REVIEW Role of Adverse Effects in Medication Nonadherence in Bipolar Disorder Rajnish Mago, MD, Dileep Borra, MBBS, and Rajeev Mahajan, MBBS Abstract: Nonadherence to medications is common and associated with poor or limited clinical outcomes in the treat-
ment of bipolar disorder. A review of the literature discloses that adverse effects are one of the commonly reported reasons for nonadherence to mood stabilizers by patients with bipolar disorder. Nevertheless, other than such broad summaries, relatively little attention has been given to the role of adverse effects in relation to nonadherence. This review article is the first to consolidate the available data on this topic. Weight gain, perceived cognitive impairment, tremors, and sedation are the adverse effects most likely to lead to nonadherence. Further research is needed to anticipate, identify, manage, and potentially minimize the impact of adverse effects. Keywords: adverse effects, bipolar disorder, cognitive impairment, mood stabilizers, nonadherence, sedation, side effects, tremors, weight gain
D
espite the availability of a variety of pharmacological treatment options for patients with bipolar disorders (BDs), long-term outcomes are far from ideal, and problems of high morbidity, recurrence, hospitalization, and suicide persist.1 Since medications are the mainstay of treatment, nonadherence to medications has a greater impact on these undesirable outcomes than any modifiable risk factor that has been studied to date. Not surprisingly, a leading textbook on BD calls nonadherence “the primary clinical problem” associated with the treatment of these disorders.2(p855) A review of 25 studies of nonadherence in BD published from 1979 to 2004 reported a nonadherence range of 23% to 68%, with a median of 42%—a troubling percentage.3 Differences in the studied populations, definitions of nonadherence, durations of follow-up, and such matters no doubt largely account for the variation in nonadherence rates. Nonetheless, it is clear that the proportion is high and clinically very significant. Many different patient, treatment, and system-related factors may be associated with nonadherence.4–6 A discussion of these factors is beyond the purview of this article. For a comprehensive overview of the factors related to nonadherence in BD, the reader is referred to Leclerc and colleagues (2013).7 From the Mood Disorders Program, Department of Psychiatry and Human Behavior, Thomas Jefferson University. Original manuscript received 18 March 2013; revised manuscript received 6 August 2013, accepted for publication subject to revision 13 September 2013; revised manuscript received 14 October 2013. Correspondence: Rajnish Mago, MD, Mood Disorders Program, Department of Psychiatry and Human Behavior, Jefferson Medical College, 833 S. Chestnut St., Suite 210 E, Philadelphia, PA 19107. Email [email protected] © 2014 President and Fellows of Harvard College DOI: 10.1097/HRP.0000000000000017
Harvard Review of Psychiatry
The focus here is specifically on the impact that adverse effects of medication have on nonadherence to mood stabilizers by BD patients. These effects have received less attention than other factors relating to nonadherence, but clinical experience and the limited research literature indicate that adverse effects play a significant role. This review article is the first to summarize the available data on this issue.
AIMS AND METHODS We aimed to systematically review the literature to determine (1) the proportion of nonadherence to medications for BD that is attributable to adverse effects and (2) the specific adverse effects that are more likely to be associated with nonadherence. We conducted a PubMed search (last date, 23 July 2013) using the MeSH terms bipolar disorder AND medication adherence (which subsumes medication compliance), and the text words adherence AND compliance AND bipolar disorder with the search limited to articles in English. Abstracts of the 207 citations retrieved were reviewed to identify articles addressing the causes of nonadherence rather than its prevalence or strategies to reduce it. Clinical trials (n = 32) were excluded because the patients may not be representative of those in real-world settings. Moreover, patients in clinical trials are usually financially compensated and may have higher motivation to continue their medications. We also excluded articles that were unrelated to nonadherence (n = 43), that were related to nonadherence but not due to adverse effects (n = 38), or that were limited to assessing the impact of only one particular factor (e.g., therapeutic alliance; n = 28). The remaining 66 articles are included in this review. They present observational studies from a variety of clinical settings (inpatient, n = 8; outpatient, n = 23; community health center, n = 12; or both inpatient and outpatient, n = 7), and 16 were review articles. www.harvardreviewofpsychiatry.org
