EDITORIAL COMMENT
Just a Spoonful of Sugar*
Roy C. Ziegelstein, MD, FACP* and
Sara D. Miller, BA
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
* Reprint requests and correspondence: Dr. Roy C. Ziegelstein, Department of Medicine, B-1-North, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, Maryland 21224-2780 (Email: rziegel{at}jhmi.edu).
"Just a spoonful of sugar helps the medicine go down/In a most delightful way."
—from Mary Poppins, by Robert B. Sherman and Richard M. ShermanWhich one of us hasn't cried to mom or dad, pinched his or her nose, and taken medicine under protest. Although bubble gum and fruit flavorings have made it easier, encouraging adherence to treatment regimens is a challenging task not only for parents but also for physicians. What we need is "just a spoonful of sugar" to help the medicine go down.
Ensuring adherence is particularly important when treating a patient who is depressed. Medical students are taught the mnemonic "SIGECAPS" to remember the cardinal features of major depression (sleep, interest, guilt, energy, concentration, appetite, psychomotor, suicidal). The "I" and the "C" indicate that depressed patients exhibit diminished "interest" and "concentration." No surprise, then, that patients with depression have difficulty adhering to treatments that might favorably impact their health. DiMatteo et al. (1) suggest that 3 factors make it more difficult for depressed patients to adhere to medical treatment regimens: 1) feelings of hopelessness that make it harder to believe that treatments will help; 2) social isolation that limits interaction with people who might offer support in adhering to medications; and 3) cognitive difficulties that make it hard to remember to take medications.
Beneficial treatments have been defined for both primary and secondary prevention of heart disease, but a substantial gap exists between the favorable results reported in clinical trials and those achieved in clinical practice. Recognizing that part of this gap relates to patients' failure to adhere to medical therapy, the American Heart Association convened an expert panel on the topic of adherence almost a decade ago (2). And, noting how depression negatively impacts adherence, Fox (3) asked a very relevant question at that time: "Would antidepressant treatment make a difference to compliance—and mortality?"
The observation by Rieckmann et al. (4) in this issue of the Journal that patients with acute coronary syndrome (ACS) who also have depression have difficulty with adherence to medications is not by itself new or novel. It has been known for several years now that depression at the time of an acute coronary event is a "litmus test" for poor adherence during the next few months (5). Yet until now, there has not been any evidence that improvement in depression might be associated with improved adherence.
Rieckmann et al. (4) monitored the adherence to daily aspirin therapy of 172 patients after a hospitalization for an ACS using an electronic medication monitoring system. Patients with the most severe depressive symptoms in the hospital demonstrated the poorest adherence. Of patients without depression, 15% did not take at least 80% of their daily aspirin. By comparison, 29% of mildly depressed patients and 37% of moderately-to-severely depressed patients did not adhere to aspirin therapy. Patients whose depression improved in the first month after the ACS demonstrated improvements in adherence rates in the subsequent 2 months.
So why should cardiologists care? Acute myocardial infarction practice guidelines recommend that the psychosocial status of patients be evaluated, "including inquiries regarding symptoms of depression" (6). Despite this recommendation, formal screening for depression generally is not part of routine care in the ACS setting. In the absence of formal screening, underrecognition of depressive illness is common (7). Perhaps the observation that when depression improves adherence does as well, and the possibility that this might improve cardiovascular outcomes, will more strongly motivate the cardiology community not only to recommend depression screening in practice guidelines, but also to incorporate it as part of routine care.
For more than a decade, investigators have fairly consistently demonstrated a relationship between depression and increased mortality after an ACS (8). Plausible mechanistic links to explain such a relationship have been documented in patients with depression, including increased platelet activation (9), increased inflammation (10), autonomic dysfunction that may predispose to ventricular arrhythmias (11), and poor adherence to medical treatment regimens (5). Although studies have also shown that selective serotonin reuptake inhibitors decrease platelet activation (12), inflammation (13), and cardiac autonomic dysfunction (14), no study has shown that selective serotonin reuptake inhibitors improve adherence. The findings by Rieckmann et al. (4) suggest that a study examining this question would be an important and logical next step.
