- Email: [email protected]
The relationship of guideline-concordant depression treatment and patient adherence to oral diabetes medications
Research in Social and Administrative Pharmacy 1 (2005) 378–388
Original research
The relationship of guideline-concordant depression treatment and patient adherence to oral diabetes medications David P. Nau, Ph.D.a,*, Jingdong Chao, Ph.D.b,1, James E. Aikens, Ph.D.c a
Department of Social and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI 48109-1065, USA b Department of Health Economics and Outcomes Research, Sanofi-Aventis Pharmaceuticals, Bridgewater, NJ 08807-2854, USA c Departments of Family Medicine and Psychiatry, University of Michigan School of Medicine, Ann Arbor, MI 48109-1065, USA
Abstract Background: Many patients with diabetes experience depression, yet it is unclear if the treatment of depression in diabetic patients is concordant with national guidelines, and whether appropriate antidepressant use is associated with better diabetes self-care behaviors. Objectives: The purpose of this study was to (1) determine whether antidepressant medication use for managed care enrollees with type 2 diabetes was concordant with The Agency for Healthcare Research and Quality depression treatment guidelines; and (2) examine the relationship between guideline concordance and oral diabetes medication adherence. Methods: Retrospective analyses were conducted using medical/pharmacy claims for 2001 from a managed care organization in the midwestern United States. Subjects were adults with type 2 diabetes treated with oral medications only. The subjects were divided into 3 groups: (1) guideline-concordant users of antidepressants; (2) * Corresponding author. Tel.: C1 734 615 9083; fax: C1 734 615 8171. E-mail address: [email protected] (D.P. Nau). 1 At the time of this study, Dr Chao was affiliated with the Department of Social and Administrative Sciences at the University of Michigan College of Pharmacy. 1551-7411/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.sapharm.2005.06.001
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those who received antidepressants not in concordance with the guidelines; and (3) nonusers of antidepressants. Antidepressant users were determined to be in concordance with the acute phase treatment guidelines if they filled at least 90 days supply of antidepressant drugs within 118 days of the first fill. Adherence to diabetes medications was measured by the medication possession ratio. A 1-way analysis of variance with Scheffe’s test was used to compare the antihyperglycemic medication possession ratio across the three groups. Results: One hundred eighty-two (12.5%) of the 1454 subjects initiated treatment with antidepressants. Eighty-nine (48.9%) of the 182 antidepressant users were in concordance with the acute phase treatment guidelines. Subjects with subconcordant antidepressant use had a lower mean diabetes medication possession ratio than those with either guideline-concordant use or no use (F Z 14.3, P ! .01). Conclusion: Over half of the diabetic patients initiating treatment for depression did not receive therapy in concordance with the Agency for Healthcare Research and Quality guidelines. Patients whose antidepressant use was not concordant with the guidelines were also less adherent to diabetes medications. Ó 2005 Elsevier Inc. All rights reserved. Keywords: Depression; Diabetes; Clinical guidelines; Compliance; Adherence
1. Introduction Major depressive disorder (which we will refer to as ‘‘depression’’) is a common comorbidity of diabetes.1–7 A recent meta-analysis revealed that depression and depressive symptoms occurred in 11% and 31%, respectively, of persons with diabetes,6 while several more studies have found that persons with diabetes have twice the odds of experiencing depressive symptoms.6,8,9 More recent research confirmed the higher prevalence of depression or depressive symptoms in diabetic patients, although the reported prevalence of depression or depressive symptoms varied.4,8-10 Major depressive disorder also appears to have a higher recurrence rate and duration in persons with diabetes.11,12 Depressive symptoms are associated with health outcomes among diabetic patients.13-18 In their meta-analysis of 69 studies, Lustman and colleagues19 showed that major depressive disorder and glycohemoglobin had a weighted mean correlation of 0.28 across studies. Other studies show an association between depression and increased incidence of microvascular and macrovascular complications,14 increased mortality,14 increased gastrointestinal symptoms,20 and diminished health-related quality of life.21 Moreover, it has been reported that individuals with both diabetes and depressive symptoms generally had higher use of health resources and incurred higher medical costs than diabetes individuals without depressive symptoms, even after excluding the use of mental health services.8,10,15 Poor health outcomes in persons with comorbid diabetes and depression may be partly due to the association of depressive symptoms with
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nonadherence to medical treatment for diabetes.16 A recent study by Ciechanowski et al15 found that diabetic patients with the greatest amount of depressive symptoms had lower adherence to dietary recommendations as well as their medication regimen. The association of depression and poor medication adherence for other chronic illnesses has also been documented,22–24 and a recent review by Piette et al25 stressed the importance of future research to further understand the relation of treatment for depression with improvement in self-management of diabetes and related health outcomes. Although well-controlled studies are needed to demonstrate the relationship between management of depression and adherence to medication, some evidence has begun to emerge. In a study among patients with both human immunodeficiency virus and depression, psychiatric care alone or combined with antidepressants was significantly associated with adherence to antiretroviral medications.26 However, it is unclear how the adequacy of antidepressant therapy may affect diabetes self-care behaviors. It is quite plausible that if depressive symptoms can be alleviated through the appropriate use of antidepressants, then diabetes self-care behaviors (eg, medication adherence) may improve. The Agency for Healthcare Research and Quality (AHRQ), formerly the Agency for Health Care Policy and Research, developed treatment guidelines for depression that include recommendations for the use of antidepressant medications.27,28 Quality measures for antidepressant drug therapy have been developed by Spettell et al29 based upon the AHRQ guidelines. For the acute phase management of depression, guideline concordance is defined by Spetell et al as patients filling at least 90 days of therapy during the 118 days from the first antidepressant fill. For the chronic phase of treatment, concordance would be defined as patients filling at least 120 days of therapy during the 155 days from the first antidepressant fill. Concordance with the AHRQ treatment guidelines has been shown to lead to fewer relapses of depression and lower costs of care.30,31 However, it is not yet clear whether concordance with the AHRQ guidelines for the treatment of depression will be associated with better diabetes medication adherence. The purpose of this study was (1) to determine whether antidepressant medication use for managed care enrollees with type 2 diabetes was concordant with the AHRQ guidelines; and (2) to examine the relationship between antidepressant guideline concordance and oral diabetes medication adherence.