Copyright @ 2014 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
363
R. Mago et al.
WHAT PROPORTION OF NONADHERENCE IS ATTRIBUTED TO ADVERSE EFFECTS? In about 20% to 40% of BD patients, adverse effects of medications are associated with nonadherence;5,8 the impact of adverse effects on adherence is therefore substantial. In an earlier review, six out of ten studies on nonadherence in BD patients found that adverse effects were one of the most frequently given reasons for nonadherence to medications.3 Some of the studies that address this question in further detail — including ones published after the above-mentioned, 2004 review—are discussed below. In an early article, published in 1976, 22% of patients discontinued medication due to lack of efficacy and 78% due to adverse effects.9 In a five-year, prospective, observational study of 402 patients with bipolar I disorder on lithium maintenance treatment, patients were evaluated five years after starting lithium; 28% of patients who stopped treatment on their own initiative (27 of 95) attributed the premature discontinuation to adverse effects.10 In a survey of 423 patients, nearly 20% reported missing all their daily doses at least once in the preceding ten days.8 In that survey, 40.2% of patients expressed frustration with the adverse effects of their medications, and 13.1% of those who had stopped all medications identified adverse effects as the reason for the discontinuation. Similarly, a survey of 115 patients found that adverse effects were the second most commonly endorsed reason for nonadherence to mood stabilizers (20.6%).11 In a recent, 2012 survey of 2448 psychiatrists by Vieta and colleagues,12 29% reported that 20% or more of their patients with bipolar I disorder had stopped their medications due to intolerable adverse effects. Negative attitudes toward medications13,14 and a general fear of mood stabilizers’ adverse effects—separate from the adverse effects as such—may also contribute to nonadherence.15 In 223 BD patients who were members of a self-help organization, low adherence to medications was associated with twice the odds of being concerned about the potential negative effects of medications, as measured by the Beliefs About Medications Questionnaire.16 In another article from the same study, over 60% of patients were dissatisfied with the information provided about potential side effects, and this dissatisfaction was, in turn, associated with lower adherence to the medications for BD.17 WHICH ADVERSE EFFECTS ARE COMMONLY ASSOCIATED WITH NONADHERENCE? Data linking specific adverse effects with nonadherence are limited, in part because studies on nonadherence have largely ignored the systematic assessment and reporting of adverse effects.18 However, the studies discussed below show that weight gain, cognitive impairment, emotional effects, nausea, tremors, and lack of coordination are more likely to be associated with nonadherence. In a pooled analysis of two randomized, placebocontrolled trials (n = 638), the incidence of discontinuation 364
www.harvardreviewofpsychiatry.org
attributed to tremor (5% vs. 1%), nausea (8% vs. 1%), and somnolence (4% vs. 1%) was significantly higher for lithium than placebo.19 Perceptions of the experts, clinicians, and patients regarding specific adverse effects as predictors of nonadherence have been assessed in three separate studies. Experts reported weight gain and sedation,20 clinicians reported weight gain,8 and patients reported weight gain and cognitive effects21 as the most likely predictors of nonadherence due to adverse effects. In another study, sedation and cognitive side effects were self-reported as the reasons for nonadherence by 30% and 27%, respectively, of Caucasian BD patients.22 Weight Gain Weight gain has been reported to frequently affect adherence in BD patients.21 Weight gain due to medications was reported as a reason for nonadherence by 59% of 145 patients with self-reported nonadherence to medications.8 Clozapine, gabapentin, lithium, olanzapine, risperidone, and valproate are associated with higher potential to cause weight gain. Weight gain is less of a concern with carbamazepine, lamotrigine, and ziprasidone, whereas topiramate may be associated with weight loss.23 Twenty percent of patients on lithium reported a weight gain of over ten kilograms.24 Lithium, valproate, and some second-generation antipsychotics are associated with a high incidence of weight gain, whereas aripiprazole, lamotrigine, and ziprasidone may cause less weight gain in most patients.23 Cognitive Impairment In order to test the association of cognitive deficits with nonadherence, cognitive function was systematically assessed in 103 patients with bipolar I or II disorder.25 While an association between poor performance on some cognitive tasks and nonadherence was actually found, the cause and effect relationship remains unclear. Mood symptoms also may