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ORIGINAL ARTICLES |
From the Rehabilitation Outcomes Research Center (L.D.R.) and the Department of Psychiatry (M.J.T.), Malcom Randall Veterans Affairs Medical Center, Department of Veterans Affairs, Gainesville, Florida; the College of Pharmacy, University of Florida, Gainesville, Florida (L.D.R.); the Department of Psychiatry (M.J.T.) and the Division of Cardiovascular Medicine, Department of Medicine (E.H., C.J.P.), College of Medicine, University of Florida, Gainesville, Florida; and Abbott Laboratories, Abbott Park, Illinois (S.K.).
Address correspondence and reprint requests to L. Douglas Ried, PhD, Pharmacy Health Care Administration, College of Pharmacy, PO Box 100496, University of Florida, Gainesville, FL 32610-0496. E-mail: ried{at}cop.ufl.edu
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ABSTRACT |
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Objectives: The objectives of this study were 1) to compare depressive symptoms by strategy and 2) to identify predictors of depressive symptoms in INVEST patients after 1 year of follow up.
Design, Setting, and Patients: Depressive symptoms were assessed in a subset (N = 2317) of consecutively randomized U.S. patients enrolled between April 1, 1999, and October 31, 1999. Patients were mailed surveys after randomization and after 1 year of treatment.
Intervention: Patients were assigned to either a verapamil SR or atenolol strategy to achieve Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure BP goals. Trandolapril and/or hydrochlorothiazide were recommended as add-on agents.
Main Outcome Measure: Depressive symptoms were measured by the Center for Epidemiologic Studies–Depression (CES-D) scale.
Results: CES-D scores improved 1.45 points (p < .001) after 1 year in patients assigned to the verapamil SR strategy, whereas a nonsignificant improvement was observed in patients assigned to the atenolol strategy (0.27 points, p = .44). Predictors of higher depressive symptoms were higher baseline CES-D score (p < .001), history of depression diagnosis (p = .03), history of stroke (p < .001), and assignment to the atenolol strategy (p < .001).
Conclusions: A verapamil SR strategy is a viable alternative to beta-blocker therapy for hypertensive patients with coronary artery disease, especially those at risk of depression.
Key Words: antihypertensive • beta-blocker • calcium channel blocker • coronary artery disease • depressive symptoms • quality of life
Abbreviations: CAD = coronary artery disease; MI = myocardial infarction; SADD-Sx = Study of Antihypertensive Drugs and Depressive Symptoms; INVEST = International Verapamil SR-Trandolapril Study; CES-D = Center for Epidemiologic Studies–Depression scale; JNC VI = Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
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INTRODUCTION |
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There is a paucity of rigorous studies comparing risk differences of depression and depressive symptoms among patients prescribed antihypertensive agents, including beta-blockers and calcium antagonists. Studies that examined risk of depression associated with antihypertensive treatment have been relatively small and limited by study design (8). Moreover, the relationship between beta-blockers and depressive symptoms may be confounded in patients with concomitant diseases. Without large, randomized studies, risk differences between hypertension treatments, including beta-blockers and calcium antagonists, remains uncertain.
To the best of our knowledge, no large-scale, prospective, randomized clinical trials have compared calcium antagonist-based and beta-blocker-based hypertension treatment strategies with respect to risk of depression or depressive symptoms among patients with CAD. Accordingly, the objectives of this study were 1) to compare depressive symptoms after 1 year of hypertension treatment with either a verapamil SR or atenolol strategy in a subset of patients with CAD from the International Verapamil SR-trandolapril Study (INVEST) and 2) to determine predictors of depressive symptoms.
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METHODS |
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50 years conducted from September 1997 to February 2003. Patients were randomized to antihypertensive treatment with either a verapamil SR- or atenolol-based strategy to achieve blood pressure (BP) control according to the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) (12). Patients were excluded from INVEST if they were taking a beta-blocker at randomization. Consecutively randomized INVEST patients residing in the United States were mailed SADD-Sx questionnaires between April 1, 1999, and October 31, 1999 (N = 2317). SADD-Sx patients were mailed a health-related quality-of-life survey that contained a measure of depressive symptoms. Information on educational level, living status, and psychiatric history was obtained by the survey. SADD-Sx was conducted according to the principles of the Declaration of Helsinki. The University of Florida Institutional Review Board approved the study protocol.
