Understanding Medication Discontinuation in Depression

Compared with schizophrenia, adherence behavior has been relatively overlooked in depression and other mood disorders.^1-3 Major depression is increasingly thought of as a chronic illness.⁴ In most chronic illnesses, ideal concordance is the exception, not the rule. Barber and colleagues⁵ found that only 16% of patients taking medication for stroke, coronary heart disease, asthma, diabetes mellitus, and rheumatoid arthritis were adherent, problem-free, and in receipt of sufficient information when examined at 10 days. Should we expect our patients with mental health problems to be more or less able to adhere to our recommendations? Furthermore, are we more or less willing than our colleagues in other medical specialties to take the time to promote problem-free adherence in our patients?

EPIDEMIOLOGY OF ANTI- DEPRESSANT ADHERENCE
Three new studies suggest that physicians should be vigilant for adherence difficulties in patients with depression (Table 1). In the Medical Expenditure Panel Survey, Olfson and colleagues⁶ looked at 829 people who had started antidepressant treatment for depression. Their findings showed that 42% discontinued antidepressants during the first 30 days and 72% had stopped within 90 days. Bambauer and colleagues⁷ documented partial nonadherence in 75% of individuals who were depressed, culminating in an average of 40% of days without taking dispensed antidepressants.

A prospective cohort study from Amsterdam used 6-month follow-up of 147 primary care patients who had been given a new prescription for a nontricyclic antidepressant.⁸ Adherence behavior was closely monitored using an electronic pill container over a total of more than 20,000 patient-days. In this sample, the mean number of correct medication intakes was 74%, with 69% of the patients exhibiting adequate adherence (taking more than 80% of medication doses). Remarkably, only 3% followed the medication regimen exactly as prescribed.

These findings are in line with those of previous studies. In a sample of 272 patients with major depression treated by 91 primary care physicians, 48% had dropped out of treatment by week 12.⁹ In a large study of 240,604 patients who were given a new antidepressant prescription, 70% discontinued within 6 months.¹⁰ Recently analyzed adherence data from a study of more than 740,000 patients in whom treatment with an SSRI was newly started showed that almost half the patients failed to adhere to therapy for 60 days or more, and only 28% were compliant at 6 months.¹¹ Even in tightly controlled trial environments, discontinuation rates for SSRIs have typically been above 70%.¹²

One important question concerns whether the choice of drug has any effect on adherence. Head-to-head studies of discontinuation rates have yet to be properly compiled, but work to date hints that discontinuation rates with tricyclics are only marginally worse than with newer antidepressants.^13-16 Physicians must decide whether this is clinically significant in conjunction with other factors. Yet even within a drug class there may be subtle differences in adherence between those taking different SSRIs, according to new data from 116,090 patients in the Integrated Healthcare Information Services National Managed Care Database who had started treatment with an SSRI.¹⁷

UNDERSTANDING DISCONTINUATION
What factors can explain these high discontinuation rates and even higher rates of missed medication doses? Evidence is slowly emerging that preexisting treatment preferences, trust in medication and the prescriber, and treatment-emergent problems are more important than severity of depression or loss of insight (Table 2). In fact, given the information available to that individual, most cases of discontinuation appear to be intentional and rational.

Confidence in antidepressant treatment
Sirey and colleagues^18,19 found that perceptions of stigma about depression at the start of treatment predicted subsequent antidepressant adherence 3 months later. Surveys in many countries consistently report that more than three quarters of people believe that antidepressants are addictive and that most prefer psychotherapy or no treatment at all.^20-23 Col and associates²⁴ found that 50% of patients who were depressed believed they did not need their antidepressants when they began to feel better or that the medications could be taken on an as-needed basis. Patients' previous negative experiences with prescribed medication had a negative influence on current adherence behavior.²⁵ Indeed, Brook and colleagues⁸ found that attitude toward antidepressants was the most important predictor in determining reliable adherence behavior. Aikens and coworkers²⁶ went further and modeled the risk as attributable to concerns about medication. Baseline skepticism about starting an antidepressant contributed to a 62% increase in the risk of premature discontinuation over 9 months.

Effectiveness
Ashton and coworkers²⁷ found that the most common reason for discontinuation was lack of efficacy (reported by 44%) in 210 patients who had been previously treated for depression. This appears to confirm the clinical impression that many patients intentionally stop antidepressants as soon as they can. However, many patients stop antidepressants intentionally when they start to feel better. In fact, 2 studies found that a third of patients stop within 3 months, citing feeling better as the reason, and 55% stop when feeling better within 6 months.^28,29 Thus, both successful and unsuccessful treatment often lead to patient-initiated discontinuation.