affect how patients perceive and tolerate somatic adverse events.26 Concepts of illness strongly influence the subjective impairment caused by medication.27 In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study of 1771 patients with at least one follow-up visit, cognitive deficit/memory impairment was the only symptom that was presumably an adverse effect and was significantly linked to nonadherence.28 Although patients on lithium frequently complain of cognitive impairment, prescribing clinicians should be aware that the cognitive deficits in BD patients can, in part, be a manifestation of the disease itself rather than an adverse effect of lithium.29 A meta-analysis of 12 studies with lithium treatment concluded that lithium’s adverse effect on memory is present but limited.30 Similarly, a prospective study conducted with 44 euthymic patients with bipolar I disorder suggested no significant difference in neurocognitive performance in patients prescribed bipolar medications in comparison to unmedicated patients.31 Volume 22 • Number 6 • November/December 2014
Copyright @ 2014 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
Adverse Effects and Medication Nonadherence
Tremors Tremors may be reported in more than 10% of patients on lithium maintenance therapy for bipolar I disorder.32 Tremors may also be associated with nonadherence to BD medications. In a study of 429 BD patients, physical awkwardness or tremor was reported as a major cause of frustration in more than 33% of the nonadherent patients.8 A pooled analysis of two studies with 638 patients reported that the discontinuation of treatment due to tremors was about five times more in patients treated with lithium than in patients treated with placebo or lamotrigine (5%, 1%, and
ment of bipolar disorder. A review of the literature discloses that adverse effects are one of the commonly reported reasons for nonadherence to mood stabilizers by patients with bipolar disorder. Nevertheless, other than such broad summaries, relatively little attention has been given to the role of adverse effects in relation to nonadherence. This review article is the first to consolidate the available data on this topic. Weight gain, perceived cognitive impairment, tremors, and sedation are the adverse effects most likely to lead to nonadherence. Further research is needed to anticipate, identify, manage, and potentially minimize the impact of adverse effects. Keywords: adverse effects, bipolar disorder, cognitive impairment, mood stabilizers, nonadherence, sedation, side effects, tremors, weight gain
D
espite the availability of a variety of pharmacological treatment options for patients with bipolar disorders (BDs), long-term outcomes are far from ideal, and problems of high morbidity, recurrence, hospitalization, and suicide persist.1 Since medications are the mainstay of treatment, nonadherence to medications has a greater impact on these undesirable outcomes than any modifiable risk factor that has been studied to date. Not surprisingly, a leading textbook on BD calls nonadherence “the primary clinical problem” associated with the treatment of these disorders.2(p855) A review of 25 studies of nonadherence in BD published from 1979 to 2004 reported a nonadherence range of 23% to 68%, with a median of 42%—a troubling percentage.3 Differences in the studied populations, definitions of nonadherence, durations of follow-up, and such matters no doubt largely account for the variation in nonadherence rates. Nonetheless, it is clear that the proportion is high and clinically very significant. Many different patient, treatment, and system-related factors may be associated with nonadherence.4–6 A discussion of these factors is beyond the purview of this article. For a comprehensive overview of the factors related to nonadherence in BD, the reader is referred to Leclerc and colleagues (2013).7 From the Mood Disorders Program, Department of Psychiatry and Human Behavior, Thomas Jefferson University. Original manuscript received 18 March 2013; revised manuscript received 6 August 2013, accepted for publication subject to revision 13 September 2013; revised manuscript received 14 October 2013. Correspondence: Rajnish Mago, MD, Mood Disorders Program, Department of Psychiatry and Human Behavior, Jefferson Medical College, 833 S. Chestnut St., Suite 210 E, Philadelphia, PA 19107. Email [email protected] © 2014 President and Fellows of Harvard College DOI: 10.1097/HRP.0000000000000017
Harvard Review of Psychiatry
The focus here is specifically on the impact that adverse effects of medication have on nonadherence to mood stabilizers by BD patients. These effects have received less attention than other factors relating to nonadherence, but clinical experience and the limited research literature indicate that adverse effects play a significant role. This review article is the first to summarize the available data on this issue.
