Richard W. Grant, MD, MPH

Depression and hyperlipidemia are common conditions that often coexist and may clinically interact with each other. Depression has a negative impact on medication adherence.

 In addition, depressed hyperlipidemic diabetes patients tend to refill their statin prescriptions less often than those without depression.

Many patients in primary care receive inadequate dose trials of antidepressant (AD) therapy.

 Prior studies have shown that patients receiving adequate AD treatment are twice as likely to adhere to chronic disease medications (including statins) than patients receiving inadequate AD treatment.

 The reason for the association between adequate AD treatment and adherence to chronic disease medications is not fully understood. Disease-related factors (resolution of depression) may play a role insofar as adequate AD treatment produces resolution of depression. However, patient-related factors (eg, baseline tendency toward adherence to all medications, medication-taking “style”) also may be involved. Patients likely to adhere to ADs also may be likely to adhere to other medications (statins). The relative impact of disease and patient-related factors in the association between AD treatment adequacy and adherence to other medications needs to be clarified.

We addressed the impact of disease- and patient-related factors among statin and AD users by focusing on statin adherence before and after AD initiation in patients with poor statin adherence at baseline. These patients may have poor statin adherence because of disease factors (the tendency of depressed patients to show poor medication adherence

) and/or patient factors (a general tendency to show poor adherence to any medication). Patient factors are likely to be stable, whereas disease factors may change if the disease that drives them—in this case, depression&mdash;resolves. Adequate AD treatment is more likely than inadequate AD treatment to produce improvement in depression.

 We hypothesize that if poorly adherent statin patients developed good statin adherence after an adequate trial of ADs significantly more often than after an inadequate trial of ADs, the change most likely would be due to the impact of the AD on the depression (eg, on medical factors).

We retrospectively analyzed a cohort of commercially insured patients receiving statin therapy. We used the Integrated Healthcare Information Services database system, a comprehensive, deidentified US healthcare claims database that is representative of the nonelderly, insurancecarrying population in the United States from more than 35 different healthcare plans serving members across 9 census regions. The database is compliant with the Health Insurance Portability and Accountability Act and features encrypted member and provider identification numbers. The average enrollment was 20 months; the annual attrition rate was roughly 15% to 25%. We identified all patients with (1) continuous plan enrollment; (2) more than 1 pharmacy claim for statin therapy (atorvastatin calcium, fluvastatin sodium, pravastatin sodium, lovastatin sodium, rosuvastatin calcium, or simvastatin calcium) in the first enrollment year; and (3) total cholesterol results measured in each of 2 consecutive enrollment years. 

From the 1.24 million patients receiving statin prescriptions during the time period studied, we were left with 49,943 patients after excluding patients who were not enrolled continuously, who did not have at least 2 statin prescriptions prior to either the onset of AD use or the midway point of their enrollment, or who did not have cholesterol levels available within the (mostly claims-based) database. Within our cohort of statin-treated patients, we identified all patients coprescribed AD therapy (AD cohort). For the purposes of our analysis, we limited our AD cohort to patients whose initial statin prescription date preceded their AD initiation date to allow the measurement of pre-AD treatment statin adherence. In addition, patients whose AD trial(s) consisted solely of low-dose tricyclic ADs or trazodone were excluded because of the likelihood that these prescriptions were used to treat chronic pain or insomnia. Approximately one-quarter of the patients in our statin cohort received AD therapy. After excluding patients whose first AD prescription preceded their initial statin prescription, our final cohort consisted of 42,227 eligible patients with complete data, including 4781 AD-treated patients (11% of the final dataset).

Pharmacy claims included the patient’s age, a unique patient identification number, the date the prescription was filled, and the drug name, dose, and number of pills supplied. Patient sex was determined from the health plan enrollment records. Using pharmacy claims for the overall study period, we defined 3 comorbid conditions related to cardiovascular disease based on prescription of condition-specific medications. Patients were categorized as having hypertension if they were prescribed any blood pressure—lowering medicines; diabetes if they were prescribed insulin or oral hypoglycemic agents (including sulfonylureas, metformin, thiazolidinediones, and alpha-glucosidase inhibitors); or ischemic heart disease if they were prescribed any nitrate-containing antianginal agents. This method of categorization does not include patients who may have been diagnosed with 1 of the above conditions but were not medically treated or, in the case of ischemic heart disease, treated with other agents.

Our primary outcome measures were statin adherence and statin refill persistence before and after each patient’s index date. The index date for AD-treated patients was the date of the first AD prescription following their initial statin prescription. For comparison purposes, the index date for non-AD patients was the midpoint of their enrollment period. To determine statin adherence, we calculated each patient’s statin medication possession ratio (MPR) in the years before and after the index date. The MPR was calculated by dividing the total number of pills received during each period (excluding the last prescription) by the days between the first and last fill dates during the period.

