Question and Answer Forum
The following question-and-answer session was prepared from a discussion with Koen Demyttenaere, MD, PhD, moderated by Steven Cally, PhD, of Advogent.
Acknowledgments: The authors acknowledge Callie Grimes, PhD, and Nicole Hilberth of Advogent for their professional medical writing and editing contributions.
This question-and-answer session was supported by Wyeth Research, Collegeville, Pennsylvania.
Discussant: Koen Demyttenaere, MD, PhD
Koen Demyttenaere, MD, PhD, is psychiatrist in the Department of Psychiatry at University Hospital Gasthuisberg in Leuven, Belgium.
Disclosures: Dr. Demyttenaere is a consultant to, on the speaker’s bureaus of, and has received research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, Lundbeck, sanofi-aventis, Servier, Takeda, and Wyeth.
Treatment with the newer generation antidepressants (eg, selective-serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs]) is considered generally effective for most patients with major depressive disorder (MDD) when taken in accordance with treatment guidelines.1 However, multiple clinical studies have demonstrated that rates of patient adherence to antidepressants (eg, SSRIs, SNRIs, tricyclic antidepressants) are inadequate.2-5 The potential for bothersome adverse events (AEs) or lack of immediate therapeutic response associated with some antidepressants can negatively impact adherence to treatment, and eventually contribute to the recurrence of MDD symptoms.6 In addition, a patient’s attitudes and beliefs concerning the perceived advantages and disadvantages of antidepressants can substantially impact adherence to treatment.7 Interestingly, the opinions of the patient’s partner or family regarding antidepressant use can also influence the patient’s opinions, such that adherence is generally greater when these individuals encourage the positive outcomes of treatment.7,8
As poor patient treatment adherence is a significant obstacle in improving clinical outcomes for patients with MDD,4 it is crucial for physicians to identify specific factors that may contribute to patient nonadherence to treatment with antidepressants. Many of the newer generation antidepressants have specific characteristics that may impact patient adherence to treatment including complicated dosing and titration schedules, antidepressant tolerability, and the potential for drug-drug interactions arising from substantial metabolism through common metabolic pathways (Table 1).9-23
What are the types of nonadherence, and how prevalent is each in treatment?
Adherence is generally defined as the extent to which a patient’s behavior, in terms of taking medication, following dietary restrictions, or executing specific lifestyle changes, coincides with medical or health advice.24 The types of nonadherence common in patients with MDD who are taking antidepressants include dropouts, drug holidays, and irregular intake of medication. In clinical trials evaluating the efficacy and safety of antidepressants in patients with MDD, the term “dropout” is applied to patients who prematurely discontinue treatment. According to treatment guidelines, patients with MDD (even those experiencing a first episode), require acute treatment with antidepressants for ≥6–8 weeks to achieve remission, followed by a minimum of an additional 5 months of continuation or maintenance treatment to preserve remission.1 Thus, patients with MDD who initiate and respond to pharmacotherapy should receive treatment for a minimum of 8–11 months, if not longer. However, ~30% of patients with MDD discontinue treatment within 1 month, with 45% to 60% discontinuing treatment within 3 months.25 Moreover, ~8% to 10% of patients with MDD who receive an antidepressant prescription never have it filled at the pharmacy.
A second type of treatment nonadherence occurs when patients take a “drug holiday,” during which time the patient allows >2 consecutive days to pass without taking any medication. In antidepressant trials, patient-initiated drug holidays have been observed in up to 50% of patients with MDD.26
Lastly, a third category of treatment nonadherence is irregular intake of medication, which includes taking extra doses and/or skipping doses. When prescribed an antidepressant, patients with MDD are instructed by their physicians to take a certain number of drug tablets per day (eg, one tablet per day for 30 days). However, on occasion, the patient will choose to instead take two tablets on one day followed by no tablets on the subsequent day. In clinical studies, this type of adherence can be monitored electronically as measured by dose-interval adherence (percentage of days with correct intake), in contrast to the more standard dose-frequency adherence (equal to the number of tablets taken divided by the number prescribed and multiplied by 100).27 A multicenter, double-blind, prospective study evaluated adherence to treatment, as determined by the percentage of days with correct intake of treatment in 46 patients with MDD who completed study treatment with the antidepressants fluoxetine and amitriptyline.27 The authors reported that only 42.5% of patients demonstrated good adherence to treatment (ie, took medication as prescribed in >80% of study days) and 28.7% demonstrated partial adherence (ie, took medicine correctly for 50% to 80% of study days). Alternatively, poor adherence to treatment, which was defined as taking the medication correctly in <50% of the study days, was observed in 28.8% patients during the 9-week trial.27
What is the impact of nonadherence on treatment outcomes?
