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Psychosomatic Medicine 67:916-920 (2005)
© 2005 American Psychosomatic Society

ORIGINAL ARTICLES

Trends in the Prescribing of Antidepressants Following Acute Myocardial Infarction, 1993–2002

Nili R. Benazon, PhD, Muhammad M. Mamdani, PharmD and James C. Coyne, PhD

From the Centre for Addiction and Mental Health and Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada (N.R.B.); Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (M.M.M.); University of Pennsylvania Health System, Philadelphia, PA (J.C.C.).

Address correspondence and reprint requests to Nili R. Benazon, PhD, Centre for Addiction and Mental Health, 250 College Street, Room 226, Toronto, Ontario, Canada M5T 1R8. E-mail: Nili_Benazon{at}camh.net


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: There has been a substantial increase in the prescribing of antidepressants on a population basis and in particular serotonin reuptake inhibitors (SSRIs). SSRIs have lower cardiac toxicity than tricyclic antidepressants (TCAs). We examined how the prescribing of antidepressants to patients post–myocardial infarction (MI) changed in the decade 1993 to 2002, including the proportion accounted for by TCAs.

Methods: A population-based study cross-sectional time series analysis was conducted in which quarterly antidepressant prescription data were obtained for 1993 to 2002 for elderly Ontarians who had experienced an MI, as well as for age- and sex-matched controls with no history of MI. The number of patients varied per quarter, for a total of 68,870 post-MI patients and an equal number of matched controls. Covariates included age, gender, income, and number of medications dispensed in the past year.

Results: Post-MI patients were more likely to receive an antidepressant relative to controls, with an overall odds ratio (OR) of 1.34; 95% confidence interval (CI), 1.29–1.38. However, with adjustment for the number of medications received, post-MI patients were 20% less likely to receive an antidepressant relative to controls, adjusted OR = 0.81; 95% CI, 0.78–0.84. The proportion of antidepressants prescribed to post-MI patients accounted for by TCAs decreased, but the proportion of post-MI patients receiving a TCA remained stable at approximately 6%.

Conclusions: Increases in the prescription of antidepressants, and in particular SSRIs, to post-MI patients reflect general population trends rather than any special importance attached to treating post-MI depression. The apparent greater likelihood that post-MI patients will receive an antidepressant is reversed when total number of medications is controlled, a proxy for medical utilization and comorbidity.

Key Words: depression • antidepressants • myocardial infarction • coronary heart disease

Abbreviations: CIHI = Canadian Institutes of Health Information; ENRICHD = Enhancing Recovery in Coronary Heart Disease; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; MAOI = monoamine oxidase inhibitors; MI = myocardial infarction; ODB = Ontario Drug Benefit; OHIP = Ontario Health Insurance Plan; RPDB = Ontario Registered Persons Database; OR = odds ratio; CI = confidence interval.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Depression is associated with increased risk for morbidity and mortality from coronary heart disease (1,2). Over the past decade, large-scale, prospective studies have identified depression as a significant independent risk factor for both first myocardial infarction (MI) and cardiovascular mortality, with an adjusted relative risk in the range of 1.5 to 2 (3–6). A seminal study by Frasure-Smith and colleagues (7) demonstrated the adverse effect of post-MI depression on subsequent cardiac mortality, independent of known predictors of mortality post-MI, such as diminished left ventricular ejection fraction. With few exceptions (8,9), subsequent studies have had consistent findings, despite variations in methods used to assess depression (10–13).

The last decade has also seen major efforts to increase the detection and treatment of depression in order to improve the outcome of depression on a population basis, (14), with most of these efforts taking place in general medical care. Studies documenting the low treatment rates (15,16) and considerable functional impairment associated with major depression (17,18) resulted in public health campaigns aimed at increasing the treatment of depression, with dramatic increases in the number of prescriptions for antidepressant medication. Further contributing to this increase in the prescribing of antidepressants has been the availability of new classes of well-marketed drugs such as the selective serotonin reuptake inhibitors (SSRIs), which provide similar rates of improvement to the well-established tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) but with lower risk of overdose and at least marginally greater tolerability (19,20). The marketing of SSRIs has also included sustained direct appeals to the public. Reflecting the combined effects of these influences, a recent report on 1.4 million elderly citizens of Ontario showed that rates of prescriptions exceed most estimates of prevalence of the disorder in this age group (21).

