ORIGINAL ARTICLE
Depressive Symptoms, Antidepressant Medication Use, and New Onset of Diabetes in Participants of the Diabetes Prevention Program and the Diabetes Prevention Program Outcomes Study David G. Marrero, PhD, Yong Ma, PhD, Mary de Groot, PhD, Edward S. Horton, MD, David W. Price, MD, Elizabeth Barrett-Connor, MD, Mercedes R. Carnethon, PhD, and William C. Knowler, MD, for the Diabetes Prevention Program Research Group ABSTRACT Objective: To assess in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study whether diagnosis of diabetes predicted elevated depressive symptoms (DS) or use of antidepressant medicine (ADM) following diagnosis; whether diabetes status or duration had significant effect on DS or ADM use; and to determine the associations between A1C, fasting plasma glucose (FPG), normalization of FPG, and DS or ADM use after diagnosis. Methods: Diabetes Prevention Program participants in three treatment arms (intensive life style, metformin, placebo) were assessed for diabetes, glucose control, ADM use, and DS, measured using the Beck Depression Inventory (BDI). Among 3234 participants, 1285 developed diabetes. Depression levels were measured before and after diabetes diagnosis. Results: Neither DS nor use of ADM increased after diagnosis; higher FPG was associated with greater ADM use in the intensive life style arm; a 10-mg/dl rise in FPG is associated with greater odds of ADM use. Higher FPG and A1C were associated with higher BDI scores in all three arms; A 10-mg/dl rise in FPG had a 0.07 increase in BDI. A 1% higher A1c was associated with a 0.21-point increase in BDI. Normalization of FPG was associated with lower BDI. When FPG had normalized, there was a decrease of 0.30 points in the BDI score compared when FPG had not normalized. Conclusions: Contrary to clinical attributions, diabetes diagnosis did not show an immediate impact on BDI scores or ADM use. Higher glucose levels after diagnosis were associated with a small but significantly higher BDI score and more ADM use. Trial Registration: DPPOS: NCT00038727; DPP: NCT00004992 Key words: diagnosis of diabetes, depressive symptoms, antidepressant medication, prediabetes, Type 2 diabetes mellitus, prevenion.
INTRODUCTION
ADM = antidepressant medicine, BDI = Beck Depression Inventory, DPP = Diabetes Prevention Program, DPPOS = Diabetes Prevention Program Outcomes Study, DS = depressive symptoms, FPG = fasting plasma glucose, ILS = intensive life style, MET = metformin, PLC = placebo
depressive symptoms are associated with Type 2 diabetes mellitus, with evidence suggesting a bidirecE levated tional relationship (1,2). Individuals with Type 2 diabetes Supplemental Content
From the Department of Medicine (Marrero, de Groot), Indiana University School of Medicine, Indianapolis, Indiana; The Biostatistics Center (Ma), George Washington University, Rockville, Maryland; Harvard Medical School (Horton), Boston, Massachusetts; Institute for Health Research (Price), Kaiser Permanente, Denver, Colorado; Department of Family Medicine (Barrett-Connor), University of California, San Diego, California; Department of Medicine (Carnethon), Northwestern University Feinberg School of Medicine, Chicago, Illinois; National Institute of Diabetes and Digestive and Kidney Diseases (Knowler), Phoenix, Arizona. Address correspondence and reprint requests to David G. Marrero, PhD, c/o The Biostatistics Center, George Washington University, 6110 Executive Blvd, Suite 750, Rockville, MD 20852. E-mail: [email protected] Received for publication May 6, 2014; revision received October 25, 2014. DOI: 10.1097/PSY.0000000000000156 Copyright © 2015 by the American Psychosomatic Society
Psychosomatic Medicine, V 77 • 303-310
303
April 2015
Copyright © 2015 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
ORIGINAL ARTICLE
depression and diabetes. In addition, glucose control may influence depressive symptoms and ADM use. In addition, the onset of diabetes may influence changes to mood that could have an impact on glycemic control downstream. The Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS) offer an opportunity to investigate the impact a diagnosis of diabetes on the development of depressive symptoms or the onset of ADM use, and the association between glucose control and depressive symptoms or ADM use. Unlike previous studies where it is not possible to ascertain when clinical diabetes began, the onset of diabetes in this sample can be determined within 6 months of its occurrence. In addition, because the DPP is a longitudinal study, it can be used to investigate how depressive symptoms and ADM use change over time. Finally, because glucose levels were tracked over time, the relationship between variations in glucose, depressive symptoms, and antidepressant use can be explored. The current study had two aims: a) to examine changes in depressive symptoms and ADM use immediately after diagnosis of diabetes in the DPP cohort and b) to examine relationships between depressive symptoms, ADM use, and glycemic control (A1c, FPG) in the DPPOS study cohort at follow-up assessment time points after diabetes diagnosis. We hypothesized that levels of depressive symptoms and ADM use would increase immediately after diabetes diagnosis, and a small but significant relationship would be observed between depressive symptoms, ADM use, and glycemic control in subsequent study assessment time points.