2. Methods 2.1. Study design and sample The study was approved by the University of Michigan IRB-Health as well as the participating managed care organization. To fulfill the study
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objectives, a retrospective database analysis was conducted using medical and pharmacy claims from a medium-sized managed care organization affiliated with a university in the midwestern United States. Adults with diabetes were identified for the period of January 1 to December 31, 2001 by applying an algorithm developed by the National Committee for Quality Assurance (NCQA).32 Pharmacy claims identified the specific agent dispensed, the quantity and strength of the agent, days of drug supply, and the date the prescription was filled. To be included in the study, subjects must have filled more than one prescription for an oral diabetes medication (eg, sulfonylureas, thiazolidenidiones, biguanides, meglitinides, and/or alpha-glucosidase inhibitors) during the observation year. For antidepressant users, subjects also had at least 118 days of eligibility for prescription drug benefits from the first fills of antidepressant. Nonusers of antidepressants were assigned pseudofirst antidepressant fills based on the distribution of dates of first antidepressant fills among users. The inclusion criterion of 118 days of eligibility from the first pseudoantidepressant fill was equally applied to the nonusers of antidepressants. To ensure that the antidepressant therapy was not a continuation of therapy from the previous year, all subjects could not have prescription fills of antidepressants in the period of 90 days before their first fill (or pseudofill) of antidepressant in the year 2001. Efforts were made to exclude prescriptions for antidepressants that may have been used for indications other than depression (eg, the use of a tricyclic antidepressant for neuropathic pain). Therefore, patients who had only one filling of a tricyclic antidepressant or trazadone were excluded from the analysis. This is consistent with the methodology used by Weilburg et al.33 2.2. Measure of antihyperglycemic medication adherence Adherence to oral antihyperglycemic medications was estimated using the medication possession ratio (MPR). In a review of the medication adherence literature, Farmer34 noted that the MPR has been used in numerous studies to quantify medication adherence. The MPR reflects the proportion of days within a time interval during which a patient possessed a supply of medication. The denominator in the MPR is the total number of days between the first and last refill date of oral antihyperglycemic prescriptions within a year. The numerator for the MPR was calculated by summing the days’ supply for all but the last filling of the oral antihyperglycemic medications. For enrollees on multiple diabetes medications, the average of the MPRs for each medication was calculated. Days when patients were in an institutionalized care setting, such as hospitals or nursing homes, were excluded from the MPR calculation. Because the MPR is based upon prescription refills, it does not measure the actual ingestion of the medication. However, obtaining the medication is a necessary antecedent to ingestion of the medication. As noted by Farmer, claims-based
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measures of adherence (eg, MPR) have been correlated with other measures of medication adherence and are widely accepted as valid measures.34 2.3. Measure of antidepressant use The use of antidepressants was also measured for each subject. The concordance of antidepressant use with the AHRQ guidelines27 was evaluated using the quality measures developed by Spettell et al.29 Guideline concordance for the acute phase of treatment was defined as filling at least 90 days of therapy during the 118 days from the first antidepressant fill. The duration of therapy was estimated from the total days of supply within the 118 days from the first antidepressant fill. All antidepressant users were considered to be initiating treatment because they had no antidepressant therapy in the 90 days preceding their first fill of antidepressant. 2.4. Statistical analyses All analyses were conducted using SAS version 8.2 (SAS Institute, Cary, NC). To assess the relationship between antidepressant guideline concordance and diabetes medication adherence, the subjects were divided into three groups: patients with ‘‘AHRQ-concordant’’ antidepressant use, those with ‘‘subconcordant’’ antidepressant use, and nonusers of antidepressants. The proportion of patients of each gender and the proportion of patients using multiple diabetes medications were compared across groups using a chi-square test, while the average age was compared using a 1-way analysis of variance. The difference in diabetes MPR across the three groups was assessed using a 1-way analysis of variance with Scheffe’s test. In addition, the least square means of MPRs for oral diabetes medications were computed for the groups after adjusting for age, gender, and types of diabetes therapy. Statistical significance was defined as P ! .05.
3. Results There were 1454 users of oral diabetes medications meeting the inclusion and exclusion criteria. The characteristics of medication recipients are presented in Table 1. The average age of the sample was 51.0 G 10.3 years and 53.7% of the subjects were male. Most subjects (896 of 1454; 61.6%) used multiple oral diabetes medications. One hundred eighty-two of the 1454 subjects (12.5%) initiated a regimen of antidepressants after at least 90 days without fills of antidepressants. About two thirds of antidepressant users (62.6%) were female, and most antidepressant users (79.7%) used only a single antidepressant product. Of the antidepressant users, a majority (61.0%) filled a selective serotonergic reuptake inhibitor as either monotherapy or in combination with another
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Table 1 The pattern of antidepressant use among the study population
Age (mean) Male Patients initiating antidepressants Class of antidepressants Selective serotonergic reuptake inhibitor and other antidepressants Selective serotonergic reuptake inhibitor only Tricyclic antidepressant only Other antidepressants only Tricyclic antidepressant and other antidepressants Antidepressant use Single drug Multidrugs Concurrent use Switchers Guideline-concordant use of antidepressantsa
Number (%)
N
51.0 780 (53.7) 182 (12.5)
1454 1454 1454
29 (15.9)
182
82 9 54 8
(45.1) (5.0) (29.7) (4.4)
182 182 182 182
139 (76.4)
182
9 (5.0) 34 (18.7)
182 182
89 (48.9)
182
a
Concordance with the AHRQ guidelines for acute-phase antidepressant use was defined as a subject receiving at least 90 days supply of antidepressant drugs within 118 days of the first fill of an antidepressant.