Patients were mailed baseline surveys the day after randomization and follow-up surveys were sent at 1 year. If surveys were not returned within 10 working days, a second survey was mailed. Approximately 2 weeks before follow-up surveys were mailed, a letter asking for continued support was mailed to each patient to enhance response rate. If patients did not respond to the second survey, no further attempts were made to contact them for the purposes of SADD-Sx.
Self-rated Depressive Symptoms
The Center for Epidemiologic Studies-Depression (CES-D) scale was used to assess depressive symptoms (13). The CES-D is a 20-item self-reported rating scale designed to measure current levels of depressive symptoms. It is widely used and is a reliable (13,14) and valid instrument (13,15–17). Scores range from 0 to 60; higher scores indicate more depressive symptoms. As a screening tool, the CES-D has been used to estimate the presence of clinically significant depression (15,17). Scores 16 are generally consistent with depressive symptoms of clinically depressed patients (13,17). People with major chronic medical conditions are most likely to score in the high depressive symptoms range (18), so a higher threshold of 23 is recommended for studies of older persons with chronic illnesses (19). Study conclusions were similar whether the 16 or 23 threshold was used, so only results of the higher threshold analysis are reported. Patients were excluded if they were missing more than four of the 20 CES-D items. If the patient was missing between one and four CES-D items, person mean imputation was used for those missing items (20,21).
Predictor Variables
Pharmacologic Hypertension Treatment Strategy
Assignment to pharmacologic hypertension treatment strategy was the primary explanatory variable of this study (10). Study patients assigned to the atenolol strategy were assigned a value of zero (0) and those assigned to the verapamil SR strategy were assigned value of one (1).
Covariates
Sociodemographic variables commonly associated with depression and depressive symptoms were included in the model as covariates. Gender, race (white versus nonwhite), cohabitation (living alone or with someone), and education (high school graduate vs nonhigh school graduate) were collected from the mail survey. Patient age and medical history were obtained during the baseline INVEST visit and abstracted from the baseline forms electronically submitted to the INVEST data coordinating center. Finally, patients self-reported their overall feeling of well-being as excellent, good, fair, or poor, which were dichotomized into "poor/fair" (0) and "good/excellent" (1).
History of cancer, stroke/transient ischemic attack, hypercholesterolemia, abnormal coronary angiogram, angina, MI, coronary artery bypass graft, left ventricular hypertrophy, congestive heart failure, and cardiac arrhythmias were noted at baseline. Other medical conditions noted were Alzheimer’s disease, diabetes, gastrointestinal bleeding, Parkinson’s disease, renal impairment, and peripheral vascular disease. Patients were assigned a value of "1" if the condition was present. In addition, patients’ smoking history (1) and history of stopping and restarting smoking (1) were included in the model.
Finally, information about patients’ psychiatric history was obtained (22). Patients were asked if "... a medical doctor or psychiatrist has ever told you that you were depressed" (0 = no or I don’t know; 1 = yes). No further corroboration of the history of treatment for depression was made, and no additional information was collected regarding onset, duration, severity, or antidepressant or psychologic treatment (23).
Statistical Analyses
Differences in sociodemographic characteristics, medical and cardiac conditions, and mental health risk factors between participants in the two treatment strategies were compared using Pearson’s chi-square and independent t tests for categorical and continuous data, respectively. Baseline and 1-year mean scores within each treatment strategy were compared using paired t tests. Unadjusted risk ratios were calculated for the explanatory variables and risk of reporting high levels of depressive symptoms (23).
Depressive symptoms were examined using multivariate models. The independent effects of sociodemographic, medical and cardiac conditions, and mental health risk factors on depressive symptoms were evaluated stepwise, entering them into the equation in clinically and theoretically relevant groups. Sociodemographic characteristics associated with depression and depressive symptoms were first entered, followed by medical conditions and mental health risk factors associated with depressive symptoms. Lastly, hypertension treatment strategy was added to the regression equation. If the change in explained variance (R2) in the final step was statistically significant, then addition of the hypertension treatment strategy significantly improved prediction of depressive symptoms. We tested for interactions in all regression models.
The a priori level of statistical significance was alpha = 0.05. A sufficient number of patients were enrolled to detect a small effect size (d = 0.20) with a power of 80 at the a priori alpha level. Statistical analyses were conducted with the Statistical Package for the Social Sciences (SPSS) version 10.0.05 (24).