So how important is it that patients adhere to what we recommend? It is now a well-known but still fascinating observation that adherence per se, whether to active treatment or to a "sugar pill," may have beneficial health effects. A recent meta-analysis of 21 studies, including 8 studies with placebo arms, confirmed that good adherence—whether to beneficial drug therapy or to placebo—is associated with lower mortality (15). "A spoonful of sugar" may not just help the medicine go down, it may also help mortality go down. In several studies in the cardiovascular literature, patients who adhered to placebo had a lower mortality than patients who did not. In the Coronary Drug Project Research Group study (16), BHAT (the Beta-Blocker Heart Attack Trial) (17), CAMIAT (the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial) (18), and CHARM (the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) trial (19), good adherence was associated with almost identically lower mortality in the active treatment and placebo groups. Perhaps the good adherers in the placebo arms of these trials who faithfully took "a spoonful of sugar" when recommended also exhibited other positive health behaviors that improved their outcome. Or, perhaps one's attitude toward treatment regimens is of critical importance in determining outcome. Regardless of the mechanism, adherence is important, and the findings by Rieckmann et al. (4) provide yet another reason why depression screening should be incorporated into routine ACS care.
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Footnotes
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Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Ziegelstein is supported by the Miller Family Scholar Program.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment Arch Intern Med 2000;160:2101-2107.[Abstract/Free Full Text]2. Miller NH, Hill M, Kottke T, Ockene IS. The multilevel compliance challenge: recommendations for a call to action. A statement for healthcare professionals Circulation 1997;95:1085-1090.[Free Full Text] 3. Fox R. Compliance, adherence, concordance Circulation 1998;97:127.[Free Full Text] 4. Rieckmann N, Gerin W, Kronish IM, et al. Course of depressive symptoms and medication adherence after acute coronary syndromes: an electronic medication monitoring study J Am Coll Cardiol 2006;48:2218-2222. 5. Ziegelstein RC, Fauerbach JA, Stevens SS, Romanelli J, Richter DP, Bush DE. Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction Arch Intern Med 2000;160:1818-1823.[Abstract/Free Full Text] 6. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction) J Am Coll Cardiol 2004;44:E1-E211. 7. Ziegelstein RC, Kim SY, Kao D, et al. Can doctors and nurses recognize depression in patients hospitalized with an acute myocardial infarction in the absence of formal screening? Psychosom Med 2005;67:393-397.[Abstract/Free Full Text] 8. Bush DE, Ziegelstein RC, Patel UV, et al. Post-myocardial infarction depression Evid Rep Technol Assess (Summ) 2005;123:1-8. 9. Serebruany VL, Glassman AH, Malinin AI, et al. Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: evidence from recent clinical trials Blood Coagul Fibrinolysis 2003;14:563-567.[CrossRef][Web of Science][Medline] 10. Ford DE, Erlinger TP. Depression and C-reactive protein in U.S. adults: data from the Third National Health and Nutrition Examination Survey Arch Intern Med 2004;164:1010-1014.[Abstract/Free Full Text] 11. Stein PK, Carney RM, Freedland KE, et al. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease J Psychosom Res 2000;48:493-500.[CrossRef][Web of Science][Medline] 12. Serebruany VL, Glassman AH, Malinin AI, et al. Sertraline AntiDepressant Heart Attack Randomized Trial Study Group Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy Circulation 2003;108:939-944.[Abstract/Free Full Text] 13. Abdel-Salam OM, Baiuomy AR, Arbid MS. Studies on the anti-inflammatory effect of fluoxetine in the rat Pharmacol Res 2004;49:119-131.[CrossRef][Web of Science][Medline] 14. McFarlane A, Kamath MV, Fallen EL, Malcolm V, Cherian F, Norman G. Effect of sertraline on the recovery rate of cardiac autonomic function in depressed patients after acute myocardial infarction Am Heart J 2001;142:617-623.[CrossRef][Web of Science][Medline] 15. Simpson SH, Eurich DT, Majumdar SR, et al. A meta-analysis of the association between adherence to drug therapy and mortality BMJ 2006;333:15.[Abstract/Free Full Text] 16. Coronary Drug Project Research Group Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project N Engl J Med 1980;303:1038-1041.[Abstract] 17. Horwitz RI, Viscoli CM, Berkman L, et al. Treatment adherence and risk of death after a myocardial infarction Lancet 1990;336:542-545.[CrossRef][Web of Science][Medline] 18. Irvine J, Baker B, Smith J, et al. Poor adherence to placebo or amiodarone therapy predicts mortality: results from the CAMIAT studyCanadian Amiodarone Myocardial Infarction Arrhythmia Trial. Psychosom Med 1999;61:566-575.[Abstract/Free Full Text] 19. Granger BB, Swedberg K, Ekman I, et al. , for the CHARM investigatorsAdherence to candesartan and placebo and outcomes in chronic heart failure in the CHARM programme: double-blind, randomised, controlled clinical trial. Lancet 2005;366:2005-2011.[CrossRef][Web of Science][Medline]
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