antidepressant. Of the 182 patients who used an antidepressant, 89 (48.9%) received at least 90 days of antidepressants within 118 days from the first antidepressant fill and were thereby deemed to be concordant with AHRQ treatment guidelines for the acute phase treatment of depression. 3.1. Guideline concordance and diabetes medication adherence Details on the association between guideline concordance and diabetes medication adherence can be found in Table 2. Subjects with subconcordant antidepressant use had a lower mean diabetes MPR than those with either guideline-concordant use or no use (F Z 14.3, P ! .01). There was no significant difference in diabetes MPR between subjects with guidelineconcordant use of antidepressants and those who did not use antidepressants. After adjusting for age, gender, and types of diabetes therapy, the pattern of MPRs across the categories did not change. 4. Discussion To summarize, 12.5% of the subjects with type 2 diabetes initiated treatment with an antidepressant medication during the 1-year timeframe. Approximately half of those who initiated treatment with an antidepressant received at least a 90-day supply of medication within 118 days of the initial
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Table 2 Diabetes medication adherence and category of antidepressant use
Concordant use Subconcordant use Nonusers a b
n
Age
Male (%)
89 93 1272
51.3 47.6 51.3
39.3 35.5 56.0
Multiple diabetes drugs (%)
Diabetes drug MPR mean G SD
Adjusted mean MPRa
Scheffeb
68.5 58.1 61.4
0.85 G 0.18 0.75 G 0.25 0.83 G 0.19
0.85 0.76 0.83
A B A
Adjusted for age, gender, and multiple diabetes drugs. Means with the same letter are not significantly different (P ! .05).
dispensing of an antidepressant. Thus, about half of the patients discontinued their antidepressant regimen before completing the acute phase of treatment for depression. Those who did not complete the acute phase of treatment were also less adherent to their diabetes medication regimen. The observed rate of guideline concordance for the acute phase of depression treatment (48.9%) was lower than that reported by the NCQA for a national sample of managed care enrollees in the acute phase of treatment for depression (60%).35 However, the subjects included in the report from NCQA reflected a much broader managed care population as compared to the patients with type 2 diabetes in this study. It is likely that the diabetic patients included in this study had a greater number of comorbid conditions than the general population and thus may face a greater burden in managing multiple disease states. Additionally, the NCQA indicator for antidepressant medication management32 differs slightly from the measure used in this study (developed more recently by Spettell et al).29 Thus, caution should be used in comparing our findings to the NCQA report. Antidepressant guideline concordance was related to antihyperglycemic medication adherence. Patients with subconcordant antidepressant use were less likely to adhere to diabetes medication, while patients with concordant antidepressant use adhered to their medications at about the same rate as those who did not receive antidepressants. If we assume that patients without antidepressant use did not have significant depressive symptoms, then the findings indicate that adequate treatment with antidepressants may ameliorate the negative impact of depression on diabetes medication use. Thus, optimizing drug therapy for depression may be important in helping diabetic patients with depression achieve adequate glycemic control. The findings are consistent with a growing body of literature that points to the impact of depression on self-care behaviors amongst persons with chronic medical illnesses.15–17,22–26,36 However, it is not yet clear whether effective treatment for depression in patients with diabetes will lead to better diabetes medication adherence. A framework for the appropriate identification and management of depression in persons with diabetes has been proposed,25 but the findings from prospective studies of depression management in diabetes have been mixed.37–40 These studies show that
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antidepressant drug therapy and/or cognitive behavior therapy are effective in treating depression among persons with diabetes, 37–40 however, the larger studies of antidepressant treatment have not demonstrated improvements in glycemic control subsequent to improvement in depressive symptoms.39–40 The lack of effect on glycemic control may have been due to the subjects having relatively good glycemic control at baseline. The findings from our study suggest that adherence to antidepressant medication in the acute phase of treatment for depression may be important for maintaining good diabetes medication-use behaviors. Consequently, attention should be given to strategies that may optimize patients’ persistence with antidepressant therapy and completion of the acute phase of treatment. This may include enhancing patient-provider communication about antidepressants, cognitive behavioral therapy, case management by nurses or clinical pharmacists, and timely follow-up via telephone or email to identify patients who are nonadherent to the treatment regimen.41–45 5. Limitations As with any study using drug claims data, the use of nonprescription drugs or nutritional supplements could not be measured. Additionally, some of the antidepressant drugs may have been prescribed for reasons other than depression. However, we did attempt to exclude some treatments that may typically have been prescribed for neuropathic pain (eg, a single filling of a tricylic antidepressant). This conservative approach may have excluded some patients being treated for depression with a tricylic antidepressant, but should have eliminated most patients who were using a tricyclic agent for a reason other than depression. Another consequence of using claims data to estimate medication adherence is that the MPR only reflects patients’ procurement of the product, and we cannot confirm that the patient actually ingested the medication they obtained. However, claims-based measures of adherence, such as the MPR, have been correlated with other measures of medication adherence.34,46 Another limitation is the possibility that the subconcordant use of antidepressants did not cause poor adherence to diabetes medications. Poor adherence to both medication regimens may have reflected a subject’s suboptimal adherence to healthy behaviors in general. A final limitation of this study is that only the duration of therapy was assessed and not the dose of the drug. Some experts argue that the dose of the therapy is at least as important as the duration of therapy.33 6. Conclusion Approximately half of the type 2 diabetic patients who initiated treatment with an antidepressant did not receive an adequate supply of medication to