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RESULTS |
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2 = 7.19, p = .007) and race (2 = 92.57, p < .001) were the only significant predictors of nonresponse to the baseline survey. Within gender and race, baseline return rates were similar for the two BP treatment strategies (females: 2 = 1.92, p = .17; males: 2 = 0.08, p = .78 and whites: 2 = 1.36, p = .24 and nonwhites: 2 = 0.15, p = .70). Figure 1 details reasons for not completing either the baseline or follow-up survey (n = 1125). Only data for those returning both the baseline and 1-year surveys are presented.
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Baseline Characteristics
Table 1 summarizes baseline characteristics, including frequently occurring medical conditions that may have influenced the patient’s mood. Nearly 44% (n = 518) of the SADD-Sx patients were female and the majority was 65 years old (59%) and white (80%). The remaining patients were black (16%), Hispanic or another ethnic origin (4.3%). At baseline, approximately 86% of SADD-Sx patients were taking antihypertensive medications. Among those who completed both surveys, nearly 68% were high school graduates or had some college education. Finally, 75% of the study patients lived with someone, usually a spouse (60%) or another relative (20%).
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At baseline, depressive symptoms, history of depression, proportion of individuals at high risk of depression (CES-D 23), and CES-D score were similar between treatment groups, as were sociodemographic characteristics, systolic and diastolic BP, medical and cardiovascular health, and history of hypertension treatment (Table 1). Similar results were observed when all randomized patients (N = 2317) were examined (data not shown).
Change in Depressive Symptoms
On average, depressive symptoms improved between baseline and 1 year in this sample of SADD-Sx patients (CES-D score = 14.12 versus 13.24, paired t test = 3.65, p < .001). Depressive symptoms were lower after 1 year among patients assigned to the verapamil SR strategy (CES-D score = 12.54, standard deviation [SD] = 10.31) compared with patients assigned to the atenolol strategy (CES-D score = 14.00, SD = 11.60; independent t test = 2.30, p = .02, Fig. 2). Patients assigned to the verapamil SR strategy improved an average of 1.45 points (14.00 versus 12.54; paired t test = 4.37, p < .001) on the CES-D scale, whereas improvement was negligible among patients assigned to the atenolol strategy (14.27 versus 14.00; 0.27 points, paired t test = 0.77, p = .44).
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Predictors of Depressive Symptoms
After 1 year, a lower proportion of patients assigned to the verapamil SR strategy reported high depressive symptoms than patients assigned to the atenolol strategy (17.0% versus 21.6%; relative risk [RR] = 0.95, 95% confidence interval [CI] = 0.89–0.99). When the unadjusted risk was examined at 1 year (Fig. 3), women, nonwhite patients, patients with lower educational level, patients with poorer perceptions of well-being, and those living alone were at higher risk. On average, patients reporting high depressive symptoms were younger. High-risk patients averaged 64.1 year compared with 67.3 years (t = 4.69, p < .001). Patients at higher risk also were more likely to have a history of smoking, stopping and restarting smoking at baseline, a history of angina, as well as stroke. All baseline depression indicators were significant risk factors for higher depressive symptoms. High baseline risk of depression increased the 1-year risk by nearly sevenfold, and a diagnosis of depression before randomization was associated with more than triple the risk.
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Multivariate Model
When entered as a group in the first model, female gender, living alone, lower educational status, poorer health status, and younger age were associated with more depressive symptoms (Table 2). Sociodemographic characteristics accounted for nearly 10% of the explained variance.
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When adjusted for baseline medical conditions, only stroke and angina added significantly to the second model. As expected, the mental health variables added to the prediction of higher depressive symptoms to the greatest degree in the third model. Patients at high risk of depression at baseline or with a history of depression before randomization reported more depressive symptoms at 1 year. Stroke was the only medical condition that remained statistically significant after adjusting for the mood-related and psychiatric history variables. After these adjustments, the influence of female gender, living alone, lower educational status, poorer well-being, younger age, and baseline angina on depressive symptoms was no longer statistically significant.
Finally, patients assigned to the verapamil SR strategy had lower depressive symptoms after adjusting for all covariates in the fourth model. When the variables were entered simultaneously, significant predictors of higher depressive symptoms after 1 year were baseline history of stroke, higher baseline levels of depressive symptoms, self-reported history of a depression diagnosis, and BP treatment strategy. After adjusting for the covariates, patients assigned to the verapamil SR strategy scored 1.49 points lower on the CES-D scale (95% CI = –0.60 to –2.38) than patients assigned to the atenolol strategy. Overall, the model explained 53% of the variance.