The relatively lower cardiac toxicity of SSRIs minimizes the barriers to treating depression in cardiac patients (22). For over a decade, it has been known that TCAs function as a type 1A antiarrhythmic, similar to encainide and flecainide, which are associated with increased mortality in patients with ischemic heart disease (23). More controversial in terms of clinical significance, it has been argued that SSRIs have the additional benefit of reducing the increased platelet activity typical of chronically depressed patients (24), thereby decreasing the likelihood of platelet-induced ischemic events (25).

The findings linking depression to cardiac morbidity and mortality, as well as findings suggesting that SSRIs are efficacious and safe for cardiac patients, provide an impetus for increasing the identification and treatment of depression among cardiac patients. Reflecting the high rates of preexisting treatment of prospective participants, inclusion criteria had to be relaxed to meet accrual goals in the US National Heart, Lung, and Blood Institute sponsored Enhancing Recovery in Coronary Heart Disease (ENRICHD) study by allowing recruitment of post-MI patients who were already receiving antidepressants (26). Yet, post-MI patients may not be receiving more antidepressants than the population from which they are drawn. It is not clear that any apparent increase in treatment of depression reflects specific attention to the needs of cardiac patients or a more general population trend in the prescribing of antidepressants.

The primary objective of the present study was to examine trends over the past decade in prescription of antidepressants to post-MI patients, relative to the general elderly population. These trends were examined without and with adjustments for total number of medications prescribed, a variable that has been shown to be a proxy for both number of medical visits and medical comorbidity (27). Given the advantages of SSRIs in terms of cardiotoxicity, a secondary objective was to examine trends in the ratio of SSRIs to TCAs for post-MI patients and matched controls over the decade of the study.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Study Design and Patient Population
We conducted a population-based cross-sectional time series analysis using administrative healthcare databases covering more than 1.4 million residents of Ontario, Canada, of age 65 and older from April 1, 1993, through March 31, 2002. This time period was divided into quarterly intervals. In each of these intervals, two groups of patients were identified: (1) incident acute MI cases, which included patients discharged from hospital with a diagnosis of MI who survived at least 6 months postdischarge and who had no history of MI 3 years before the discharge date and (2) a randomly selected control group matched to the post-MI patients on sex and age at hospital discharge (1:1 matching) with no history of MI 3 years before the discharge date. The number of patients included per quarter ranged from 1637 to 2231, for a total of 68,870 post-MI patients and an equal number of matched controls.

Data Sources
Analyses required linking four separate population-based data sources using subjects’ encrypted Ontario health insurance numbers: the Ontario Drug Benefit (ODB) prescription claims database, the Canadian Institutes of Health Information (CIHI) hospital discharge abstract database, the Ontario Health Insurance Plan (OHIP) database, and the Ontario Registered Persons Database (RPDB). All Ontario residents have universal, publicly funded health insurance for hospital care, and each discharge from the hospital results in the production of a CIHI discharge abstract that must be submitted to the provincial government. This discharge abstract contains information pertaining to the hospital admission, the demographic characteristics of the patient, coexisting illnesses, in-hospital procedures, and mortality. The OHIP database contains information on physician claims, and the RPDB database contains information on vital status. The ODB prescription claims database has been used in other pharmacoepidemiology studies assessing drug use in patients with cardiac disease (28,29), and it contains information on outpatient prescription drug use for all 1.4 million elderly residents of Ontario. The specific antidepressant medications found in the database are outlined in Table 1.


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  		TABLE 1. Antidepressants Included in the Study

 

Exposure Assessment
We examined levels of exposure to four antidepressant medications within 6 months following the discharge date: (1) any antidepressant; (2) TCA/MAOI; (3) SSRI; and (4) other antidepressant.

Assessment of Matching Variables and Covariates
Post-MI patients and control subjects were matched on the basis of age and gender. All analyses included median neighborhood income as a covariate. Total number of medications prescribed was used as a proxy for number of medical visits and medical comorbidity (27), and analyses were conducted without and with this variable as a covariate.