AIMS AND METHODS We aimed to systematically review the literature to determine (1) the proportion of nonadherence to medications for BD that is attributable to adverse effects and (2) the specific adverse effects that are more likely to be associated with nonadherence. We conducted a PubMed search (last date, 23 July 2013) using the MeSH terms bipolar disorder AND medication adherence (which subsumes medication compliance), and the text words adherence AND compliance AND bipolar disorder with the search limited to articles in English. Abstracts of the 207 citations retrieved were reviewed to identify articles addressing the causes of nonadherence rather than its prevalence or strategies to reduce it. Clinical trials (n = 32) were excluded because the patients may not be representative of those in real-world settings. Moreover, patients in clinical trials are usually financially compensated and may have higher motivation to continue their medications. We also excluded articles that were unrelated to nonadherence (n = 43), that were related to nonadherence but not due to adverse effects (n = 38), or that were limited to assessing the impact of only one particular factor (e.g., therapeutic alliance; n = 28). The remaining 66 articles are included in this review. They present observational studies from a variety of clinical settings (inpatient, n = 8; outpatient, n = 23; community health center, n = 12; or both inpatient and outpatient, n = 7), and 16 were review articles. www.harvardreviewofpsychiatry.org
Copyright @ 2014 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
363
R. Mago et al.
WHAT PROPORTION OF NONADHERENCE IS ATTRIBUTED TO ADVERSE EFFECTS? In about 20% to 40% of BD patients, adverse effects of medications are associated with nonadherence;5,8 the impact of adverse effects on adherence is therefore substantial. In an earlier review, six out of ten studies on nonadherence in BD patients found that adverse effects were one of the most frequently given reasons for nonadherence to medications.3 Some of the studies that address this question in further detail — including ones published after the above-mentioned, 2004 review—are discussed below. In an early article, published in 1976, 22% of patients discontinued medication due to lack of efficacy and 78% due to adverse effects.9 In a five-year, prospective, observational study of 402 patients with bipolar I disorder on lithium maintenance treatment, patients were evaluated five years after starting lithium; 28% of patients who stopped treatment on their own initiative (27 of 95) attributed the premature discontinuation to adverse effects.10 In a survey of 423 patients, nearly 20% reported missing all their daily doses at least once in the preceding ten days.8 In that survey, 40.2% of patients expressed frustration with the adverse effects of their medications, and 13.1% of those who had stopped all medications identified adverse effects as the reason for the discontinuation. Similarly, a survey of 115 patients found that adverse effects were the second most commonly endorsed reason for nonadherence to mood stabilizers (20.6%).11 In a recent, 2012 survey of 2448 psychiatrists by Vieta and colleagues,12 29% reported that 20% or more of their patients with bipolar I disorder had stopped their medications due to intolerable adverse effects. Negative attitudes toward medications13,14 and a general fear of mood stabilizers’ adverse effects—separate from the adverse effects as such—may also contribute to nonadherence.15 In 223 BD patients who were members of a self-help organization, low adherence to medications was associated with twice the odds of being concerned about the potential negative effects of medications, as measured by the Beliefs About Medications Questionnaire.16 In another article from the same study, over 60% of patients were dissatisfied with the information provided about potential side effects, and this dissatisfaction was, in turn, associated with lower adherence to the medications for BD.17 WHICH ADVERSE EFFECTS ARE COMMONLY ASSOCIATED WITH NONADHERENCE? Data linking specific adverse effects with nonadherence are limited, in part because studies on nonadherence have largely ignored the systematic assessment and reporting of adverse effects.18 However, the studies discussed below show that weight gain, cognitive impairment, emotional effects, nausea, tremors, and lack of coordination are more likely to be associated with nonadherence. In a pooled analysis of two randomized, placebocontrolled trials (n = 638), the incidence of discontinuation 364