A greater percentage of patients who prematurely discontinue antidepressants experience relapse compared with those who remain on therapy.5,28,29 A pooled analysis of 31 randomized, placebo-controlled trials that had continuation or maintenance phases after an acute treatment period (>4,000 patients) showed that continuing treatment with antidepressants reduced the risk of symptom relapse by ~67%.28 With specific regard to short-term outcomes, in a multicenter, randomized, controlled, prospective study, Demyttenaere and colleagues26 evaluated the consequences of nonadherence (measured by skipping doses, drug holidays, or taking extra doses) in patients with MDD taking fluoxetine or amitriptyline for 9 weeks. Findings demonstrated that patients with lower treatment adherence discontinued therapy more frequently, and 10% of the variance (ie, the amount of variance explained after controlling for other variables in the general linear model analysis) in the primary outcome of final 17-item Hamilton Rating Scale for Depression (HAM-D17) score was explained by nonadherence. However, the authors conceded that this 10% difference was a rough estimation of the effect of adherence on treatment outcomes, and specifically noted that the effect of treatment adherence on the final HAM-D17 score was only significant for patients treated with amitriptyline, and not those taking fluoxetine.26
In a long-term, 2-year follow-up study, Melfi and colleagues29 evaluated whether adherence to treatment guidelines reduced the risk of relapse or recurrence in >4,000 patients included in a Medicaid database who had filled a prescription for an antidepressant at an initial diagnosis of MDD. The authors reported that premature treatment discontinuation (defined in this study as stopping medication within the first 4 months of treatment) was a significant predictor of relapse/recurrence (P<.01) and increased the risk of recurrence by 77% (risk ratio = 1.77; 95% CI, 1.47-2.14).29 Other factors that significantly predicted relapse/recurrence were substance abuse, number of prior hospitalizations for MDD, or number of comorbid illnesses (P<.01 for each).
Regarding functional outcomes, in a retrospective, observational, cohort study of >2,000 employed individuals undergoing a new episode of antidepressant treatment, Burton and colleagues30 evaluated the relationship between patient nonadherence and short-term disability by reviewing employee disability absences in the 365 days following initiation of antidepressant treatment. Of the 2,112 patients evaluated, 61.6% adhered to treatment (defined as taking medication on ≥84 of 114 days during the acute phase, and on ≥180 of 231 days during the continuation phase of treatment). A significantly greater percentage of patients who were nonadherent to treatment experienced short-term disability-related absences (n=103; 12.7%) compared with those who met adherence criteria (n=115; 8.8%; P=.03).30
MDD is often characterized by impaired social functioning,31 and nonadherence to or discontinuation of antidepressants can ultimately worsen these functional symptoms. Kocsis and colleagues32 evaluated psychosocial functioning using the Social Adjustment Scale-Self Report (SAS-SR), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and Longitudinal Interval Follow-up Evaluation (LIFE) in patients with chronic MDD during long-term maintenance treatment with sertraline, and following the double-blind discontinuation of treatment. Results showed that the significant improvements observed in measures of psychosocial functioning during 16 weeks of acute and continuation treatment with sertraline were sustained with maintenance treatment. However, patients who discontinued treatment with sertraline (ie, patients who were randomized to placebo during maintenance treatment) experienced a substantial, rapid decline in psychosocial function to baseline levels.32 It is important to note that this study examined treatment discontinuation during maintenance therapy—not patient nonadherence as it is typically conceptualized in research and clinical practice. Regardless, the observations that antidepressant discontinuation can negatively impact both improvement of psychosocial functioning and MDD symptoms underscore the need for physician and patient awareness of the need for continued treatment with antidepressants, and of the potential factors associated with the risk for nonadherence, in order to improve short- and long-term clinical outcomes for patients with MDD.
What specific factors contribute to the phenomenon of nonadherence?
Specific aspects of MDD illness (ie, disorder-specific variables) can impact patient adherence to treatment. For example, comorbid symptoms of MDD and anxiety can potentially reduce patient compliance (ie, dropping out/stopping treatment altogether) because of the requirement for concomitant medications, more complicated dosing schedules, and greater risk of AEs,33 as patients with comorbid anxiety are more likely to experience anxiety about and/or experience AEs. However, the identification of reliable predictors of treatment adherence across studies is difficult, and the evidence for a relationship between MDD severity and poor patient compliance or adherence is mixed. Findings of the multicenter, prospective study by Demyttenaere and colleagues27 demonstrated that MDD severity did not significantly impact patient compliance (ie, patients dropping out of treatment). The authors also reported that the initial HAM-D17 score did not predict a greater risk of drop out. It is possible that this observation could be the result of a counterbalance of forces, such that patients with mild MDD may be more likely to stop treatment due to stigma regarding their illness or antidepressants, and patients with more severe MDD may be more likely to drop out due to hopelessness; in sum, the two possibilities balance out.