Statistical Analyses
A time series analysis was conducted using exponential smoothing models and autoregressive integrated moving average (ARIMA) models. Observations having a temporal sequence are often autocorrelated (i.e., the value at time X is affected by the value at time X – 1). As a result, the error terms are not independent, making simple regression inappropriate for their analysis. Time series analysis is a collection of techniques for modeling autocorrelation in temporally sequenced data. Numerous smoothing models were fit to the data using the SAS/ETS software package for Windows, Version 6.11 (SAS Institute Inc., Cary, NC). The level (a), trend (g), damping (f), and seasonality (d) smoothing weights were set to optimize the fit of the model to the data. Model appropriateness was assessed by standard methods, including visual inspection of the autocorrelation functions, the Ljung-Box {chi}2 statistic for assessing autocorrelations at various lags for the presence of white noise, and the augmented Dickey-Fuller test for the assessment of stationarity. Univariate and multivariate logistic regression analyses were used to compare rates of antidepressant use between post-MI patients and matched controls. Data on age, gender, median neighborhood income, and the number of distinct drugs as a marker of comorbidity were collected for each quarter of the study period and served as covariates.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
The proportion of post-MI patients treated with antidepressants within six months of their infarction steadily increased and doubled from 7.8% (n = 128/1637) in the second quarter of 1993 to 15.7% (n = 350/2231) by the first quarter of 2002, p < .01 (see Figure 1). The number of post-MI patients treated with an antidepressant in any given quarter within the study period ranged from 128 to 357. Parallel increases were observed in matched control subjects, with rates of prescriptions for antidepressants increasing from 6.4% (n = 105/1637) in the second quarter of 1993 to 12.2% (n = 273/2231) by the first quarter of 2002, p < .01 (see Figure 1). The number of control subjects treated with an antidepressant in any given quarter within the study period ranged from 105 to 273. Across the decade, post-MI patients were consistently more likely to receive an antidepressant relative to controls, with an overall OR of 1.34; 95% confidence interval (CI), 1.29–1.38. However, once we adjusted for the number of medications received, post-MI patients were consistently nearly 20% less likely to receive an antidepressant relative to matched controls, adjusted odds ratio (OR) = 0.81; 95% CI, 0.78–0.84.



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  		Figure 1. Proportion of post-MI and matched controls using antideprssants in a population-based study of elderly Ontario residents, 1993–2002.

 

Among post-MI patients and matched controls, the greatest shifts in prescribing patterns occurred with SSRIs both in terms of the proportion of SSRIs prescribed relative to TCAs and in the overall number of SSRI prescriptions dispensed. For instance, in the second quarter of 1993, 23% of the prescriptions dispensed to post-MI patients were for an SSRI, and this figure increased to 62% by the first quarter of 2002 (p < .01). Whereas TCAs accounted for 83% of the antidepressant prescriptions dispensed to post-MI patients in the second quarter of 1993, this figure fell to 36% by the first quarter of 2002 (p < .01). Some patients received prescriptions for both an SSRI and a TCA. Parallel changes were observed among control subjects in that SSRIs accounted for 24% of the antidepressant prescriptions dispensed by the second quarter of 1993 and increased to 56% by the first quarter of 2002 (p < .01).

The percentage of post-MI patients receiving an SSRI prescription over the decade increased steadily from 2% in the second quarter of 1993 to 10% by the first quarter of 2002. Similarly, 1.5% of control subjects were dispensed SSRIs in the second quarter of 1993, and this figure increased to 7% by the first quarter of 2002. However, the percentage of post-MI patients who received prescriptions for TCAs was relatively constant, 6% in the second quarter of 1993 and 6% in the first quarter of 2002. Similarly, 5% of matched controls were dispensed TCAs in 1993, and this rate remained at 5% in the first quarter of 2002 (see Figure 2B).



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  		Figure 2. Percentage of post-MI patients and matched controls receiving a prescription for (A) an SSRI or (B) a TCA/MAOI in a population-based study of elderly Ontario residents, 1993–2002.