www.harvardreviewofpsychiatry.org
attributed to tremor (5% vs. 1%), nausea (8% vs. 1%), and somnolence (4% vs. 1%) was significantly higher for lithium than placebo.19 Perceptions of the experts, clinicians, and patients regarding specific adverse effects as predictors of nonadherence have been assessed in three separate studies. Experts reported weight gain and sedation,20 clinicians reported weight gain,8 and patients reported weight gain and cognitive effects21 as the most likely predictors of nonadherence due to adverse effects. In another study, sedation and cognitive side effects were self-reported as the reasons for nonadherence by 30% and 27%, respectively, of Caucasian BD patients.22 Weight Gain Weight gain has been reported to frequently affect adherence in BD patients.21 Weight gain due to medications was reported as a reason for nonadherence by 59% of 145 patients with self-reported nonadherence to medications.8 Clozapine, gabapentin, lithium, olanzapine, risperidone, and valproate are associated with higher potential to cause weight gain. Weight gain is less of a concern with carbamazepine, lamotrigine, and ziprasidone, whereas topiramate may be associated with weight loss.23 Twenty percent of patients on lithium reported a weight gain of over ten kilograms.24 Lithium, valproate, and some second-generation antipsychotics are associated with a high incidence of weight gain, whereas aripiprazole, lamotrigine, and ziprasidone may cause less weight gain in most patients.23 Cognitive Impairment In order to test the association of cognitive deficits with nonadherence, cognitive function was systematically assessed in 103 patients with bipolar I or II disorder.25 While an association between poor performance on some cognitive tasks and nonadherence was actually found, the cause and effect relationship remains unclear. Mood symptoms also may affect how patients perceive and tolerate somatic adverse events.26 Concepts of illness strongly influence the subjective impairment caused by medication.27 In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study of 1771 patients with at least one follow-up visit, cognitive deficit/memory impairment was the only symptom that was presumably an adverse effect and was significantly linked to nonadherence.28 Although patients on lithium frequently complain of cognitive impairment, prescribing clinicians should be aware that the cognitive deficits in BD patients can, in part, be a manifestation of the disease itself rather than an adverse effect of lithium.29 A meta-analysis of 12 studies with lithium treatment concluded that lithium’s adverse effect on memory is present but limited.30 Similarly, a prospective study conducted with 44 euthymic patients with bipolar I disorder suggested no significant difference in neurocognitive performance in patients prescribed bipolar medications in comparison to unmedicated patients.31 Volume 22 • Number 6 • November/December 2014
Copyright @ 2014 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
Adverse Effects and Medication Nonadherence
Tremors Tremors may be reported in more than 10% of patients on lithium maintenance therapy for bipolar I disorder.32 Tremors may also be associated with nonadherence to BD medications. In a study of 429 BD patients, physical awkwardness or tremor was reported as a major cause of frustration in more than 33% of the nonadherent patients.8 A pooled analysis of two studies with 638 patients reported that the discontinuation of treatment due to tremors was about five times more in patients treated with lithium than in patients treated with placebo or lamotrigine (5%, 1%, and