In contrast, Sirey and colleagues34 showed that the severity of MDD was positively correlated with treatment adherence, such that patient-rated severity of illness—but not MDD severity based on HAM-D17 baseline scores—predicted treatment adherence in 134 outpatients with MDD. Thus, patients who considered their disease severe adhered to the prescribed treatment regimen. It is important to note that the patient population assessed this clinical study was selected, and thus represented patients who were aware of their medical problem, sought treatment, and agreed to participate in a trial on antidepressants. Such characteristics may have contributed to patients being more likely to remain on therapy regardless of their illness severity. This possibility is substantiated by the significant interaction between good treatment adherence with greater MDD severity and higher education level (P<.001).27
The phenomenon of depression can influence patient compliance to medications for other chronic diseases. One meta-analysis examined the impact of MDD on adherence to prescribed treatment regimens for various medical conditions (eg, cancer, renal disease, arthritis), and found that the presence of MDD was considered a risk factor for treatment nonadherence, such that patients with MDD were 3 times more likely to prematurely discontinue treatment compared with nondepressed individuals.35 This is possibly the result of overwhelming feelings of hopelessness, which are common among patients with MDD, as well as reductions in cognitive function, which may impair a patient’s ability to follow-through with the required treatment regimen. Adherence to a treatment regimen likely proves difficult for such individuals with the overall perception that very few actions are worthwhile or provide meaningful results. In contrast to the studies described above, this study included a population of patients who were being assessed, but were not seeking or receiving treatment for MDD, and had not agreed to be part of a clinical trial of antidepressants. Taken together, these findings illustrate the potentially complicated relationship between MDD severity and treatment adherence.
Somatic symptoms can also substantially impact adherence to antidepressants. van Dijk and colleagues34 evaluated patients included in a Dutch general practice database who were taking antidepressants (n=4,877), antihypertensives (n=14,219), or oral hypoglycemics (n=2,428). Early dropouts and refill nonadherence (<80%) were highest for patients who were taking antidepressants (24.6%), and patients with comorbid somatic symptoms were more frequently nonadherent to antidepressants (P<.05 for early dropouts and refill nonadherence). In a separate clinical study,37 researchers assessed a sample of patients with MDD from a series of double-blind, placebo-controlled studies of various antidepressants (N=940), and reported that patients with MDD who prematurely discontinued antidepressants due to intolerable AEs had significantly greater somatic symptoms (based on Symptom Check List [SCL]-90 somatization scores) compared with study completers (P<.001) and patients who dropped out for miscellaneous reasons (P=.001).37 Overall, the relationship between somatic symptoms and treatment adherence is complex, such that comorbid somatic complaints associated with other chronic illnesses, and somatic symptoms associated with MDD may be related to treatment nonadherence through distinct mechanisms. Interestingly, in an earlier study, Marcos and Cancro38 proposed the possibility that AEs may be interpreted as exacerbation of MDD among patients with somatic symptoms of MDD, leading to the conclusion that the medication is not effective, and thus prematurely discontinue treatment.