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be concordant with the AHRQ guidelines for the acute phase of depression treatment. Patients who received subconcordant antidepressant therapy tended to be less adherent to their diabetes medication regimens, as compared to those who either received guideline-concordant antidepressant treatment or did not receive antidepressants. Consequently, the findings are consistent with the possibility that providing guideline-concordant antidepressant therapy to patients with both depression and diabetes may help maintain appropriate diabetes medication use. Acknowledgments This study was funded by the University of Michigan Health System through the Collaborative Health Services Research Initiative (D. Nau, PI). The authors would like to thank MCARE (especially Thom Spafford) for assistance in selecting the sample for the survey. References 1. Grandinetti A, Kaholokula JK, Crabbe KM, Kenui CK, Chen R, Chang HK. Relationship between depressive symptoms and diabetes among native Hawaiians. Psychoneuroendocrinology. 2000;25:239–246. 2. Lloyd CE, Dyer PH, Barnett AH. Prevalence of symptoms of depression and anxiety in a diabetes clinic population. Diabet Med. 2000;17:198–202. 3. Gary TL, Crum RM, Cooper-Patrick L, Ford D, Brancati FL. Depressive symptoms and metabolic control in African-Americans with type 2 diabetes. Diabetes Care. 2000;23:23–29. 4. Tellez-Zenteno JF, Cardiel MH. Risk factors associated with depression in patients with type 2 diabetes mellitus. Arch Med Res. 2002;33:53–60. 5. Lustman PJ, Griffith LS, Clouse RE. Depression in adults with diabetes. Semin Clin Neuropsychiatry. 1997;2:15–23. 6. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001;24:1069–1078. 7. Eaton WW. Epidemiologic evidence on the comorbidity of depression and diabetes. J Psychosom Res. 2002;53:903–906. 8. Egede LE, Zheng D, Simpson K. Comorbid depression is associated with increased health care use and expenditures in individuals with diabetes. Diabetes Care. 2002;25:464–470. 9. Nichols GA, Brown JB. Unadjusted and adjusted prevalence of diagnosed depression in type 2 diabetes. Diabetes Care. 2003;26:744–749. 10. Finkelstein EA, Bray JW, Chen H, et al. Prevalence and costs of major depression among elderly claimants with diabetes. Diabetes Care. 2003;26:415–420. 11. Talbot F, Nouwen A. A review of the relationship between depression and diabetes in adults: is there a link? Diabetes Care. 2000;23:1556–1562. 12. Lustman PJ, Griffith LS, Freedland KE, Clouse RE. The course of major depression in diabetes. Gen Hosp Psychiatry. 1997;19:138–143. 13. Wang PS, Bohn RL, Knight E, Glynn RJ, Mogun H, Avorn J. Noncompliance with antihypertensive medications: the impact of depressive symptoms and psychosocial factors. J Gen Intern Med. 2002;17:504–511. 14. Black SA, Markides KS, Ray LA. Depression predicts increased incidence of adverse health outcomes in older Mexican Americans with type 2 diabetes. Diabetes Care. 2003;26: 2822–2828.
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15. Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of depressive symptoms on adherence, function, and costs. Arch Intern Med. 2000;160:3278–3285. 16. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000;160:2101–2107. 17. Wing RR, Phelan S, Tate D. The role of adherence in mediating the relationship between depression and health outcomes. J Psychosom Res. 2002;53:877–881. 18. Kinder LS, Kamarck TW, Baum A, Orchard TJ. Depressive symptomatology and coronary heart disease in type I diabetes mellitus: a study of possible mechanisms. Health Psychol. 2002;21:542–552. 19. de Groot M, Anderson R, Freedland KE, Clouse RE, Lustman PJ. Association of depression and diabetes complications: a meta-analysis. Psychosom Med. 2001;63:619–630. 20. Talley SJ, Bytzer P, Hammer J, Young L, Jones M, Horowitz M. Psychological distress is linked to gastrointestinal symptoms in diabetes mellitus. Am J Gastroenterol. 2001;96: 1033–1038. 21. Jacobson AM, de Groot M, Samson JA. The effects of psychiatric disorders and symptoms on quality of life in patients with type I and type II diabetes mellitus. Qual Life Res. 1997;6:11–20. 22. Starace F, Ammassari A, Trotta MP, et al. Depression is a risk factor for suboptimal adherence to highly active antiretroviral therapy. JAIDS. 2002;31:S136–S139. 23. Carney RM, Freedland KE, Eisen SA, Rich MW, Jaffe AS. Major depression and medication adherence in elderly patients with coronary artery disease. Health Psychol. 1995;14:88–90. 24. Katon W, Ciechanowski P. Impact of major depression on chronic medical illness. J Psychosom Res. 2002;53:859–863. 25. Piette JD, Richardson C, Valenstein M. Addressing the needs of patients with multiple chronic illnesses: the case of diabetes and depression. Am J Manag Care. 2004;10: 152–162. 26. Turner BJ, Laine C, Cosler L, Hauck WW. Relationship of gender, depression, and health care delivery with antiretroviral adherence in HIV-infected drug users. J Gen Intern Med. 2003;18:248–257. 27. Agency for Health Policy and Research (AHCPR). Treatment of Major Depression: Clinical Practice Guidelines. Rockville, Md: Department of Health and Human Services; 1993. 28. Schulberg HC, Katon W, Simon GE, Rush AJ. Treating major depression in primary care practice: an update of the Agency for Health Care Policy and Research Practice Guidelines. Arch Gen Psychiatry. 1998;55:1121–1127. 29. Spettell CM, Wall TC, Allison J, et al. Identifying physician-recognized depression from administrative data: consequences for quality measurement. Health Serv Res. 2003;38: 1081–1102. 30. Melfi CA, Chawla AJ, Croghan TW, Hanna MP, Kennedy S, Sredl K. The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression. Arch Gen Psychiatry. 1998;55:1128–1132. 31. Crown WH, Treglia M, Meneades L, White A. Long-term costs of treatment for depression: impact of drug selection and guideline adherence. Value Health. 2001;4: 295–307. 32. National Committee for Quality AssuranceIn: HEDIS 2001 Technical Specifications, vol. 2. Washington, DC: National Committee for Quality Assurance; 2001: 102–108. 33. Weilburg JB, O’Leary KM, Meigs JB, Hennen J, Stafford RS. Evaluation of the adequacy of outpatient antidepressant treatment. Psychiatr Serv. 2003;54:1233–1239. 34. Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. Clin Ther. 1999;21:1074–1090. 35. National Committee for Quality Assurance. State of Health Care Quality. Washington, DC: National Committee for Quality Assurance; 2003.
