. those who were not.

Table 3 presents an estimate of variation in antidepressant medication use and presence of elevated depressive symptoms at baseline and year 3, by cohort. In the WHI-OS, 4.9 % of women were using antidepressant medication at both time-points, whereas 88.5 % never used them. 2.2 % of women who were using antidepressant medication at baseline had stopped by year 3, and 4.5 % who were not using antidepressant medication at baseline had started by year 3. 6.4 % experienced elevated depressive symptoms at both baseline and year 3, while 76.3 % never did. 8 % of women who experienced elevated depressive symptoms at baseline did not report experiencing those symptoms at year 3, and 9.3 % without elevated depressive symptoms at baseline did experience them by year 3. Similar patterns were observed in the WHI-CT.
Table 3

Estimate of variation in presence of depressive symptoms and antidepressant medication use over time

 

WHI-OS N = 68,169

 

Antidepressant use at baseline

No antidepressant use at baseline

 

N (%)

N (%)

Antidepressant use at year 3

3321 (4.9 %)

3083 (4.5 %)

No antidepressant use at year 3

1468 (2.2 %)

60297 (88.5 %)

 

Presence of elevated symptoms at baseline

No presence of elevated symptoms at baseline

 

N (%)

N (%)

Presence of elevated symptoms at year 3

4348 (6.4 %)

6333 (9.3 %)

No presence of elevated symptoms at year 3

5458 (8.0 %)

52030 (76.3 %)

 

Baseline

Year 3

 

Mean (SD)

Mean (SD)

BMI

26.80 (5.5)

27.09 (5.6)

 

WHI-CT N = 52,326

 

Antidepressant use at baseline

No antidepressant use at baseline

 

N (%)

N (%)

Antidepressant use at year 3

2031 (3.9 %)

1979 (3.8 %)

No antidepressant use at year 3

1156 (2.2 %)

47160 (90.1 %)

 

Baseline

Year 3

 

Mean (SD)

Mean (SD)

BMI

28.54 (5.7)

28.78 (5.9)

Table 5 (Appendix) presents the HRs and 95 % CIs for all covariates in the MSMs, in the WHI-OS and CT cohorts. Table 6 (Appendix) presents the distributions of the IPTW weights, including the estimated probability of having one’s own observed treatment history and censoring history at follow-up time points. The probability of remaining uncensored was close to 1 for both cohorts at each follow-up time point given both the baseline and time-varying covariates. There was variation in the probability of having one’s own observed treatment history, but the mean and median were close to 1 at 36 month follow-up in the WHI-OS and 12 and 36 month follow-up in the WHI-CT.

Discussion

Previous research has shown that the prevalence of elevated depressive symptoms and diabetes is high in postmenopausal women [1, 26]. Ma and colleagues [9] found an increased risk of type 2 diabetes among women in the WHI cohorts who reported elevated depressive symptoms (HR 1.13 [95 % CI 1.07–1.20]) and antidepressant use at baseline (1.18 [95 % CI 1.10–1.28]), based on Cox models. Multivariable longitudinal analyses confirmed this relationship with recent antidepressant medication use, but found only prolonged elevated depressive symptoms to be significantly associated with increased risk. Our analyses were performed on 120,495 women in the WHI and adjusted for the same confounders, but utilized Cox models as well as propensity score adjusted models and MSMs. Our analyses found a consistent, significant increase in diabetes risk among those reporting antidepressant medication use by four different statistical approaches. In all approaches considered, presence of elevated depressive symptoms was rendered marginally or non-significant after adjusting for confounders. Our results are consistent with previous studies examining the relationship of antidepressant medication use and risk of type 2 diabetes [36, 27, 28].

Of the four different modeling approaches considered in this paper, MSMs are the gold standard for use in observational studies in which the presence of time-dependent confounding (Fig. 2, Appendix) is a possibility. For observational study settings in the absence of time-dependent confounding, propensity score adjusted models can be used to adjust for bias in exposure assignment. Propensity score adjusted models correct for confounding by indication – this bias is present in studies in which individuals who are prescribed or take a medication are inherently different in their risk profile with respect to outcome when compared to those who do not take the drug. In the absence of confounding by indication and time-dependent confounding, simpler Cox models with or without time-varying covariates are appropriate.