Specific characteristics of antidepressants can also impact patient adherence to treatment. For example, complicated dosing schedules have been associated with increased treatment nonadherence.33,39 Patients are more likely to comply with treatment regimens that require intake of one tablet per day versus those that require ≥2 per day.39 In addition, complex dose titration requirements can also influence patient adherence to treatment,33 as titration to a therapeutic dose can be a slow process, during which the patient continues to experience symptoms of MDD, or may experience AEs associated with the initial doses of treatment. As a result, most patients being titrated to a therapeutic dose continually receive suboptimal antidepressant doses. Thus, continuous visits with the physician are crucial during the titration period to reassure the patient that symptoms of MDD will be alleviated once an adequate, therapeutic dose of treatment is achieved.33
Importantly, the tolerability of antidepressants can significantly impact patient adherence to treatment. Tolerability issues associated with antidepressants can increase the risk for patient nonadherence and result in subsequent relapse of MDD symptoms.40 Treatment-emergent AEs are considered a common reason for patient nonadherence to antidepressants.33 Lin and colleagues4 evaluated factors that influence adherence to treatment regimens, and showed that the number of treatment-emergent severe AEs was a significant predictor of early adherence to treatment (defined as adherence for >31 days), such that patients who had a greater number of AEs were significantly more likely to prematurely discontinue treatment within 30 days (P=.049). Burra and colleagues41 assessed predictors of nonadherence to treatment by surveying hospital and community mood disorder outpatients (N=80) and reported that male patients were significantly more likely to report nonadherence if they experienced a sexual side effect while taking an antidepressant compared with men who did not experience a sexual side effect (P<.05).41 Demyttenaere and colleagues3 administered an Antidepressant Compliance Questionnaire42 (ADCQ), which assesses the attitudes and beliefs about MDD causes, antidepressant use, and the doctor-patient relationship (Table 2),42 to 272 patients. The authors found that AE incidence (23%) was one of the most frequently cited reasons for early treatment discontinuation.3
A patient’s beliefs and attitudes regarding the personal experience of having a diagnosis of MDD, and perceived advantages and disadvantages of psychotropic medication can substantially impact adherence to treatment.7 A randomized clinical trial evaluated prevention of MDD relapse in primary care patients (N=386) considered at high-risk for recurrent MDD.43 Adherence was evaluated by self-report and was defined as taking medication on ≥25 days in the previous month. A favorable attitude toward antidepressants was identified as a significant predictor of adherence to treatment (P<.0001).43 In addition, the attitudes and beliefs of the patient’s partner or family can also influence those of the patient, such that adherence is generally higher when these individuals encourage the positive outcomes of treatment.7
Many patients have erroneous beliefs concerning antidepressants that can subsequently influence treatment adherence. Chakraborty and colleagues8 assessed the relationship of attitudes and beliefs with treatment adherence by administering the ADCQ to 50 patients who had experienced a first episode of unipolar MDD without psychotic symptoms. Overall, the majority of patients adhered to treatment, such that 88% of patients missed a dose <25% of treatment days during the 3-month study and only 4% of patients missed taking medication on >75% of treatment days. However, results from various components of the ADCQ (ie, preserved autonomy, positive beliefs about antidepressants) demonstrated that 88% of patients believed that antidepressants can alter a patient’s personality; 58% of patients thought that an individual could develop immunity to antidepressants; 36% of patients believed that a patient can become addicted to antidepressants; and 30% of patients believed that occasionally skipping medication prevents the development of immunity to antidepressants. In addition, 72% of patients believed that fewer medication tablets could be taken on days that one feels better, and alternatively, 42% thought that extra tablets could be taken when one feels more depressed.8 In this study, a significant negative correlation was observed between negative attitudes toward antidepressants (ie, ADCQ score) and the percentage of days of missed medication (Spearman rho=−0.33; P<.05).8 These findings were similar to those of Kessing and colleagues44 which showed that 56% of patients with bipolar and depressive disorders believed that an individual could become addicted to antidepressants; 43% held the belief that antidepressants could alter an individual’s personality, and 40% thought that their body could develop immunity to antidepressants. Physicians treating patients with MDD should be aware of any erroneous or unhelpful beliefs that may reduce treatment adherence, and focus on identifying and addressing these invalid perceptions of antidepressants due to potential negative impact on long-term patient outcomes.
Specific personality traits have also been associated with poor patient adherence to treatment. Using the Karolinska Scales of Personality, Ekselius and colleagues45 demonstrated that patients with MDD who exhibited poor treatment adherence had significantly higher scores for sensation seeking (as measured specifically by the Monotony Avoidance component and the Impulsive Sensation Seeking Factor component) compared with patients who were compliant to treatment (P=.04 for both components). Similarly, additional clinical studies have reported a significant association between extraverted personality and poor adherence (P=.01),46 and between low rate of narcissistic personality traits and improved adherence.47
Interestingly, ten Doesschate and colleagues48 found no significant relationship between specific personality traits (assessed by the Personality Disorder Questionnaire-4+) with adherence to antidepressants. However, the authors concluded that the small sample size of the study (N=91) may have lacked sufficient power to identify significant nonadherence predictors.48
In general, physicians expect that patients should follow their orders.49 However, a physician’s attitude toward the diagnosis and treatment of MDD, and interaction with patients can also influence patient adherence. In an early study by Heszen-Klemens,49 researchers interviewed 60 physicians regarding their behavior toward nonadherence and assessed the individual differences in physicians’ attitudes. The most prevalent physician tactic (34%) concerning patient nonadherence was medical threat (ie, informing the patient of the dire consequences that would occur if advice is not followed). Other frequently used tactics included exhibiting an authoritarian attitude (18%) or providing the patient additional medical information (24%). Few physicians reported determining the cause of premature discontinuation of treatment (3%) or enlisting family support for the patient (3%). None of the physicians interviewed reported using a personalized approach in addressing the concern of nonadherence.49
Recent studies have noted that physician involvement in educational strategies to improve patients’ perceptions of antidepressants, as well as ongoing follow-up visits with the physician, help patients achieve greater long-term adherence to antidepressants.43,50 Thus, to benefit patients with MDD, physicians should attempt to improve patient adherence by providing patients with an environment in which they feel free to discuss their expectations for and concerns about antidepressants.