have been shown to have a higher risk of developing depression (3–10). Conversely, individuals with a lifetime history of depression as well as those with antidepressant medication (ADM) use have been shown to be at higher risk for developing Type 2 diabetes (3,9,10). This relationship is hypothesized to be bidirectional, but few studies have been capable of assessing this relationship from a life span perspective (11). In one meta-analysis exploring this issue, the presence of depression was shown to be associated with the onset of Type 2 diabetes, whereas the iagnosis of the disease was only modestly associated with the onset of depression (11). Previous research investigating these relationships is mitigated by the fact that it is difficult to know when the onset of diabetes occurred. Indeed, most studies have used cross-sectional samples in which it cannot be determined accurately when diabetes began. In many cases, diabetes may have been present for years before a clinical diagnosis was made. Thus, it is impossible to ascertain if there is a dose or duration effect of either diabetes or depressive symptoms. There is a paucity of literature characterizing the psychosocial impacts, including depressive symptoms, of newonset diabetes among adults (12) with most of psychosocial studies using samples with a wide range of diabetes duration. Development theories have posited that the onset of diabetes is characterized by emotional adjustment that may include a period of grief and mourning or denial of the illness and its consequences (13). These theories suggest that the onset of diabetes may set the stage for elevated depressive symptoms that may have preceded or resulted from the onset of diabetes. In a study of adults newly diagnosed as having either Type 1 (n = 41) or Type 2 diabetes (n = 48), Rane and colleagues (12) found that 41% of participants reported psychosocial problems ranging from relationships, work, personal finances, and social support. More than 17% of patients reporting psychosocial problems also reported depressive symptoms representing a significantly higher rate than participants without psychosocial problems. The literature documenting the relationship of depressive symptoms to glycemic control has been mixed with evidence suggesting a small hyperglycemic effect of depressive symptoms (7). More recent studies in which depressive symptoms, depressive disorders, and diabetesdistress were assessed and compared directly within the same participant sample have shown no association between depressive symptoms and A1c, but significant relationships between diabetes-related distress and glycemic outcomes (14). In this study, participants had an average duration of Type 2 diabetes of 8.1 years. To date, no studies have examined the relationship of fasting plasma glucose (FPG), A1c, and depression symptom scores before and after diabetes onset using a precise definition of diabetes diagnosis. Glucose may play a role in the relationship between Psychosomatic Medicine, V 77 • 303-310
DESIGN AND METHODS Study Population The DPP enrolled individuals at high risk for Type 2 diabetes and was conducted at 27 US centers. DPP methods and results are described in detail elsewhere (15–17). The protocol is available at http://www.bsc.gwu.edu/dpp. At each DPP center, an institutional review board approved the protocol and all participants gave written informed consent. Participants were 25 years or older, had a body mass index (BMI) of at least 24 kg/m2 (≥22 kg/m2 in Asian Americans) and had a plasma glucose concentration of 95 to 125 mg/dl (5.3–6.9 M) in the fasting state (≤125 mg/dl in American Indians) and 140 to 199 mg/dl (7.8–11.0 M) 2 hours after a 75-g oral glucose load. Exclusion criteria included ADM use that might contribute to weight loss, conditions that could seriously reduce the ability to participate in the DPP (including major psychiatric disorders or serious clinical depressive symptoms), or inability to complete the 3-week run-in period during which participants took placebo (PLC) medicines and recorded their usual eating and physical activity patterns. Eligible participants were randomly assigned to one of three interventions: standard life style recommendations plus metformin (MET) at a dose of 850 mg twice daily
304
April 2015
Copyright © 2015 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
Depression, ADM Use, and New Onset Diabetes
TABLE 1. Baseline Characteristics of Participants Diagnosed With Diabetes Characteristics a
Age at randomization , median (IQR), y Sex Male Female Race/Ethnicity White African American Hispanic American Indian Asian Household incomeb