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36. Lin E, Katon W, Von Korff M, et al. Relationship of depression and diabetes self-care, medication adherence, and preventive care. Diabetes Care. 2004;27:2154–2160. 37. Lustman PJ, Griffith LS, Clouse RE, et al. Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial. Psychosom Med. 1997;59:241–250. 38. Lustman PJ, Griffith LS, Freedland KE, Clouse RE. Fluoxetine for depression in diabetes: a randomized, double-blind, placebo-controlled trial. Diabetes Care. 2000;23:618–623. 39. Lustman PJ, Griffith LS, Freedland KE, et al. Cognitive behavior therapy for depression in type 2 diabetes mellitus: a randomized, controlled trial. Ann Intern Med. 1998;129:613–621. 40. Katon W, Von Korff M, Lin E, et al. The Pathways Study: a randomized trial of collaborative care in patients with diabetes and depression. Arch Gen Psychiatry. 2004;61: 1042–1049. 41. Bultman DC, Svarstad BL. Effects of pharmacist monitoring on patient satisfaction with antidepressant medication therapy. J Am Pharm Assoc. 2002;42:36–43. 42. Katon W, Von Korff M, Lin E, et al. Collaborative management to achieve treatment guidelines. Impact on depression in primary care. JAMA. 1995;273:1026–1031. 43. Lin E, Von Korff M, Katon W, et al. The role of the primary care physician in patients’ adherence to antidepressant therapy. Med Care. 1995;33:67–74. 44. Wells KB, Sherbourne C, Schoenbaum M, et al. Impact of disseminating quality improvement programs for depression in managed primary care. JAMA. 2000;283:212–220. 45. Simon GE, Von Korff M, Rutter C, Wagner E. Randomised trial of monitoring, feedback, and management of care by telephone to improve treatment of depression in primary care. BMJ. 2000;320:550–554. 46. Steiner JF, Prochazka AV. The assessment of refill compliance using pharmacy records: methods, validity and applications. J Clin Epidemiol. 1997;50:105–116.
Original research
The relationship of guideline-concordant depression treatment and patient adherence to oral diabetes medications David P. Nau, Ph.D.a,*, Jingdong Chao, Ph.D.b,1, James E. Aikens, Ph.D.c a
Department of Social and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI 48109-1065, USA b Department of Health Economics and Outcomes Research, Sanofi-Aventis Pharmaceuticals, Bridgewater, NJ 08807-2854, USA c Departments of Family Medicine and Psychiatry, University of Michigan School of Medicine, Ann Arbor, MI 48109-1065, USA
Abstract Background: Many patients with diabetes experience depression, yet it is unclear if the treatment of depression in diabetic patients is concordant with national guidelines, and whether appropriate antidepressant use is associated with better diabetes self-care behaviors. Objectives: The purpose of this study was to (1) determine whether antidepressant medication use for managed care enrollees with type 2 diabetes was concordant with The Agency for Healthcare Research and Quality depression treatment guidelines; and (2) examine the relationship between guideline concordance and oral diabetes medication adherence. Methods: Retrospective analyses were conducted using medical/pharmacy claims for 2001 from a managed care organization in the midwestern United States. Subjects were adults with type 2 diabetes treated with oral medications only. The subjects were divided into 3 groups: (1) guideline-concordant users of antidepressants; (2) * Corresponding author. Tel.: C1 734 615 9083; fax: C1 734 615 8171. E-mail address: [email protected] (D.P. Nau). 1 At the time of this study, Dr Chao was affiliated with the Department of Social and Administrative Sciences at the University of Michigan College of Pharmacy. 1551-7411/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.sapharm.2005.06.001
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those who received antidepressants not in concordance with the guidelines; and (3) nonusers of antidepressants. Antidepressant users were determined to be in concordance with the acute phase treatment guidelines if they filled at least 90 days supply of antidepressant drugs within 118 days of the first fill. Adherence to diabetes medications was measured by the medication possession ratio. A 1-way analysis of variance with Scheffe’s test was used to compare the antihyperglycemic medication possession ratio across the three groups. Results: One hundred eighty-two (12.5%) of the 1454 subjects initiated treatment with antidepressants. Eighty-nine (48.9%) of the 182 antidepressant users were in concordance with the acute phase treatment guidelines. Subjects with subconcordant antidepressant use had a lower mean diabetes medication possession ratio than those with either guideline-concordant use or no use (F Z 14.3, P ! .01). Conclusion: Over half of the diabetic patients initiating treatment for depression did not receive therapy in concordance with the Agency for Healthcare Research and Quality guidelines. Patients whose antidepressant use was not concordant with the guidelines were also less adherent to diabetes medications. Ó 2005 Elsevier Inc. All rights reserved. Keywords: Depression; Diabetes; Clinical guidelines; Compliance; Adherence
1. Introduction Major depressive disorder (which we will refer to as ‘‘depression’’) is a common comorbidity of diabetes.1–7 A recent meta-analysis revealed that depression and depressive symptoms occurred in 11% and 31%, respectively, of persons with diabetes,6 while several more studies have found that persons with diabetes have twice the odds of experiencing depressive symptoms.6,8,9 More recent research confirmed the higher prevalence of depression or depressive symptoms in diabetic patients, although the reported prevalence of depression or depressive symptoms varied.4,8-10 Major depressive disorder also appears to have a higher recurrence rate and duration in persons with diabetes.11,12 Depressive symptoms are associated with health outcomes among diabetic patients.13-18 In their meta-analysis of 69 studies, Lustman and colleagues19 showed that major depressive disorder and glycohemoglobin had a weighted mean correlation of 0.28 across studies. Other studies show an association between depression and increased incidence of microvascular and macrovascular complications,14 increased mortality,14 increased gastrointestinal symptoms,20 and diminished health-related quality of life.21 Moreover, it has been reported that individuals with both diabetes and depressive symptoms generally had higher use of health resources and incurred higher medical costs than diabetes individuals without depressive symptoms, even after excluding the use of mental health services.8,10,15 Poor health outcomes in persons with comorbid diabetes and depression may be partly due to the association of depressive symptoms with