We did not observe differences in hazard ratio estimates between the four modeling approaches that were considered. One explanation for the concordance of estimates from these different approaches suggests that time-dependent confounding by BMI was not a substantial factor in these data – thus, BMI measured over the course of observation may not be strongly affected by exposure (i.e., as an intermediate) and/or did not exert a strong influence on our exposure and outcome of interest (i.e., as a confounder). However, other potential explanations for this observed concordance of results include limited longitudinal measurements of the key exposure variables, measurement error of the confounder and/or incorrect model specification of the dose response relationship with respect to the effects of the confounder on both exposure and outcome. However, this study was not designed to pinpoint the specific factor that caused the concordance of estimates from the various models.

A limitation of this work is that we had limited longitudinal follow up. The WHI-OS had two repeated measures, at baseline and at year 3. The WHI-CT had more repeated measures available, but we were only able to utilize three time points (baseline, year 1, year 3) due to high levels of missing data at later time points. In addition, in the WHI-CT, because presence of elevated depressive symptoms was measured on only a small percentage of participants after year 1, our models could not incorporate this factor as a time varying exposure. Due to limitations of the available data, the analysis did not account for antidepressant dose and adherence. While a bidirectional association between depression and diabetes risk is biologically plausible, our study was not designed to tease out the direction of association. Lastly, due to cost considerations, diabetes status was ascertained through self-reported questionnaires – this could result in modest levels of outcome misclassification. Statistical models that account for the error-prone self-reported outcomes would be useful in this context.

Conclusions

Our analyses provide further evidence that a significant increase in diabetes risk is observed for those on antidepressant medications in the WHI. In addition, our results comparing modeling approaches demonstrates that in some settings, results from more complex methods such as MSMs may not differ substantially from traditional methods of analysis – however, we recommend that these methods be explored to establish the validity of initial findings.

Abbreviations

WHI-CT: 

Women’s health initiative clinical trials cohort

WHI-OS: 

Women’s health initiative observational cohort

WHI: 

Women’s Health Initiative

BMI: 

Body mass index

IPTW: 

Inverse probability of treatment weights

CES-D: 

Center for Epidemiological Studies Depression Scale

PH: 

Cox Proportional Hazards

CI: 

Confidence interval

HR: 

Hazard ratio

MSMs: 

Marginal structural models

Declarations

Acknowledgements

This work was supported by National Institutes of Health grants 1R01HL122241 and 1R21 DK083700-01A1. The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. A list of WHI investigators is available in Supplementary Data online. The authors thank the principal investigators of all WHI clinical centers and the data coordinating center for their contribution to the study. They are also indebted to the dedicated and committed participants of the WHI.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Division of Preventive and Behavioral Medicine, Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
(2)
Division of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, 715 North Pleasant Street, Amherst, MA 01003, USA