Are there demographic characteristics of patients at risk for nonadherence?
Although there is no specific demographic profile to identify patients at risk for nonadherence, clinical studies have identified demographic characteristics that correlate with nonadherence. One important demographic characteristic associated with patient nonadherence is age, such that younger patients are usually at greater risk for nonadherence to treatment compared with older patients.34,51 For instance, Sirey and colleagues34 demonstrated that younger age, as well as a higher perceived stigma, lower patient-rated severity of illness, and greater interpersonal problems were significantly associated with lower adherence (measured on Likert scale of 0 [not taking medication] to 6 [full adherence]) to acute treatment with antidepressants. However, as with baseline severity of MDD, investigations of the relationship between age and treatment nonadherence have yielded mixed results, such that treatment adherence is related to older age in some studies,34,52 but not in others.3,53,54 Interestingly, the authors reported that lower perceived stigma regarding MDD and antidepressant treatment remained significantly related to better treatment adherence (P=.05) after controlling for variables of age and interpersonal problems.34
Multiple clinical studies have demonstrated that gender can impact patient adherence to treatment, such that women exhibit better treatment adherence compared with men.5,8,51 For example, using total scores on the ADCQ, Chakraborty and colleagues8 assessed beliefs about antidepressants in patients experiencing a first MDD episode. The findings showed that housewives and those who were doing household work had significantly higher scores on the ADCQ (P<.01), indicating that they had more positive attitudes concerning antidepressants. In addition, men scored significantly lower on the ADCQ than women (P<.05), indicating more negative attitudes about taking antidepressants, which could be less conducive to proper adherence.8
Overall, sociodemographic and cultural characteristics do not seem to substantially influence patient adherence to antidepressants. In the study conducted by Sirey and colleagues,34 race, marital status, and living arrangements (ie, alone versus with another person) were not significant predictors of adherence to treatment in 134 patients with MDD. Similarly, a separate study investigated reasons for premature discontinuation of treatment with SSRIs in 406 patients with MDD, and reported that treatment nonadherence was significantly more common in employed versus unemployed individuals (P=.011), but not significantly associated with race, ethnicity, marital status, or education.51
What strategies can improve patient treatment adherence in clinical practice?
Increased physician-patient communication (ie, involving the patient in discussions about expectations of treatment) can enhance patient adherence to treatment. In a randomized clinical trial, Lin and colleagues43 evaluated intervention effects on attitudes toward medication and self-management of MDD. The authors reported that intervention strategies to prevent symptom relapse (eg, visits with MDD prevention specialists, telephone contact with nurses to monitor patient progress, personalized letters) improved patient attitudes about taking antidepressants, increased their confidence in managing AEs, and increased self-monitoring of MDD symptoms. Overall, the relapse prevention program helped patients achieve greater long-term adherence to antidepressants.43 Similar results were demonstrated in a separate clinical study that found patient discussions with a physician or pharmacist regarding management of treatment-related AEs as well as having ≥3 follow-up visits within the first 3 months of initiating treatment significantly decreased the risk of premature treatment discontinuation (P=.004 and P<.001, respectively).51
It is interesting to note that factors driving antidepressant selection are not always similar for patients and physicians. Gardner and colleagues55 surveyed patients and general practitioners on their preferences regarding antidepressants, and observed significant differences in ranking distributions between patients and physicians for 12 differentiating factors regarding antidepressants. For example, although the risk of potential AEs were ranked as the most important selection factor by both groups, physicians rated prescription cost and dosing schedules significantly higher than patients. The authors concluded that a moderate disagreement exists between patients and physicians regarding the value of specific antidepressant selection factors, thus highlighting the importance of collaborative decision-making.