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nonadherence to medical treatment for diabetes.16 A recent study by Ciechanowski et al15 found that diabetic patients with the greatest amount of depressive symptoms had lower adherence to dietary recommendations as well as their medication regimen. The association of depression and poor medication adherence for other chronic illnesses has also been documented,22–24 and a recent review by Piette et al25 stressed the importance of future research to further understand the relation of treatment for depression with improvement in self-management of diabetes and related health outcomes. Although well-controlled studies are needed to demonstrate the relationship between management of depression and adherence to medication, some evidence has begun to emerge. In a study among patients with both human immunodeficiency virus and depression, psychiatric care alone or combined with antidepressants was significantly associated with adherence to antiretroviral medications.26 However, it is unclear how the adequacy of antidepressant therapy may affect diabetes self-care behaviors. It is quite plausible that if depressive symptoms can be alleviated through the appropriate use of antidepressants, then diabetes self-care behaviors (eg, medication adherence) may improve. The Agency for Healthcare Research and Quality (AHRQ), formerly the Agency for Health Care Policy and Research, developed treatment guidelines for depression that include recommendations for the use of antidepressant medications.27,28 Quality measures for antidepressant drug therapy have been developed by Spettell et al29 based upon the AHRQ guidelines. For the acute phase management of depression, guideline concordance is defined by Spetell et al as patients filling at least 90 days of therapy during the 118 days from the first antidepressant fill. For the chronic phase of treatment, concordance would be defined as patients filling at least 120 days of therapy during the 155 days from the first antidepressant fill. Concordance with the AHRQ treatment guidelines has been shown to lead to fewer relapses of depression and lower costs of care.30,31 However, it is not yet clear whether concordance with the AHRQ guidelines for the treatment of depression will be associated with better diabetes medication adherence. The purpose of this study was (1) to determine whether antidepressant medication use for managed care enrollees with type 2 diabetes was concordant with the AHRQ guidelines; and (2) to examine the relationship between antidepressant guideline concordance and oral diabetes medication adherence.
2. Methods 2.1. Study design and sample The study was approved by the University of Michigan IRB-Health as well as the participating managed care organization. To fulfill the study
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objectives, a retrospective database analysis was conducted using medical and pharmacy claims from a medium-sized managed care organization affiliated with a university in the midwestern United States. Adults with diabetes were identified for the period of January 1 to December 31, 2001 by applying an algorithm developed by the National Committee for Quality Assurance (NCQA).32 Pharmacy claims identified the specific agent dispensed, the quantity and strength of the agent, days of drug supply, and the date the prescription was filled. To be included in the study, subjects must have filled more than one prescription for an oral diabetes medication (eg, sulfonylureas, thiazolidenidiones, biguanides, meglitinides, and/or alpha-glucosidase inhibitors) during the observation year. For antidepressant users, subjects also had at least 118 days of eligibility for prescription drug benefits from the first fills of antidepressant. Nonusers of antidepressants were assigned pseudofirst antidepressant fills based on the distribution of dates of first antidepressant fills among users. The inclusion criterion of 118 days of eligibility from the first pseudoantidepressant fill was equally applied to the nonusers of antidepressants. To ensure that the antidepressant therapy was not a continuation of therapy from the previous year, all subjects could not have prescription fills of antidepressants in the period of 90 days before their first fill (or pseudofill) of antidepressant in the year 2001. Efforts were made to exclude prescriptions for antidepressants that may have been used for indications other than depression (eg, the use of a tricyclic antidepressant for neuropathic pain). Therefore, patients who had only one filling of a tricyclic antidepressant or trazadone were excluded from the analysis. This is consistent with the methodology used by Weilburg et al.33 2.2. Measure of antihyperglycemic medication adherence Adherence to oral antihyperglycemic medications was estimated using the medication possession ratio (MPR). In a review of the medication adherence literature, Farmer34 noted that the MPR has been used in numerous studies to quantify medication adherence. The MPR reflects the proportion of days within a time interval during which a patient possessed a supply of medication. The denominator in the MPR is the total number of days between the first and last refill date of oral antihyperglycemic prescriptions within a year. The numerator for the MPR was calculated by summing the days’ supply for all but the last filling of the oral antihyperglycemic medications. For enrollees on multiple diabetes medications, the average of the MPRs for each medication was calculated. Days when patients were in an institutionalized care setting, such as hospitals or nursing homes, were excluded from the MPR calculation. Because the MPR is based upon prescription refills, it does not measure the actual ingestion of the medication. However, obtaining the medication is a necessary antecedent to ingestion of the medication. As noted by Farmer, claims-based
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measures of adherence (eg, MPR) have been correlated with other measures of medication adherence and are widely accepted as valid measures.34 2.3. Measure of antidepressant use The use of antidepressants was also measured for each subject. The concordance of antidepressant use with the AHRQ guidelines27 was evaluated using the quality measures developed by Spettell et al.29 Guideline concordance for the acute phase of treatment was defined as filling at least 90 days of therapy during the 118 days from the first antidepressant fill. The duration of therapy was estimated from the total days of supply within the 118 days from the first antidepressant fill. All antidepressant users were considered to be initiating treatment because they had no antidepressant therapy in the 90 days preceding their first fill of antidepressant. 2.4. Statistical analyses All analyses were conducted using SAS version 8.2 (SAS Institute, Cary, NC). To assess the relationship between antidepressant guideline concordance and diabetes medication adherence, the subjects were divided into three groups: patients with ‘‘AHRQ-concordant’’ antidepressant use, those with ‘‘subconcordant’’ antidepressant use, and nonusers of antidepressants. The proportion of patients of each gender and the proportion of patients using multiple diabetes medications were compared across groups using a chi-square test, while the average age was compared using a 1-way analysis of variance. The difference in diabetes MPR across the three groups was assessed using a 1-way analysis of variance with Scheffe’s test. In addition, the least square means of MPRs for oral diabetes medications were computed for the groups after adjusting for age, gender, and types of diabetes therapy. Statistical significance was defined as P ! .05.