Depressive Symptoms, Antidepressant Medication Use, and New Onset of Diabetes in Participants of the Diabetes Prevention Program and the Diabetes Prevention Program Outcomes Study David G. Marrero, PhD, Yong Ma, PhD, Mary de Groot, PhD, Edward S. Horton, MD, David W. Price, MD, Elizabeth Barrett-Connor, MD, Mercedes R. Carnethon, PhD, and William C. Knowler, MD, for the Diabetes Prevention Program Research Group ABSTRACT Objective: To assess in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study whether diagnosis of diabetes predicted elevated depressive symptoms (DS) or use of antidepressant medicine (ADM) following diagnosis; whether diabetes status or duration had significant effect on DS or ADM use; and to determine the associations between A1C, fasting plasma glucose (FPG), normalization of FPG, and DS or ADM use after diagnosis. Methods: Diabetes Prevention Program participants in three treatment arms (intensive life style, metformin, placebo) were assessed for diabetes, glucose control, ADM use, and DS, measured using the Beck Depression Inventory (BDI). Among 3234 participants, 1285 developed diabetes. Depression levels were measured before and after diabetes diagnosis. Results: Neither DS nor use of ADM increased after diagnosis; higher FPG was associated with greater ADM use in the intensive life style arm; a 10-mg/dl rise in FPG is associated with greater odds of ADM use. Higher FPG and A1C were associated with higher BDI scores in all three arms; A 10-mg/dl rise in FPG had a 0.07 increase in BDI. A 1% higher A1c was associated with a 0.21-point increase in BDI. Normalization of FPG was associated with lower BDI. When FPG had normalized, there was a decrease of 0.30 points in the BDI score compared when FPG had not normalized. Conclusions: Contrary to clinical attributions, diabetes diagnosis did not show an immediate impact on BDI scores or ADM use. Higher glucose levels after diagnosis were associated with a small but significantly higher BDI score and more ADM use. Trial Registration: DPPOS: NCT00038727; DPP: NCT00004992 Key words: diagnosis of diabetes, depressive symptoms, antidepressant medication, prediabetes, Type 2 diabetes mellitus, prevenion.
INTRODUCTION
ADM = antidepressant medicine, BDI = Beck Depression Inventory, DPP = Diabetes Prevention Program, DPPOS = Diabetes Prevention Program Outcomes Study, DS = depressive symptoms, FPG = fasting plasma glucose, ILS = intensive life style, MET = metformin, PLC = placebo
depressive symptoms are associated with Type 2 diabetes mellitus, with evidence suggesting a bidirecE levated tional relationship (1,2). Individuals with Type 2 diabetes Supplemental Content
From the Department of Medicine (Marrero, de Groot), Indiana University School of Medicine, Indianapolis, Indiana; The Biostatistics Center (Ma), George Washington University, Rockville, Maryland; Harvard Medical School (Horton), Boston, Massachusetts; Institute for Health Research (Price), Kaiser Permanente, Denver, Colorado; Department of Family Medicine (Barrett-Connor), University of California, San Diego, California; Department of Medicine (Carnethon), Northwestern University Feinberg School of Medicine, Chicago, Illinois; National Institute of Diabetes and Digestive and Kidney Diseases (Knowler), Phoenix, Arizona. Address correspondence and reprint requests to David G. Marrero, PhD, c/o The Biostatistics Center, George Washington University, 6110 Executive Blvd, Suite 750, Rockville, MD 20852. E-mail: [email protected] Received for publication May 6, 2014; revision received October 25, 2014. DOI: 10.1097/PSY.0000000000000156 Copyright © 2015 by the American Psychosomatic Society
Psychosomatic Medicine, V 77 • 303-310
303
April 2015
Copyright © 2015 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
ORIGINAL ARTICLE
depression and diabetes. In addition, glucose control may influence depressive symptoms and ADM use. In addition, the onset of diabetes may influence changes to mood that could have an impact on glycemic control downstream. The Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS) offer an opportunity to investigate the impact a diagnosis of diabetes on the development of depressive symptoms or the onset of ADM use, and the association between glucose control and depressive symptoms or ADM use. Unlike previous studies where it is not possible to ascertain when clinical diabetes began, the onset of diabetes in this sample can be determined within 6 months of its occurrence. In addition, because the DPP is a longitudinal study, it can be used to investigate how depressive symptoms and ADM use change over time. Finally, because glucose levels were tracked over time, the relationship between variations in glucose, depressive symptoms, and antidepressant use can be explored. The current study had two aims: a) to examine changes in depressive symptoms and ADM use immediately after diagnosis of diabetes in the DPP cohort and b) to examine relationships between depressive symptoms, ADM use, and glycemic control (A1c, FPG) in the DPPOS study cohort at follow-up assessment time points after diabetes diagnosis. We hypothesized that levels of depressive symptoms and ADM use would increase immediately after diabetes diagnosis, and a small but significant relationship would be observed between depressive symptoms, ADM use, and glycemic control in subsequent study assessment time points.