Adverse effects
Treatment-emergent adverse effects are an important but avoidable (or at least reversible) reason for discontinuing treatment and not wanting to restart. Intentional nonadherence was associated with concerns about adverse effects of antidepressants as well as the associated stigma.³⁰ In a survey of 344 persons taking antidepressants, the most common reason for less than perfect compliance was the risk of adverse effects. The experience of 1 or more bothersome adverse effects meant that an individual was 3 times more likely to stop medication.³¹ Such complications include weight gain (31%), erectile dysfunction (25%), difficulty in reaching orgasm (24%), and fatigue (21%).²⁷

Accidental omissions
If one examines missed doses rather than full discontinuation, then "forgetting to take the tablet" is the most common explanation. This is encouraging because it allows scope for reminder systems (see below). In the large Alberta Mental Health Telephone Survey from Calgary, poor compliance was assessed in 5323 adults. Asked whether they take less medication than they are supposed to, 42% taking a single medication reported noncompliance; forgetfulness may have been the most common reason for missed medication (64.9%).³² Similarly, Ashton and associates²⁷ found that difficulty in remembering to take medication accounted for 43% of cases of poor compliance. Forgetting to take all doses is related to regimen complexity, cognitive impairment, duration of institutionalization, and ironically, depression.³³

REDUCING ANTIDEPRESSANT NONADHERENCE
Evidence-based adherence studies in depression
There are numerous potential ways of improving adherence behavior, from simple to complex (Table 3). Unfortunately, data from large-scale studies in medical settings hint that dramatic effects on adherence behavior are rare.³⁴ Only a few strategies have been rigorously tested for patients with depression.^35-37 Vergouwen and colleagues³⁸ reviewed 6 studies of interventions involving mental health outpatients and 13 studies comprising primary care patients. Of those studies conducted in psychiatric settings, 5 tested education as an adherence-enhancing intervention, and 3 of these did not demonstrate any appreciable effect.^39-41 However, 2 studies demonstrated significantly better adherence in patients who received verbal and/or written information about side effects of antidepressant medication.^42,43 One study tested the influence of dosing complexity as well as the effectiveness of allowing patients to choose their own dosage regimen.⁴⁴ Adherence was significantly better in those patients who were allowed to choose.

Of the 13 primary care studies reviewed, 3 tested educational interventions but 2 of these involved only a leaflet. None were successful at improving adherence.^45-47 Since early 2003, 8 more studies have been published.⁴⁸ The largest was a randomized study involving 1031 patients with depression. This study looked at an educational program and therapeutic drug monitoring in patients who took sertraline for 24 weeks.⁴⁹ Neither of the interventions resulted in a significant increase in adherence rate. Also of note, Bambauer and colleagues⁷ found that a simple intervention of faxed alerts regarding patient adherence was not successful in improving antidepressant adherence. Despite these disappointments, collaborative care packages have been more successful and demonstrated a benefit in 14 of 28 studies that used adherence as an outcome.⁴⁸

The role of the physician
The potential for physicians to reduce unexpected discontinuations is often more signficant than many imagine. Conversely, the potential for physicians to do nothing is also high. This is even with the knowledge that of all those who discontinue medication, 60% have not informed their doctor by 3 months, and a quarter have not done so by 6 months. Thus, all physicians must maintain a high index of suspicion for possible treatment-emergent problems (adverse events and missed medication)-but this should be manifested in a supportive rather than doubting manner.

Simply discussing the possibility of an adverse event reduces the rate of unanticipated discontinuation by half. Similarly, the chance of discontinuation is about 60% less in patients who are simply told to take medication for at least 6 months, compared with those who did not recall being given this information.⁵⁰ Like most patients, those who have depression want to be involved in decision making.^51,52 Indeed, there is some evidence that adherence improves if more relevant information is given.⁵³ Yet analysis of doctor-patient discourses illustrates that clinicians only ask about 1 of 5 patients how well their antidepressants are working and only 1 of 10 patients if they are experiencing any adverse effects.⁵⁴

Two recent studies analyzed audio recordings of interactions between 152 physicians (internists and primary care) and patients for whom antidepressants were prescribed. Loh and coauthors⁵⁵ observed 34 primary care physicians in Freiburg, Germany. Only 5% of time was spent discussing treatment options and information about these options. Young and colleagues⁵⁶ discovered a mixed picture of communication. Whereas drug purpose and side effects were usually mentioned, barriers to use and "what to do if you miss a dose" were mentioned less than 2% of the time.

Furthermore, advice to continue to take the medicine even when feeling better and advice to continue to take the medication until further review were discussed in only 5.4% and 3.9% of the visits, respectively. Physicians provided information about the duration of antidepressant treatment in 35% of interactions, which is interesting because investigators had previously found that although 71% of physicians claimed to specify treatment duration, 64% of patients recalled no such instructions.⁵⁰ This has led some to suggest it is physician behavior that is the major remediable barrier to poor concordance.⁵⁷

CONCLUSIONS
Most patients for whom an antidepressant is prescribed will experience some kind of problem with insufficient information, adverse effects, or lack of efficacy. This often leads to missed doses of medication and later discontinuation. Rather than being an aberration, I suggest that partial nonadherence should be considered normal. Missing doses and even stopping completely may be the most rational approach to health, given patients' understanding of their illness and the information available to them.⁵⁸ As a consequence, many patients for whom medication is prescribed to be taken regularly will, in fact, take their medication "as required," ie, for symptomatic relief only.⁵⁹ This may well conflict with evidence-based guidance to continue medication for 6 months or longer once well to prevent future relapse.²

Physicians who are alert to patients' medication problems and patients who are considering stopping medication will be able to discuss alternatives that prevent unmonitored discontinuation. Patients who have difficulty in remembering to take their medication might be helped by simple reminder systems. Both partial nonadherence and discontinuation can be helped by enhanced collaborative care for depression.