The effectiveness of specific interventions to improve patient adherence to treatment remains uncertain. In a meta-analysis, Haynes and colleagues24 summarized the efficacy of interventions implemented to help patients adhere to medication prescriptions. The 14 clinical studies included in this meta-analysis evaluated a wide range of intervention methods: increased instructional material for patients; programmed learning; automated computer-assisted patient monitoring and/or counseling; family intervention; appointment and prescription refill reminders; and various ways to increase convenience of taking medication, among others. The findings demonstrated that 49% of the interventions tested (19 of 39) were associated with significant increases in treatment adherence, and only 17 (44%) interventions were associated with significant improvements in treatment outcomes. However, the authors asserted that a limitation of the meta-analysis was that most of the included studies lacked the statistical power to detect clinically significant effects.24 In addition, this meta-analysis focused specifically on nonpersonalized interventions to increase treatment adherence (eg, telephone contact, computerized messages).
In an updated meta-analysis, Haynes and colleagues56 reported that, for short-term treatments, four of 10 interventions used in nine clinical trials had a positive effect on adherence and, in one case, clinical outcome. For long-term treatments, 36 of 81 interventions described in 69 clinical trials were associated with improved treatment adherence, and 26 interventions resulted in a positive treatment outcome. However, the majority of the interventions that were successful for long-term treatment adherence were complex, including combinations of more convenient care (eg, provision of care at worksite or simplicity of dosing), patient information, prescription refill reminders, self-monitoring, reinforcement, counseling, family therapy, psychological therapy, crisis intervention, manual telephone follow-up, and supportive care. Regardless, even the most effective interventions did not result in substantial improvements in adherence to treatment or clinical outcomes.56
Regardless of the specific intervention employed, physicians should involve the patient in the decision-making process when selecting an antidepressant, and consider an individualized approach for each specific patient to improve adherence. Specifically, physicians’ should address the patients’ attitudes, beliefs, and concerns regarding the use of antidepressants. In addition, the physician should consistently follow-up with the patient to ensure the prescription for the antidepressant has been filled, encourage self-monitoring of treatment of adherence, and question patients about their specific behavior when they skip or miss a dose of treatment. The chronicity of MDD requires that patients take antidepressants for months, if not years, to achieve optimal outcomes; therefore, patients with MDD require long-term physician interaction and management to prevent the negative clinical sequelae of nonadherence to treatment. As these patient-physician interactions are crucial to achieve treatment success and remission of MDD symptoms, physicians should receive training regarding the primary predictors of adherence, and the most effective intervention strategies to address these factors, including the optimal communication style to produce patient satisfaction and enhance adherence.
Future progress in implementing health information technology (eg, e-prescribing, electronic health records) will likely prove beneficial for both monitoring and improving treatment adherence.57 In addition, pharmacy management strategies, such as collaborative networks and medication therapy management, will also help overcome the hurdle of nonadherence.58 In the meantime, significant innovations in the field of adherence research are more likely to occur if investigators join across clinical disciplines to better understand the problem of nonadherence.24 As low adherence negatively impacts all self-administered treatments, and the numbers of effective, self-administered treatments continues to grow, investment in adherence research is likely to offer substantial positive outcomes.
Adherence to antidepressant therapy is critical to achieve successful treatment outcomes for patients with MDD. However, various factors, including MDD severity, certain patient demographics and characteristics, perceived stigma or negative beliefs about antidepressants, poor patient-physician communication, and concern about the unwanted AEs associated with these medications can contribute to poor patient adherence to treatment and negatively impact long-term patient outcomes. To achieve long-term treatment success, both physicians and patients must be knowledgeable of specific factors that impact patient nonadherence.59 Patients who participate in discussions with their physicians or other intervention specialists regarding treatment strategies are more likely to adhere to therapy.4,43,51,59 In addition, physicians can improve patient treatment adherence by discussing realistic treatment expectations.59 To this end, administering the ADCQ may be a reasonable first-step when initiating antidepressant treatment.
To achieve positive outcomes with antidepressants, both the patient and practitioner must consider various factors when choosing the appropriate treatment. However, factors influencing antidepressant choice are not always similar for patients and physicians.55 Thus, selecting patient-specific antidepressant therapy is markedly different from simply choosing the antidepressant that is considered generally more advantageous.60
Physician communication with a patient when considering the most appropriate treatment choice is critical.4,43,50,59 Discussion of various antidepressant characteristics as they relate to the patient, allowance for patient participation, and arrival at a consensus as to which antidepressant best meets the patient needs can optimize patient adherence to treatment and help to achieve successful long-term patient outcomes, likely as the result of increased patient knowledge and overall satisfaction with the decision-making process.60
1. Practice guideline for the treatment of patients with major depressive disorder (revision). American Psychiatric Association. Am J Psychiatry. 2000;157(4 suppl):1-45.