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DISCUSSION |
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Few studies have directly compared strategies containing a calcium antagonist versus a beta-blocker with regard to depression or depressive symptoms. Our results appear to differ from previous studies. Two nonrandomized, retrospective studies found no differences between treatments containing a beta-blocker versus a calcium antagonist for measures of depression (25,26). In a prospective, observational study, calcium antagonists and beta-blockers were both associated with depressive symptoms, but only calcium antagonists were associated with a depression diagnosis (27). In each of these studies, beta-blockers and calcium antagonists were examined as drug classes.
Our study’s design has other important distinctions from previous studies (8). First, to reduce confounding, we focused on patients with medical conditions that already placed them at high risk of depressive symptoms. It also used a prospective study design, random allocation to treatment, and adequate statistical power. To our knowledge, ours is the first trial to compare risk of depression between atenolol and verapamil strategies with JNC VI BP target goals (12). More importantly, this study is applicable to everyday practice. The strategy approach of BP treatment for patients with cardiovascular disease reflects everyday practice and treatment guidelines (12,28). Our most important finding is that the improvement in depressive symptoms with the verapamil SR strategy was significant, even after considering patients’ mental health history and baseline depressive symptoms.
Several explanations for our findings are possible. First, the observed difference in depressive symptoms could be explained if there was a corresponding difference in clinical end points. However, risk for the INVEST primary outcome (first occurrence of death, nonfatal MI, or nonfatal stroke) was similar for the verapamil SR- and atenolol-strategy groups at 1 year in SADD-Sx (RR = 1.02, 95% CI = 0.73–1.42) and was similar to all US INVEST patients (RR = 0.93, 95% CI = 0.80–1.07). Although no difference in adverse outcome was seen in both cases, higher mortality has been observed at levels of depressive symptoms not generally considered clinically significant and below levels usually considered predictive of increased postacute MI mortality (3). In those studies, longer time periods than we were able to observe in INVEST transpired before a relation between depression and cardiovascular outcomes became apparent (29–31).
Next, physiological mechanisms that account for the improvement in BP could account for the decline in depressive scores at 1 year. Vascular disease burden (i.e., hypertension, diabetes, heart disease, metabolic syndrome) contributes to small-vessel disease and has been hypothesized to be associated with depressive symptoms (32–34). INVEST patients in both strategies achieved similar levels of BP control (11). So, the finding that changes in depressive symptoms at 1 year was not associated with follow-up systolic or diastolic BP is not completely explained by the vascular burden hypothesis and may indicate differential effects from the verapamil SR strategy. One plausible explanation for the observed difference between the two INVEST BP treatment strategies is verapamil’s mood-related effects. Clinically, although verapamil is not indicated as first-line monotherapy for major depressive disorder, it does have a role as an add-on to a mood stabilizer in bipolar affective disorder or antidepressant treatment for mood enhancement among severely depressed or refractory patients (35). Although verapamil was prescribed for its BP-lowering effects in this study, a latent benefit might be its effect on patients’ mood, albeit small. On the other hand, although BP reduction may have improved depressive symptoms of patients assigned to the atenolol strategy, its adverse somatic side effects such as decreased energy and increased fatigue may have negated its beneficial effects, resulting in no observable change in patients’ depressive symptoms.
Our findings add to the evidence regarding atenolol and depressive symptoms. On average, patients’ depressive symptoms did not change over the 1-year period when assigned to the atenolol strategy. With the exception of the Beta-Blocker Heart Attack Trial (BHAT) (36,37), ours is the only prospective, randomized study designed to evaluate the association between depression and an atenolol-containing antihypertensive strategy. This finding has important clinical implications given the value of beta-blockers in the treatment of specific conditions (i.e., acute MI). Beta-blockers may be underused in elderly MI survivors because of concerns about their depressogenic effects, leading to measurable adverse outcomes (9). SADD-Sx provides new evidence that a BP treatment strategy containing atenolol can be given to patients with hypertension and CAD without significantly increasing their risk for depression. All the same, when both are equally clinically indicated, it seems prudent to recommend a verapamil SR strategy rather than an atenolol strategy for patients with CAD who already are despondent, depressed, dysphoric, or have a personal or family history of depression.
The patients’ initial mental health status, history of stroke, and hypertension treatment strategy were important predictors of subsequent depressive symptoms. Of these predictors, the most potent one was the initial level of depressive symptoms. It is important for physicians making decisions about hypertension treatment to do a brief screening to ascertain whether a specific patient may be at greater risk. Brief screening instruments are available that require only 2 to 5 minutes to fully complete and may indicate the need for further assessment of the patient’s mood before making a final decision regarding therapy.