have been shown to have a higher risk of developing depression (3–10). Conversely, individuals with a lifetime history of depression as well as those with antidepressant medication (ADM) use have been shown to be at higher risk for developing Type 2 diabetes (3,9,10). This relationship is hypothesized to be bidirectional, but few studies have been capable of assessing this relationship from a life span perspective (11). In one meta-analysis exploring this issue, the presence of depression was shown to be associated with the onset of Type 2 diabetes, whereas the iagnosis of the disease was only modestly associated with the onset of depression (11). Previous research investigating these relationships is mitigated by the fact that it is difficult to know when the onset of diabetes occurred. Indeed, most studies have used cross-sectional samples in which it cannot be determined accurately when diabetes began. In many cases, diabetes may have been present for years before a clinical diagnosis was made. Thus, it is impossible to ascertain if there is a dose or duration effect of either diabetes or depressive symptoms. There is a paucity of literature characterizing the psychosocial impacts, including depressive symptoms, of newonset diabetes among adults (12) with most of psychosocial studies using samples with a wide range of diabetes duration. Development theories have posited that the onset of diabetes is characterized by emotional adjustment that may include a period of grief and mourning or denial of the illness and its consequences (13). These theories suggest that the onset of diabetes may set the stage for elevated depressive symptoms that may have preceded or resulted from the onset of diabetes. In a study of adults newly diagnosed as having either Type 1 (n = 41) or Type 2 diabetes (n = 48), Rane and colleagues (12) found that 41% of participants reported psychosocial problems ranging from relationships, work, personal finances, and social support. More than 17% of patients reporting psychosocial problems also reported depressive symptoms representing a significantly higher rate than participants without psychosocial problems. The literature documenting the relationship of depressive symptoms to glycemic control has been mixed with evidence suggesting a small hyperglycemic effect of depressive symptoms (7). More recent studies in which depressive symptoms, depressive disorders, and diabetesdistress were assessed and compared directly within the same participant sample have shown no association between depressive symptoms and A1c, but significant relationships between diabetes-related distress and glycemic outcomes (14). In this study, participants had an average duration of Type 2 diabetes of 8.1 years. To date, no studies have examined the relationship of fasting plasma glucose (FPG), A1c, and depression symptom scores before and after diabetes onset using a precise definition of diabetes diagnosis. Glucose may play a role in the relationship between Psychosomatic Medicine, V 77 • 303-310
DESIGN AND METHODS Study Population The DPP enrolled individuals at high risk for Type 2 diabetes and was conducted at 27 US centers. DPP methods and results are described in detail elsewhere (15–17). The protocol is available at http://www.bsc.gwu.edu/dpp. At each DPP center, an institutional review board approved the protocol and all participants gave written informed consent. Participants were 25 years or older, had a body mass index (BMI) of at least 24 kg/m2 (≥22 kg/m2 in Asian Americans) and had a plasma glucose concentration of 95 to 125 mg/dl (5.3–6.9 M) in the fasting state (≤125 mg/dl in American Indians) and 140 to 199 mg/dl (7.8–11.0 M) 2 hours after a 75-g oral glucose load. Exclusion criteria included ADM use that might contribute to weight loss, conditions that could seriously reduce the ability to participate in the DPP (including major psychiatric disorders or serious clinical depressive symptoms), or inability to complete the 3-week run-in period during which participants took placebo (PLC) medicines and recorded their usual eating and physical activity patterns. Eligible participants were randomly assigned to one of three interventions: standard life style recommendations plus metformin (MET) at a dose of 850 mg twice daily
304
April 2015
Copyright © 2015 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
Depression, ADM Use, and New Onset Diabetes
TABLE 1. Baseline Characteristics of Participants Diagnosed With Diabetes Characteristics a
Age at randomization , median (IQR), y Sex Male Female Race/Ethnicity White African American Hispanic American Indian Asian Household incomeb
