Adherence to Treatment Regimens in Major Depression: Perspectives, Problems, and Progress

Adherence, in a medical context, refers to the degree to which a patient follows the treatment plan that has been agreed on between the prescriber (usually, but not always, a physician) and the patient. Although the term "compliance" is often used by caregivers, it is a less desirable term than "adherence," because it implies an all-or-nothing obedience to the will of others. Adherence, like a religious belief, involves recognition that there may be aspects that are less acceptable than to others; accordingly, the patient may subscribe more to certain tenets than others. This is often (and more so than we believe) what patients do in practice.¹ They skip doses because of adverse effects or to use recreational drugs. They may forget the treatment plan or come to disagree with it on the basis of something they have heard or read on the Internet.

There are different degrees of adherence, from complete to rare or nonexistent adherence. This article seeks to examine what underlies difficulties and challenges with treatment adherence of major depressive disorder and identifies approaches that the clinician can use to improve patient adherence to treatment.

Perspectives on adherence

Adherence, from a dimensional perspective, can be defined as the percentage of time the patient takes his or her medicines as prescribed or how many times he perfoms the prescribed life-style interventions (eg, exercise). From a categorical perspective, nonadherence is often described in terms of the point below which a therapeutic benefit from an intervention is likely to be realized. Both definitions are dynamic and variable for each intervention and each patient.

Nonadherence may be willful or active: the individual consciously decides not to follow the prescribed treatment plan. One study found that 25% of patients told their doctors they were taking their medication when, in fact, the pharmacy database showed that they were not.¹ Alternatively, nonadherence may be passive--patients forget or do not understand the instructions, or are unable to perform the activity correctly.²

Assessment of adherence has been both direct and indirect. The most common example of a direct measure is the serum blood levels that are routinely used for management of lithium as well as many of the tricyclic antidepressants (TCAs). The downside to measuring blood levels is that they reflect the concentration of drug only at the time the blood is taken; there is no equivalent to the hemoglobin A_1c assay for diabetes that is used to measure blood sugar concentrations over the preceding 3 months.

The most common indirect measures of adherence are the patient's self-report and the report of the family. It is generally accepted that the self-report meth-od overestimates the degree of adher-ence.^3-5 Some research studies have used pill-counting strategies or electronic caps on medicine containers to record the number of times the container is opened.^6,7 Although this approach monitors medication-taking behavior, it cannot account for doses removed that are not actually taken. At a population level, claims records from public and private health insurance organizations can be used to estimate the number of prescriptions filled and refilled.⁴

There are no sociological⁸ or personality characteristics⁹ that consistently predict difficulties with adherence; moreover, adherence varies over time and in response to different aspects of prescribed treatments.¹⁰ However, it is recognized that comorbid medical conditions¹¹ and concomitant substance abuse¹² are generally associated with compromised adherence. Use of the newer antidepressant classes of medications is generally associated with modest improvements in adherence, but it is receiving individually targeted mental health care services that con- sistently has been shown to be the strongest factor associated with increased adherence to antidepressant treatment.^13,14

Older versus newer antidepressants

Before the advent of the SSRIs, TCAs were the primary choice of pharmacological treatment for major depression. It has long been recognized that adherence to TCAs is often poor,¹⁵ particularly in primary care practice.¹⁶ There are a host of reasons patients may have treatment-adherence difficulties with TCAs, including adverse effects and complicated dosing (eg, starting with a low dose and titrating to a therapeutic range).

It was assumed that the simplified dosing scheduling with SSRIs, as well as less problematic adverse effects, would result in improved adherence in patients with major depression. However, the results of recent studies have not been as resoundingly favorable as was anticipated.

A number of meta-analyses of comparative treatment studies that examined dropout rates of patients taking SSRIs compared with those of patients taking older TCAs failed to find significant overall differences,¹⁷ although the rates were lower in the SSRI groups when adverse effects were identified as the reason for discontinuation.¹⁸ Direct comparisons of TCAs and SSRIs have only provided modest support for the belief that adherence is improved with SSRIs.

Thompson and colleagues⁷ randomized 152 patients in 10 primary care settings in the United Kingdom, in an open-label parallel-group study comparing fluoxetine and the TCA do-thiepin at therapeutic dosages for 12 weeks. Similar numbers of patients dropped out of the study in both groups (37% vs 39%); the rate of withdrawal from the study because of an adverse event was 20% in the dothiepin group and 14% in the fluoxetine group, suggesting a modest advantage of fluoxetine. The level of adherence in the treated groups was nonsignificantly greater in the fluoxetine group (76%) than in the dothiepin group (64%) as measured by pill counts. The investigators concluded that there were, in fact, modest differences in the levels of adherence in the 2 groups; however, they pointed out that the study sample was insufficient to detect such a small effect size.

Adherence measures at the population level

The study of adherence to antidepressant treatment has evolved to examination of larger data sets from large health care organizations. The metric used to assess adherence is based on the criteria from the National Committee for Quality Assurance (NCQA) standardized performance measures that are voluntarily reported by health plans to the Health Plan Employer Data and Information Set (HEDIS). Adherence is simply defined as being in possession of the prescribed antidepressant as measured by pharmacy claims and attending mental health appointments identified by health claims (Table 1).