References

  1. Kim CK, McGorray SP, Bartholomew BA, Marsh M, Dicken T, Wassertheil-Smoller S, et al. Depressive symptoms and heart rate variability in postmenopausal women. Arch Intern Med. 2005;165(11):1239–44. doi:10.1001/archinte.165.11.1239.View ArticlePubMedGoogle Scholar
  2. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.View ArticlePubMedGoogle Scholar
  3. Brown LC, Majumdar SR, Johnson JA. Type of antidepressant therapy and risk of type 2 diabetes in people with depression. Diabetes Res Clin Pract. 2008;79(1):61-7. doi:10.1016/j.diabres.2007.07.009View ArticlePubMedGoogle Scholar
  4. Rubin RR, Ma Y, Marrero DG, Peyrot M, Barrett-Connor EL, Kahn SE et al. Elevated depression symptoms, antidepressant medicine use, and risk of developing diabetes during the diabetes prevention program. Diabetes Care. 2008;31(3):420-6. doi:10.2337/dc07-1827View ArticlePubMedGoogle Scholar
  5. Andersohn F, Schade R, Suissa S, Garbe E. Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry. 2009;166(5):591-8. doi:10.1176/appi.ajp.2008.08071065View ArticlePubMedGoogle Scholar
  6. Campayo A, de Jonge P, Roy JF, Saz P, de la Camara C, Quintanilla MA et al. Depressive disorder and incident diabetes mellitus: the effect of characteristics of depression. Am J Psychiatry. 2010;167(5):580-8. doi:10.1176/appi.ajp.2009.09010038View ArticlePubMedGoogle Scholar
  7. Olfson M, Marcus SC. National patterns in antidepressant medication treatment. Arch Gen Psychiatry. 2009;66(8):848-56. doi:10.1001/archgenpsychiatry.2009.81View ArticlePubMedGoogle Scholar
  8. The Medicated Americans: Antidepressant Prescriptions on the Rise July 15, 2013.http://www.sciam.com/article.cfm?id=the-medicated-americans
  9. Ma Y, Balasubramanian R, Pagoto SL, Schneider KL, Culver AL, Olendzki B et al. Elevated depressive symptoms, antidepressant use, and diabetes in a large multiethnic national sample of postmenopausal women. Diabetes Care. 2011;34(11):2390-2. doi:10.2337/dc11-1223View ArticlePubMedPubMed CentralGoogle Scholar
  10. Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology. 2000;11(5):561–70.View ArticlePubMedGoogle Scholar
  11. Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11(5):550–60.View ArticlePubMedGoogle Scholar
  12. Robins JM. Causal inference from complex longitudinal data. In: Berkane M, editor. Latent Variable Modeling and Applications to Causality. Lecture Notes in Statistics (120). New York, NY: Springer Verlag; 1997. p. 69–117.Google Scholar
  13. Geoffroy MC, Li L, Power C. Depressive symptoms and body mass index: co-morbidity and direction of association in a British birth cohort followed over 50 years. Psychol Med.44(12):2641-52. doi:10.1017/S0033291714000142
  14. Chen AB, Li L, Cronin A, Schrag D. Comparative Effectiveness of Intensity-Modulated Versus 3D Conformal Radiation Therapy Among Medicare Patients with Stage III Lung Cancer. J Thorac Oncol. 2014. doi:10.1097/JTO.0000000000000331Google Scholar
  15. Farber HW, Miller DP, McGoon MD, Frost AE, Benton WW, Benza RL. Predicting outcomes in pulmonary arterial hypertension based on the 6-minute walk distance. J Heart Lung Transplant. 2014. doi:10.1016/j.healun.2014.08.020Google Scholar
  16. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials. 1998;19(1):61-109.Google Scholar
  17. Ritenbaugh C, Patterson RE, Chlebowski RT, Caan B, Fels-Tinker L, Howard B et al. The Women's Health Initiative Dietary Modification trial: overview and baseline characteristics of participants. Ann Epidemiol. 2003;13(9 Suppl):S87–97.View ArticlePubMedGoogle Scholar
  18. Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR. The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol. 2003;13(9 Suppl):S78–86.View ArticlePubMedGoogle Scholar
  19. Langer RD, White E, Lewis CE, Kotchen JM, Hendrix SL, Trevisan M. The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol. 2003;13(9 Suppl):S107–21.View ArticlePubMedGoogle Scholar
  20. Margolis KL, Lihong Q, Brzyski R, Bonds DE, Howard BV, Kempainen S et al. Validity of diabetes self-reports in the Women's Health Initiative: comparison with medication inventories and fasting glucose measurements. Clin Trials. 2008;5(3):240-7. doi:10.1177/1740774508091749View ArticlePubMedPubMed CentralGoogle Scholar
  21. Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening for depression in well older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). Am J Prev Med. 1994;10(2):77–84.PubMedGoogle Scholar
  22. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70(1):41–55.View ArticleGoogle Scholar
  23. Harlow S, Linet M. Reviews and commentary: Agreement between questionnaire data and medical records: the evidence for accuracy of recall. American journal of epidemiology. 1989;129(2):233–48.PubMedGoogle Scholar
  24. Pearl J. Understanding propensity scores. Causality: Models, Reasoning, and Inference. 2nd ed. New York: Cambridge University Press; 2009.Google Scholar
  25. Pearl J. Causality: Models, Reasoning, and Inference. New York: Cambridge University Press; 2000.Google Scholar
  26. Marcus A, Crane L. Smoking behavior among U.S. Latinos: an emerging challenge for public health. American journal of public health. 1985;75:169–72.View ArticlePubMedPubMed CentralGoogle Scholar
  27. Pan A, Sun Q, Okereke OI, Rexrode KM, Rubin RR, Lucas M et al. Use of antidepressant medication and risk of type 2 diabetes: results from three cohorts of US adults. Diabetologia. 2012;55(1):63-72. doi:10.1007/s00125-011-2268-4View ArticlePubMedGoogle Scholar
  28. Fruchter R, Boyce J, Hunt M. Missed opportunities for early diagnosis of cancer of the cervix. American journal of public health. 1980;70:418–20.View ArticlePubMedPubMed CentralGoogle Scholar

Copyright

© Frisard et al. 2015

Advertisement