The magnitude of change in CES-D scores for patients in the verapamil-SR strategy was small but statistically significant. Previous research has shown that an increase of five points or more in the CES-D score may be associated with increased risk of stroke, MI, and mortality (38). Potent interventions such as exercise have resulted in five-point improvements in CES-D score (39). Our finding of an average 1.5-point reduction for patients assigned to the verapamil-SR strategy was a little less than one third of the five-point difference deemed clinically significant in these studies. Nevertheless, this was not an intervention study specifically intended to modify mood. The optimization of BP control using two equally effective strategies, however, did result in differences in CES-D scores between the two strategies. In SADD-Sx, 23% of patients assigned to the atenolol strategy worsened by five points or more over the year, whereas 19% assigned to the verapamil SR strategy worsened by five points or more. Conversely, 29% of patients assigned to the verapamil-SR strategy improved by five points or more, whereas 26% of patients assigned to the atenolol strategy improved by a similar amount. In both cases, the direction of change favored the verapamil-SR strategy. Even more importantly, although the clinical significance of the choice of BP medication may be small by itself, it may become significant in combination with other depression risk factors. For example, the risk of depression is typically greater for females than males. In SADD-Sx, females assigned to the atenolol strategy were 63% more likely to worsen by five points or more than females assigned to the verapamil SR group (p < .04). In contrast, males’ risk for worsening by five points or more was similar for both BP treatment strategies. Finally, an issue to consider when placing these findings into clinical perspective is the influence of BP treatment choice relative to other clinical factors known to foreshadow depression. In SADD-Sx, BP treatment strategy choice was similar in magnitude to stroke and a history of depression in the prediction of depressive symptoms. Moreover, it was even greater than other signs and symptoms of serious cardiovascular disease that foreshadow depression, including congestive heart failure, arrhythmias, angina, and MI, to name a few. In summary, although the impact of BP treatment choice on clinical outcomes may be small by itself, it may be significant in combination with patients’ other risk factors. One goal of preventive care is to modify risk factors to reduce the likelihood of adverse outcomes. Why add another risk factor without a clinically compelling indication if given an equivalent choice? The next step in this line of inquiry is an in-depth study to ascertain the clinical significance of the role of medication choice in the relationship between worsening mood and the occurrence of death, nonfatal MI, and nonfatal stroke.
Limitations of this study should be noted. First, although study noncompletion and survey nonresponse are potential confounders, patients assigned to the treatment strategies were similar with respect to noncompletion and survey nonresponse rates. In addition, none of the other sociodemographic factors associated with nonresponse were significant in the final model, although potential limitations resulting from the sample being largely older and approximately one third without a high school degree is acknowledged and should be investigated. Second, the nonsignificant finding between BP and depressive symptoms may be partially explained by a floor effect. The baseline mean diastolic blood pressure was within normal range and the mean systolic BP only was about 148 mm Hg in both BP strategies. The implications of these findings merits further investigation with respect to the depressogenic effects of higher vascular burden found in persons with higher BP or for persons with combinations of cardiovascular risk factors (i.e., high BP, diabetes, and hypercholesterolemia). Finally, whether the findings from this study are generalizable to the whole U.S. INVEST population is unclear. For example, the proportion of females and Hispanic patients was lower in SADD-Sx compared with the entire U.S. INVEST sample (data available on request). This finding needs further investigation.
In conclusion, the primary implication of our findings is that a practitioner’s choice between two equally effective hypertension treatment strategies may affect a patient’s mood to the same extent as other important depression risk factors, including stroke or history of depression. On average, the mood of patients assigned to the verapamil SR strategy improved, whereas it did not improve among those assigned to the atenolol strategy. A verapamil SR strategy is a viable alternative to a beta-blocker strategy for hypertensive patients, especially those already at risk of depression.
We thank Wolfgang Wittenberg, Heather Bristol, Rhonda Cooper-DeHoff, and Summana Moolasarn for their support during the conduct of the study and writing of the manuscript.
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NOTES |
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This study was supported by Abbott Laboratories and the University of Florida.
DOI:10.1097/01.psy.0000160468.69451.7f
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This article has been cited by other articles:
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  L D. Ried, M. J Tueth, M. D Taylor, B. C Sauer, L. M Lopez, and C. J Pepine Depressive Symptoms in Coronary Artery Disease Patients After Hypertension Treatment Ann. Pharmacother., April 1, 2006; 40(4): 597 - 604. [Abstract] [Full Text] [PDF]
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