2. Kobak KA, Taylor L, Katzelnick DJ, et al. Antidepressant medication management and Health Plan Employer Data Information Set (HEDIS) criteria: reasons for nonadherence. J Clin Psychiatry. 2002;63(8):727-732.
3. Demyttenaere K, Enzlin P, Dewé W, et al. Compliance with antidepressants in a primary care setting, 1: Beyond lack of efficacy and adverse events. J Clin Psychiatry. 2001;62 (suppl 22):30-33.
4. Lin EH, Von Korff M, Katon W, et al. The role of the primary care physician in patients’ adherence to antidepressant therapy. Med Care. 1995;33(1):67-74.
5. Melartin TK, Rytsälä HJ, Leskelä US, et al. Continuity is the main challenge in treating major depressive disorder in psychiatric care. J Clin Psychiatry. 2005;66(2):220-227.
6. Ereshefsky L, Jhee S, Grothe D. Antidepressant drug-drug interaction profile update. Drugs R D. 2005;6(6):323-336.
7. Demyttenaere K. Compliance during treatment with antidepressants. J Affect Disord. 1997;43(1):27-39.
8. Chakraborty K, Avasthi A, Kumar S, Grover S. Attitudes and beliefs of patients of first episode depression towards antidepressants and their adherence to treatment. Soc Psychiatry Psychiatr Epidemiol. 2009;44(6):482-488.
9. Celexa [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc.; 2006.
10. Lexapro [package insert]. St Louis, MO: Forest Laboratories, Inc.; 2009.
11. Prozac [package insert]. Indianapolis, IN: Eli Lilly and Company; 2006.
12. Paroxetine [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2006.
13. Zoloft [package insert]. New York, NY: Roerig; 2006.
14. Pristiq [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; 2008.
15. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009.
16. Ixel [package insert]. France: Pierre Fabre Medicaments; 2003.
17. Puozzo C, Lens S, Reh C, et al. Lack of interaction of milnacipran with the cytochrome p450 isoenzymes frequently involved in the metabolism of antidepressants. Clin Pharmacokinet. 2005;44(9):977-988.
18. Effexor [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc; 2004.
19. Effexor XR [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2008.
20. Elavil [package insert]. Wilmington, DE: Zeneca Pharmaceuticals; 2000.
21. Tofranil [package insert]. Spring Valley, NY: Par Pharmaceutical Co.; 2007.
22. Wellbutrin XI [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
23. Remeron [package insert]. Roseland, NJ: Organon USA Inc.; 2007.
24. Haynes RB, McDonald H, Garg AX, Montague P. Interventions for helping patients to follow prescriptions for medications. Cochrane Database Syst Rev. 2002;(2):CD000011.
25. Lingam R, Scott J. Treatment non-adherence in affective disorders. Acta Psychiatr Scand. 2002;105(3):164-172.
26. Demyttenaere K, Mesters P, Boulanger B, et al. Adherence to treatment regimen in depressed patients treated with amitriptyline or fluoxetine. J Affect Disord. 2001;65(3):243-252.
27. Demyttenaere K, Van Ganse E, Gregoire J, Gaens E, Mesters P. Compliance in depressed patients treated with fluoxetine or amitriptyline. Belgian Compliance Study Group. Int Clin Psychopharmacol. 1998;13(1):11-17.
28. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003;361(9358):653-661.
29. Melfi CA, Chawla AJ, Croghan TW, Hanna MP, Kennedy S, Sredl K. The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression. Arch Gen Psychiatry. 1998;55(12):1128-1132.
30. Burton WN, Chen CY, Conti DJ, Schultz AB, Edington DW. The association of antidepressant medication adherence with employee disability absences. Am J Manag Care. 2007;13(2):105-112.
31. Hirschfeld RM, Montgomery SA, Keller MB, et al. Social functioning in depression: a review. J Clin Psychiatry. 2000;61(4):268-75.
32. Kocsis JH, Schatzberg A, Rush AJ, et al. Psychosocial outcomes following long-term, double-blind treatment of chronic depression with sertraline vs placebo. Arch Gen Psychiatry. 2002;59(8):723-728.
33. Masand PS. Tolerability and adherence issues in antidepressant therapy. Clin Ther. 2003;25(8):2289-2304.
34. Sirey JA, Bruce ML, Alexopoulos GS, Perlick DA, Friedman SJ, Meyers BS. Stigma as a barrier to recovery: Perceived stigma and patient-rated severity of illness as predictors of antidepressant drug adherence. Psychiatr Serv. 2001;52(12):1615-1620.
35. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000;160(14):2101-2107.