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
Increases in the prescription of antidepressants to post-MI patients over the past decade simply reflect general trends for the population from which these patients are drawn. Thus, a decade of accumulating evidence for depression as a risk factor for reinfarction and mortality among post-MI patients and the availability of antidepressants with lower cardiac toxicity have not yet been translated into a proportionally greater increase in the prescribing of antidepressants to post-MI patients, relative to other elderly patients. Specifically, post-MI patients were consistently more likely than matched controls to receive an antidepressant, but when the total number of medications prescribed was entered as a covariate, the adjusted OR reversed, with post-MI patients then consistently less likely to receive an antidepressant throughout the decade. This contrasting pair of findings deserves interpretative comment. Schneeweiss and colleagues (27) suggest that total number of prescribed medications can serve as a valid surrogate for either medical comorbidity or physician visits. Redelmeier and colleagues (30) proposed that the management of a chronic disease interferes with the treatment of unrelated conditions. It is therefore plausible that the likelihood that an elderly post-MI patient will receive a prescription for an antidepressant increases with the number of medical visits, but the competing demands of managing the cardiac condition decrease the likelihood that antidepressants will be prescribed in a given visit. In sum, health care following a MI might thus be characterized by more visits but less likelihood of a prescription for an antidepressant in any given visit, yielding the contrast between higher unadjusted odds of receiving an antidepressant and lower adjusted odds.

It is important to note that at present, clinical epidemiological findings that post-MI depression predicts reinfarction and death have not yet been translated into demonstrations that treating depression will have an impact on the rate of mortality or cardiac morbidity (31). Moreover, the number of studies failing to find an association between post-MI depression and mortality is increasing (8,13,32), perhaps due to improvements in the immediate care provided to post-MI patients, as well as to secondary prevention. Regardless, as Lesperance and Frasure-Smith (33) have cogently argued, interventions that reduce suffering and improve well-being but fail to change survival are nonetheless valuable. Indeed, two recent trials, namely, the ENRICHD trial, as well as the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), showed that depressive symptoms could be reduced in post-MI patients who received either cognitive behavior therapy or pharmacotherapy with sertraline (22). A recent study by Strik and colleagues (34) demonstrated that health care consumption was predicted by major/minor depression and depressive symptoms, suggesting that for cardiologic prognostic purposes, it remains important to recognize and treat post-MI depression, particularly with the availability of agents with reduced cardiac toxicity.

Findings pertaining to our secondary objective to examine trends over the decade in the ratio of SSRIs to TCAs for post-MI patients and matched controls were equally provocative. In 2002, post-MI patients and matched controls were more likely to receive an SSRI relative to a TCA, but the likelihood that they would receive a TCA remained fixed at 6% and 5%, respectively. The persistent prescribing of TCAs to approximately 6% of post-MI patients over the past decade should be given immediate attention, given the availability of SSRIs that are effective but lacking in the cardiac toxicity associated with TCAs. TCAs are sometimes prescribed for conditions other than depression (e.g., for insomnia or chronic pain) at doses that may not be cardiotoxic. Yet, after searching the existing literature, we have not been able to obtain any estimate of what proportion of TCAs are prescribed for this purpose. Further, at the beginning of our observational period in 1993, SSRIs were not an alternative for treating depression, necessitating greater reliance on TCAs. That there has been no reduction in the proportion of patients receiving TCAs over the last decade suggests that there is a problem in continued prescription for depression, and presumably at cardiotoxic dosages, but we cannot establish the magnitude of the problem.

Our data reflect rates of prescribing and do not indicate the specificity of prescribing to patients with major depression or dysthymia, conditions for which efficacy of antidepressants is established. Patten and Beck (35) estimated from the recent Canadian National Population Health Survey data that 70% of people in the community with a prescription for an antidepressant have not met criteria for major depression in over a year. Thus, rates of prescription of antidepressants equaling or exceeding presumed prevalence of depression are nonetheless compatible with a considerable proportion of depressed patients remaining undiagnosed and untreated.

Our data similarly do not address the adequacy of treatment. The bulk of treatment with antidepressants occurs in general medical rather than specialty mental health care. Recent findings indicate that only 20% to 30% of patients receiving treatment for depression in general medical care obtain adequate care (36–38). Questions of the specificity and adequacy of treatment being provided for depression are important in evaluating the progressive increase in the prescription of antidepressants to post-MI patients and elderly patients more generally, but answering these questions requires going beyond the data available in our integrated data set.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

Dr. Benazon is supported by an award from the Institute on Aging of the Canadian Institutes for Health Research (CIHR). Dr. Mamdani is supported by a New Investigator award from the New Emerging Teams (NETs) of CIHR. The NET program receives joint sponsorship from the Canadian Diabetes Association, the Kidney Foundation of Canada, the Heart and Stroke Foundation of Canada, and the CIHR Institutes of Nutrition, Metabolism & Diabetes and Circulatory & Respiratory Health.

DOI:10.1097/01.psy.0000188399.80167.aa


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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