3. Results There were 1454 users of oral diabetes medications meeting the inclusion and exclusion criteria. The characteristics of medication recipients are presented in Table 1. The average age of the sample was 51.0 G 10.3 years and 53.7% of the subjects were male. Most subjects (896 of 1454; 61.6%) used multiple oral diabetes medications. One hundred eighty-two of the 1454 subjects (12.5%) initiated a regimen of antidepressants after at least 90 days without fills of antidepressants. About two thirds of antidepressant users (62.6%) were female, and most antidepressant users (79.7%) used only a single antidepressant product. Of the antidepressant users, a majority (61.0%) filled a selective serotonergic reuptake inhibitor as either monotherapy or in combination with another
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Table 1 The pattern of antidepressant use among the study population
Age (mean) Male Patients initiating antidepressants Class of antidepressants Selective serotonergic reuptake inhibitor and other antidepressants Selective serotonergic reuptake inhibitor only Tricyclic antidepressant only Other antidepressants only Tricyclic antidepressant and other antidepressants Antidepressant use Single drug Multidrugs Concurrent use Switchers Guideline-concordant use of antidepressantsa
Number (%)
N
51.0 780 (53.7) 182 (12.5)
1454 1454 1454
29 (15.9)
182
82 9 54 8
(45.1) (5.0) (29.7) (4.4)
182 182 182 182
139 (76.4)
182
9 (5.0) 34 (18.7)
182 182
89 (48.9)
182
a
Concordance with the AHRQ guidelines for acute-phase antidepressant use was defined as a subject receiving at least 90 days supply of antidepressant drugs within 118 days of the first fill of an antidepressant.
antidepressant. Of the 182 patients who used an antidepressant, 89 (48.9%) received at least 90 days of antidepressants within 118 days from the first antidepressant fill and were thereby deemed to be concordant with AHRQ treatment guidelines for the acute phase treatment of depression. 3.1. Guideline concordance and diabetes medication adherence Details on the association between guideline concordance and diabetes medication adherence can be found in Table 2. Subjects with subconcordant antidepressant use had a lower mean diabetes MPR than those with either guideline-concordant use or no use (F Z 14.3, P ! .01). There was no significant difference in diabetes MPR between subjects with guidelineconcordant use of antidepressants and those who did not use antidepressants. After adjusting for age, gender, and types of diabetes therapy, the pattern of MPRs across the categories did not change. 4. Discussion To summarize, 12.5% of the subjects with type 2 diabetes initiated treatment with an antidepressant medication during the 1-year timeframe. Approximately half of those who initiated treatment with an antidepressant received at least a 90-day supply of medication within 118 days of the initial
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Table 2 Diabetes medication adherence and category of antidepressant use
Concordant use Subconcordant use Nonusers a b
n
Age
Male (%)
89 93 1272
51.3 47.6 51.3
39.3 35.5 56.0
Multiple diabetes drugs (%)
Diabetes drug MPR mean G SD
Adjusted mean MPRa
Scheffeb
68.5 58.1 61.4
0.85 G 0.18 0.75 G 0.25 0.83 G 0.19
0.85 0.76 0.83
A B A
Adjusted for age, gender, and multiple diabetes drugs. Means with the same letter are not significantly different (P ! .05).