The claims of 4312 patients with newly diagnosed major depression, who were members of a large health care organization in the northeastern United States, were studied: 96% of these patients were treated with the newer classes of antidepressants.¹⁹ Adherence in the acute treatment phase was 51%, and this dropped to 42% in the continuation phase of treatment. Being younger and having a comorbid substance abuse or medical condition were associated with lower adherence. Only 28% of the patients received follow-up care with a psychiatrist, and this mode of care was significantly associated with greater adherence to the treatment plan.

In another study, the MarketScan Commercial Claims and Encounters database for medical and pharmacy claims was used to assess adherence to NCQA quality-of-care measures.¹³ The study examined benefit claims from 60,386 patients with major depression identified from a database of 562,808 individuals with recent-onset depression who were receiving treatment. Outcome measures were adequate dos-ages of medications for 84 of 114 days in the acute phase and 180 of 214 days in the maintenance phase; 70% of patients were treated with SSRIs. Across the entire group, and for the total study period, only 19% of patients met all 3 of the HEDIS criteria (Table 1); 65% met the acute treatment criteria, of whom 44% were adherent through the maintenance phase, and 39% had 3 or more practitioner visits in the acute phase.

The group treated with a serotonin-norepinephrine reuptake inhibitor (8.7%) were most likely to meet HEDIS compliance measures; there was no overall difference between the TCA and SSRI groups. However, in the acute phase, patients in the TCA group were less likely to be adherent, suggesting that adverse effects for this cohort were most problematic. The combination of troublesome adverse effects and delayed onset of action is significant and is an understandable impediment to sustaining therapy. The most significant finding was that individuals who had at least one contact with a psychiatrist, psychologist, or mental health treatment facility were 5 times more likely to be adherent throughout the acute and maintenance treatment phases. Those who had contact with a psychiatric nurse increased their adherence by 1.4 times during the 2 phases.

Adherence to medical management of major depression is a complex phenomenon that goes far beyond the adverse effects issue of the old versus the new antidepressants. The adherence measures of HEDIS assume that the practitioner is prescribing care consistent with the guidelines; it is recognized that there may be practitioner variables that dilute adherence to treatment (such as not scheduling follow-up appointments or not prescribing for sufficient periods).²⁰

Psychological facets of adherence

Patients' attitudes about themselves and their illness, as well as their perception of how society views the illness and its treatment, have a significant effect on their willingness to seek treatment and maintain an adequate treatment regimen. A number of factors contribute to nonadherence (Table 2); for instance, stigma that is real, or perceived as real by the patient, interferes with adherence to treatment plans. In a study by Sirey and associates,²¹ 134 depressed patients were assessed for perception of stigma related to depression as well as their view of the severity of the depressive disorder. Findings showed that lower perceived stigma and higher self-rated severity of illness were associated with better adherence to the recommended treatment regimen. In this study, 52% of patients were taking an SSRI, 23% were taking a TCA, and 25% were taking another antidepressant; adverse effects were not associated with adherence.

Reducing the stigma of depression and other mental health disorders needs to be a priority for psychiatrists, primary care providers, and policy makers alike. Education at the patient, provider, and community levels is necessary to reduce stigma and increase opportunities for patients to receive the necessary care.

Increasing adherence in the depressed patient

The patient with depression is most likely to be seen by a primary care physician. On the other hand, successful treatment for depression will be best achieved by an integrated effort between the primary and specialty care providers. Table 3 provides a brief overview of what can be done to increase treatment adherence. The Depression in Primary Care program, sponsored by the Robert Wood Johnson Foundation, proposed the "6Ps" conceptual framework for treating depression and increasing adherence.²² Although developed for the primary care setting, the 6Ps apply equally well to specialty practice, and the approach can be used for any chronic medical or psychiatric illness.

• Patients are the entry point; each has preferences and biases, and needs education on his or her illness and medications, as well as self-management tools to reduce stigma.
• Providers are key to educating the patient and his family; providers need to ensure ease of access to primary and specialty care. The involvement of specialty care improves adherence measures.
• Practices and delivery systems need to establish chronic care models for treatment of depression using evidence-based care and information delivery systems between practices and with patients and families.
• Plans (insurance and other payers) need to be able to monitor quality of care and identify outliers at both the patient and practice levels. Incentives could be considered for success in achieving HEDIS quality measures.
• Purchasers of plans at the corporate and individual levels need to be educated on the need for quality treatment of depression.
• Policy at the population level should be enhanced to increase demand for quality care of patients with depression and to develop capacities at the local, state, and national levels. The adage "think globally but act locally" comes to mind.

Conclusion

Adherence is a complicated phenomenon that is heavily influenced by prevailing beliefs at the patient, provider, and population levels. It is important to remember that patients are more likely to be adherent to medication regimens for treatment of depression if they are convinced of the necessity of treatment and have sufficient concern regarding their health; thus, patient education will enhance the likelihood of treatment adherence.

It is humbling to realize that overall adherence measures have not improved dramatically with the advent of the newer classes of antidepressants. What has been found to be effective in enhancing adherence is increased interaction with specialty care providers. In reality, it is impossible for all patients with depression to receive specialty care; however, every community can strive to enhance interactions between primary and specialty care providers in a collaborative care model that will effectively use the specialist to advise on care to increase adherence to treatment plans.

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