We also calculated statin refill persistence. Patients were determined to be persistent for 1 year if they had prescriptions filled more than 1 year after the index date. Patients whose enrollment period ended before the 1-year time frame were censored from the refill persistence calculation if they received enough pills at their last fill date to bring them within 30 days of their enrollment ending period. We calculated second year persistence in a similar manner. Our analysis was weighted more heavily with patients who persisted in their statin therapy because we required at least 2 post—index date statin prescriptions in order to determine MPR.

The AD cohort was further divided into those who received adequate AD treatment and those who did not. Adequacy of AD treatment was defined as the continuous use of an AD for 90 or more days at a minimum likely effective dose as determined by prescription refills.

Univariate analysis of adherence predictors was performed using t tests for normally distributed continuous variables and χ2 tests for dichotomous variables. For MPR, linear regression models were constructed to assess the impact of AD therapy after controlling for significant covariables such as age and sex. Logistic regression equations were used to model predictors of the dichotomous outcomes of 1-year and 2-year statin persistence. Because depressed patients with poor baseline statin adherence would likely have the most potential to benefit from AD therapy, we also planned an a priori analysis of all patients whose baseline statin adherence (MPR) was less than 80%. SAS version 9 was used for all analyses (SAS Institute, Cary, NC), and P <.05 was taken to indicate statistical significance. The study was approved by our institutional review board.

Patients with AD treatment were younger (54.0 years vs 55.4 years for patients without AD treatment) and more likely to be women (45% vs 37%; 

). Prevalences of diabetes (18% in both groups), hypertension (65% vs 63%), and ischemic heart disease (13% vs 10%) were similar in the 2 groups. Baseline adherence to statin medication was not significantly different in the AD group versus the non-AD group (MPR = 87%). Patients who received ADs had higher baseline total cholesterol levels (196 vs 193 mg/dL; P <.01).

Among patients who received AD treatment, 1769 received adequate treatment regimens (37%) and 3012 received inadequate regimens (63%). Clinical characteristics were similar in the adequately and inadequately treated patients (Table 1). Patients with adequate AD therapy had better baseline statin adherence than the inadequately treated group (90% vs 85%; P <.01). 

For the overall cohort, statin adherence for AD-treated and non—AD-treated patients changed less than 1% in the year after the index date. Patients who received inadequate AD treatment slightly increased their statin adherence in the first year and experienced no change in the second year. Adequately treated AD patients had no change in statin adherence in either the first or second year. There were 11,687 patients with poor baseline adherence (MPR <80%, 28% of analysis cohort) (

). In this poorly adherent subset, patients receiving adequate doses of ADs had greater MPR improvement (+18%, n = 414) in the first follow-up year than patients with either inadequate AD therapy (+12%, n = 974) or no AD therapy (+12%, n = 10,299; P <.01 for both comparisons) (

). In multivariate models that controlled for baseline differences between groups, AD adequacy was associated with a 6% greater MPR than inadequate therapy (P <.01) and a 7% greater MPR than no AD therapy (P <.01).

For the overall cohort, statin refill persistence remained high in the first follow-up year (88% for both groups) before dropping in the second year (67% for AD-treated patients and 68% for patients not treated with ADs; P = .33).

Persistence with statin therapy also was greater for the group receiving adequate AD treatment compared with patients receiving inadequate AD treatment or not receiving any AD treatment. Ninety-three percent of patients receiving adequate AD treatment persisted with statin therapy in the first follow-up year versus 85% of the inadequate AD group and 88% of the non-AD group (P <.01 for both comparisons). Similarly, 77% of the adequate AD group continued refilling statin prescriptions in the second year versus 61% of the inadequate AD group and 68% of the non-AD group (P <.01 for both comparisons). Differences in persistence remained significant in multiple regression analyses after controlling for age, sex, medical comorbidities, and baseline statin adherence.

The pattern of greater refill persistence among patients with adequate AD treatment also was seen in the subset of patients poorly adherent to statins at baseline (MPR <80%). Patients who were treated adequately with ADs had an 87% persistence rate in the first year, compared with an 82% persistence rate for patients who were not treated with ADs (P = .02) and an 80% persistence rate for those who were inadequately treated (P <.01). Statin refill persistence in the second year was 66% among patients with adequate treatment, 56% among patients not treated with ADs, and 51% among patients inadequately treated with ADs (P <.01 for both comparisons).