dispensing of an antidepressant. Thus, about half of the patients discontinued their antidepressant regimen before completing the acute phase of treatment for depression. Those who did not complete the acute phase of treatment were also less adherent to their diabetes medication regimen. The observed rate of guideline concordance for the acute phase of depression treatment (48.9%) was lower than that reported by the NCQA for a national sample of managed care enrollees in the acute phase of treatment for depression (60%).35 However, the subjects included in the report from NCQA reflected a much broader managed care population as compared to the patients with type 2 diabetes in this study. It is likely that the diabetic patients included in this study had a greater number of comorbid conditions than the general population and thus may face a greater burden in managing multiple disease states. Additionally, the NCQA indicator for antidepressant medication management32 differs slightly from the measure used in this study (developed more recently by Spettell et al).29 Thus, caution should be used in comparing our findings to the NCQA report. Antidepressant guideline concordance was related to antihyperglycemic medication adherence. Patients with subconcordant antidepressant use were less likely to adhere to diabetes medication, while patients with concordant antidepressant use adhered to their medications at about the same rate as those who did not receive antidepressants. If we assume that patients without antidepressant use did not have significant depressive symptoms, then the findings indicate that adequate treatment with antidepressants may ameliorate the negative impact of depression on diabetes medication use. Thus, optimizing drug therapy for depression may be important in helping diabetic patients with depression achieve adequate glycemic control. The findings are consistent with a growing body of literature that points to the impact of depression on self-care behaviors amongst persons with chronic medical illnesses.15–17,22–26,36 However, it is not yet clear whether effective treatment for depression in patients with diabetes will lead to better diabetes medication adherence. A framework for the appropriate identification and management of depression in persons with diabetes has been proposed,25 but the findings from prospective studies of depression management in diabetes have been mixed.37–40 These studies show that
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antidepressant drug therapy and/or cognitive behavior therapy are effective in treating depression among persons with diabetes, 37–40 however, the larger studies of antidepressant treatment have not demonstrated improvements in glycemic control subsequent to improvement in depressive symptoms.39–40 The lack of effect on glycemic control may have been due to the subjects having relatively good glycemic control at baseline. The findings from our study suggest that adherence to antidepressant medication in the acute phase of treatment for depression may be important for maintaining good diabetes medication-use behaviors. Consequently, attention should be given to strategies that may optimize patients’ persistence with antidepressant therapy and completion of the acute phase of treatment. This may include enhancing patient-provider communication about antidepressants, cognitive behavioral therapy, case management by nurses or clinical pharmacists, and timely follow-up via telephone or email to identify patients who are nonadherent to the treatment regimen.41–45 5. Limitations As with any study using drug claims data, the use of nonprescription drugs or nutritional supplements could not be measured. Additionally, some of the antidepressant drugs may have been prescribed for reasons other than depression. However, we did attempt to exclude some treatments that may typically have been prescribed for neuropathic pain (eg, a single filling of a tricylic antidepressant). This conservative approach may have excluded some patients being treated for depression with a tricylic antidepressant, but should have eliminated most patients who were using a tricyclic agent for a reason other than depression. Another consequence of using claims data to estimate medication adherence is that the MPR only reflects patients’ procurement of the product, and we cannot confirm that the patient actually ingested the medication they obtained. However, claims-based measures of adherence, such as the MPR, have been correlated with other measures of medication adherence.34,46 Another limitation is the possibility that the subconcordant use of antidepressants did not cause poor adherence to diabetes medications. Poor adherence to both medication regimens may have reflected a subject’s suboptimal adherence to healthy behaviors in general. A final limitation of this study is that only the duration of therapy was assessed and not the dose of the drug. Some experts argue that the dose of the therapy is at least as important as the duration of therapy.33 6. Conclusion Approximately half of the type 2 diabetic patients who initiated treatment with an antidepressant did not receive an adequate supply of medication to
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be concordant with the AHRQ guidelines for the acute phase of depression treatment. Patients who received subconcordant antidepressant therapy tended to be less adherent to their diabetes medication regimens, as compared to those who either received guideline-concordant antidepressant treatment or did not receive antidepressants. Consequently, the findings are consistent with the possibility that providing guideline-concordant antidepressant therapy to patients with both depression and diabetes may help maintain appropriate diabetes medication use. Acknowledgments This study was funded by the University of Michigan Health System through the Collaborative Health Services Research Initiative (D. Nau, PI). The authors would like to thank MCARE (especially Thom Spafford) for assistance in selecting the sample for the survey. References 1. Grandinetti A, Kaholokula JK, Crabbe KM, Kenui CK, Chen R, Chang HK. Relationship between depressive symptoms and diabetes among native Hawaiians. Psychoneuroendocrinology. 2000;25:239–246. 2. Lloyd CE, Dyer PH, Barnett AH. Prevalence of symptoms of depression and anxiety in a diabetes clinic population. Diabet Med. 2000;17:198–202. 3. Gary TL, Crum RM, Cooper-Patrick L, Ford D, Brancati FL. Depressive symptoms and metabolic control in African-Americans with type 2 diabetes. Diabetes Care. 2000;23:23–29. 4. Tellez-Zenteno JF, Cardiel MH. Risk factors associated with depression in patients with type 2 diabetes mellitus. Arch Med Res. 2002;33:53–60. 5. Lustman PJ, Griffith LS, Clouse RE. Depression in adults with diabetes. Semin Clin Neuropsychiatry. 1997;2:15–23. 6. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001;24:1069–1078. 7. Eaton WW. Epidemiologic evidence on the comorbidity of depression and diabetes. J Psychosom Res. 2002;53:903–906. 8. Egede LE, Zheng D, Simpson K. Comorbid depression is associated with increased health care use and expenditures in individuals with diabetes. Diabetes Care. 2002;25:464–470. 9. Nichols GA, Brown JB. Unadjusted and adjusted prevalence of diagnosed depression in type 2 diabetes. Diabetes Care. 2003;26:744–749. 10. Finkelstein EA, Bray JW, Chen H, et al. Prevalence and costs of major depression among elderly claimants with diabetes. Diabetes Care. 2003;26:415–420. 11. Talbot F, Nouwen A. A review of the relationship between depression and diabetes in adults: is there a link? Diabetes Care. 2000;23:1556–1562. 12. Lustman PJ, Griffith LS, Freedland KE, Clouse RE. The course of major depression in diabetes. Gen Hosp Psychiatry. 1997;19:138–143. 13. Wang PS, Bohn RL, Knight E, Glynn RJ, Mogun H, Avorn J. Noncompliance with antihypertensive medications: the impact of depressive symptoms and psychosocial factors. J Gen Intern Med. 2002;17:504–511. 14. Black SA, Markides KS, Ray LA. Depression predicts increased incidence of adverse health outcomes in older Mexican Americans with type 2 diabetes. Diabetes Care. 2003;26: 2822–2828.
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