36. van Dijk L, Heerdink ER, Somai D, et al. Patient risk profiles and practice variation in nonadherence to antidepressants, antihypertensives and oral hypoglycemics. BMC Health Serv Res. 2007;7:51.
37. Agosti V, Quitkin FM, Stewart JW, McGrath PJ. Somatization as a predictor of medication discontinuation due to adverse events. Int Clin Psychopharmacol. 2002;17(6):311-314.
38. Marcos LR, Cancro R. Pharmacotherapy of Hispanic depressed patients: clinical observations. Am J Psychother. 1982;36(4):505-512.
39. Viale G. An economic analysis of physician prescribing of selective serotonin reuptake inhibitors. Hosp Pharm. 1998;33(7):847-850.
40. Papakostas GI. Tolerability of modern antidepressants. J Clin Psychiatry. 2008;69(suppl E1):8-13.
41. Burra TA, Chen E, McIntyre RS, Grace SL, Blackmore ER, Stewart DE. Predictors of self-reported antidepressant adherence. Behav Med. 2007;32(4):127-134.
42. Demyttenaere K, Bruffaerts R, Albert A, et al. Development of an antidepressant compliance questionnaire. Acta Psychiatr Scand. 2004;110(3):201-207.
43. Lin EH, Von Korff M, Ludman EJ, et al. Enhancing adherence to prevent depression relapse in primary care. Gen Hosp Psychiatry. 2003;25(5):303-310.
44. Kessing LV, Hansen HV, Demyttenaere K, Bech P. Depressive and bipolar disorders: patients’ attitudes and beliefs towards depression and antidepressants. Psychol Med. 2005;35(8):1205-1213.
45. Ekselius L, Bengtsson F, von Knorring L. Non-compliance with pharmacotherapy of depression is associated with a sensation seeking personality. Int Clin Psychopharmacol. 2000;15(5):273-278.
46. Cohen NL, Ross EC, Bagby RM, Farvolden P, Kennedy SH. The 5-factor model of personality and antidepressant medication compliance. Can J Psychiatry. 2004;49(2):106-113.
47. Tedlow JR, Fava M, Uebelacker LA, Alpert JE, Nierenberg AA, Rosenbaum JF. Are study dropouts different from completers? Biol Psychiatry. 1996;40(7):668-670.
48. ten Doesschate MC, Bockting CL, Koeter MW, Schene AH. Predictors of nonadherence to continuation and maintenance antidepressant medication in patients with remitted recurrent depression. J Clin Psychiatry. 2009;70(1):63-69.
49. Heszen-Klemens I. Patients’ noncompliance and how doctors manage this. Soc Sci Med. 1987;24(5):409-416.
50. Bull SA, Hu XH, Hunkeler EM, et al. Discontinuation of use and switching of antidepressants: influence of patient-physician communication. JAMA. 2002;288(11):1403-1409.
51. Goethe JW, Woolley SB, Cardoni AA, Woznicki BA, Piez DA. Selective serotonin reuptake inhibitor discontinuation: side effects and other factors that influence medication adherence. J Clin Psychopharmacol. 2007;27(5):451-458.
52. Sirey JA, Bruce ML, Alexopoulos GS, et al. Perceived stigma as a predictor of treatment discontinuation in young and older outpatients with depression. Am J Psychiatry. 2001;158(3):479-481.
53. Sánchez-Lacay JA, Lewis-Fernández R, Goetz D, et al. Open trial of nefazodone among Hispanics with major depression: efficacy, tolerability, and adherence issues. Depress Anxiety. 2001;13(3):118-124.
54. Myers ED, Branthwaite A. Out-patient compliance with antidepressant medication. Br J Psychiatry. 1992;160:83-86.
55. Gardner DM, MacKinnon N, Langille D, Andreou P. Comparison of factors used by physicians and patients in the selection of antidepressant agents. Paper presented at: 17th Congress of the European College of Neuropsychopharmacology; October 9–13, 2004; Stockholm, Sweden.
56. Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X. Interventions for enhancing medication adherence. Cochrane Database Syst Rev. 2008;(2):CD000011.
57. Balfour DC 3rd, Evans S, Januska J, et al. Health information technology–results from a roundtable discussion. J Manag Care Pharm. 2009;15(1 suppl A):10-17.
58. Fleming WK. Pharmacy management strategies for improving drug adherence. J Manag Care Pharm. 2008;14(6 suppl B):16-20.
59. Ruoff G. A method that dramatically improves patient adherence to depression treatment. J Fam Pract. 2005;54(10):846-852.
60. Cates M. Selecting antidepressant therapy for patients with major depression. Am J Pharm Educ. 2001;65:190-194.