We used pharmacy claims data for a large cohort of insured patients prescribed statins to examine the effect of AD therapy on hyperlipidemia management. Among patients with poor baseline statin adherence, an adequate (eg, guideline concordant) course of AD therapy was associated with a greater tendency to persist with statin therapy and an increase in statin adherence among the patients who persisted with statin therapy. In contrast, patients receiving inadequate AD regimens had poorer rates of persistence and adherence that were not significantly different from those of the poorly adherent control patients not prescribed ADs. We infer from these findings that an effective course of AD therapy can have a significant impact on adherence behaviors for unrelated chronic medical conditions.

 found a significant correlation between AD treatment adequacy and statin adherence, but did not determine whether and how patient or disease factors might contribute to this correlation. Our work addressed this issue. We posited that patient factors include a tendency to take medications. This “adherence style” should be consistent across medications and over time. The impact of adherence style may explain our observation, consistent with that of Katon et al,

 that patients adherent to statins also tended to adhere to ADs. In contrast, disease factors (eg, interference with medication adherence related to depression1) may change over time and may respond to treatment. We suggest that resolution of depression-mediated interference with adherence may explain why patients who received adequate AD treatment tended to shift their statin adherence pattern from poor to good in the period after the AD treatment, whereas patients with inadequate AD treatment did not. 

Persistence (the tendency to remain on a statin by the 12th month of each calendar year) also was significantly greater for patients receiving adequate AD treatment in both years of the study. The difference between persistence and adherence underscores the complexity of patient behavior regarding use of medications for chronic illness over extended time periods and suggests that medication-taking styles may have multiple determinants.

We anticipated that patients with adequate AD treatment and good or improved statin adherence would show a reduction in total cholesterol compared with patients who had inadequate AD treatment and poor statin adherence. Rather, we found that patients with inadequate or no AD treatment had relatively lower total cholesterol than those with adequate AD treatment. This may be explained at least in part by the tendency of some selective serotonin reuptake inhibitors to raise cholesterol.

 Patients with adequate AD treatment were more likely to be exposed to the cholesterol-raising impact of selective serotonin reuptake inhibitors than those with inadequate or no AD treatment.

Our results have limitations and must be interpreted in the context of the study design. Without direct patient assessment, we could not determine whether all patients receiving ADs had depression. Some patients may have received AD treatment for anxiety, or anxiety plus depression. Patients receiving low-dose ADs were removed from the analysis, so it is likely we excluded most, if not all, patients receiving ADs for insomnia, pain, or other conditions where AD treatment adequacy would not be relevant. We could not determine whether AD treatment resulted in resolution of depression-related symptoms. However, other studies have generally found that adequate AD treatment is more likely than inadequate AD treatment to produce resolution of depression.

 Likewise, we could not assess the severity of patients’ depression, hyperlipidemia, or comorbid medical problems, so we could not determine whether illness severity before or after treatment played a role.

The pharmacy claims refill method is an indirect measure of adherence. In contrast to more direct methods such as self-report, pill counts, or electronic monitoring, however, patients are not aware that adherence is being measured and therefore do not alter their usual adherence behavior during the period of measurement.

 Moreover, although filling a prescription does not confirm actual ingestion of the medicines, the opposite remains true: patients with an insufficient number of pills for a given time period cannot be fully adherent. Thus, our method is well suited for identifying suboptimal adherence over time. Recognizing the inherent limitations of administrative database analyses, our study benefits from the large sample size and from our ability to assess 2 different parameters of medication adherence: daily pill taking and long-term refill persistence.

In summary, we demonstrated that among a large cohort of commercially insured patients receiving statin therapy, most patients with poor statin adherence in the first study year tended to remain poorly adherent in subsequent study years. This continued tendency toward poor statin adherence was likely driven by patient factors (eg, medication adherence style). An exception to the pattern of chronic poor adherence was seen in the subset of patients who received adequate courses of AD treatment. Our results suggest that an intervention—in this case, adequate AD treatment&mdash;that impacts disease-related factors may affect adherence and persistence with a medication prescribed for an unrelated chronic medical condition.

Because of the limitations inherent in this retrospective data analysis, further work is required to establish a causal relationship between AD treatment adequacy, resolution of depression, and change in adherence. However, given the high prevalence of depression and the impact of depression on medication adherence, mortality, and costs, future efforts to improve the management of patients with chronic medical conditions should include screening for and effectively treating depression, particularly among patients with poor medication adherence.

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Among patients with poor statin adherence, adequate antidepressant treatment significantly improved adherence and persistence compared with inadequate or no antidepressant treatment.