by Colin A. Depp, PhD; and Barry D. Lebowitz, PhD

Dr. Depp is from the Department of Psychiatry, University of California, San Diego (UCSD); and Dr. Lebowitz is from the Sam and Rose Stein Institute for Research on Aging, University of California, San Diego.

Disclosure: This work was supported by the National Institute of Mental Health grants MH77225, MH019934, and MH06624.

Key Words: Bipolar disorder, medication adherence, older adults, psychosocial interventions

Abstract

Objective: The number of older adults with bipolar disorder is increasing, yet little is known about the optimal clinical management of these patients. Medication adherence is a vital to effective long-term treatment of these patients; thus enhancement of adherence is often an important clinical goal.

Design: We reviewed available evidence about the characteristics of later-life bipolar disorder along with behavioral and organizational strategies to enhance adherence in this population.

Results: Based on available data, cognitive impairment, medical comorbidity, and functional limitations are frequent and are likely to impact treatment adherence in this population. In terms of treatment, there have been no placebo-controlled randomized clinical trials of medications or psychosocial interventions for this population. Based on extrapolation from intervention research on younger adults with bipolar disorder and older adults with other chronic illness, psychosocial interventions that reduce effortful cognitive processing in managing medications and reduce organizational barriers to adherence may be beneficial in enhancing adherence in this population.

Conclusions: Much more research needs to be done to understand the impact of aging on bipolar disorder, along with optimization of treatment. Interventions to enhance adherence in this population need to be adapted to fit with the unique needs of older adults with bipolar disorder.

Introduction

As a result of population aging, the number of older persons with severe psychiatric disorders, including bipolar disorder, will increase two- to three-fold over the next several decades.[1] Despite renewed interest in aging and bipolar disorder, there remain tremendous gaps in the knowledge about the features and optimal treatment strategies for this group of patients.[2] Understanding of late life bipolar disorder is substantially behind that of other later-life psychiatric diagnoses, such as schizophrenia and major depression. Fundamental questions remain as to whether this illness “burns out” or deteriorates over the life span; very few longitudinal studies are available on aging and bipolar disorder, and observations about its long-term course are sometimes at odds. For instance, the kindling theory of bipolar disorder posits that episodes become less environmentally determined over the course of the illness, yet early psychiatrists such as Kraeplin believed that long term outcome of bipolar disorder was generally positive.[3] Moreover, it remains unclear which medications are safest and most effective, and whether and which psychosocial treatments can provide additional therapeutic benefit. The purpose of this article is to provide an overview of available data on the prevalence and clinical features of late life bipolar disorder, and then discuss the relationship between these aging-related changes and a particularly vital aspect of clinical management: medication adherence.

Prevalence and Course of Late Life Bipolar Disorder

Community-survey data indicate that prevalence of bipolar disorder declines with age. The lifetime prevalence of bipolar disorder in the Epidemiological Catchment Area (ECA) Survey[4] was estimated as 0.4 percent among persons aged 45 to 64 and 0.1 percent among persons older than age 65 (compared to 1.4 percent among persons aged 18-44). Other community-based surveys suggest that the prevalence of bipolar disorder in persons 65 and older ranges between 0.1 percent and 0.5 percent.[5,6] However, within specialty mental health settings, the proportion of older adults with bipolar disorder is roughly similar as that found in younger patients, accounting for between 8 and 10 percent of all diagnoses among older adults.[7]ts is increasing due to the increase in the aging population, as 50 percent of patients in a VA bipolar disorder registry are over age 50[8] five-fold between 1980 and 1998 in a study of public mental health users in Australia.[9]

In terms of the course of late-life bipolar disorder, longitudinal research indicates that the majority of early-onset patients with bipolar disorder continue to experience relapsing or chronic course.[10,11] In one of the few follow-up studies of older adults with mania, higher mortality was found relative to patients with unipolar depression.[12 ]The majority of older adults with bipolar disorder experience age of onset prior to age 30 and have simply gotten older (‘early-onset’), yet about 10 to 15 percent experience onset of this illness after the age of 50. So far, sharp distinctions in functioning and psychiatric symptomatology between early- and late-onset groups are not apparent.[7] is often assumed that late-onset bipolar disorder is less genetically mediated early-onset variants, yet a review of studies in later-life bipolar disorder found that age of onset was not consistently related to family history of mood and other psychiatric disorders.[7] However, neurological comorbidity/signs (e.g., white matter hyperintensities) did appear to be more prevalent in late onset cases, which is parallel to what has been found in late-onset depression. In any case, the emergence of manic symptoms in later life can be secondary to dementia or medication-related influences (i.e., secondary mania). Organic causes need to be ruled out, particularly in late-onset cases.

Associated Features

Psychiatric symptoms. There is little evidence available about age-related changes in symptom severity, duration and degree of inter-episode recovery, or alterations in symptom profiles. Older adults can and do experience the full range of manic, mixed, and depressive symptomatology. However, community-dwelling older adults who screened positive for bipolar disorder reported experiencing more depression- and mania-free days, according to a large survey.[13] Data on inpatients suggests that that mania may be less severe among older adults.[14,15] In one study, Young and Falk (1989) found that age attenuation was most evident on the item reflecting increase energy/activation on a mania rating scale.[14] Two possible reasons for lower severity of manic symptoms may be changes in the disease state over time, or selective mortality of individuals with more severe manic symptoms. However, symptom resolution and duration of hospitalization may be longer.[8,16]

Substance use comorbidity. Substance use disorder appears to be less common among older adults. For example, in a study of 392 hospitalized bipolar disorder patients, the rate of lifetime substance use disorders among those over 60 was 29 percent, half that of younger groups.[17] The “baby boom” generation will have greater exposure to substances, and thus the next wave of older adults with bipolar disorder will be more likely that the current generation of older people to have substance use disorder comorbidity.

Medical comorbidity. Chronic physical illnesses are common among adults with mood disorders, and perhaps especially so among those with bipolar disorder. Among 4310 veterans diagnosed with bipolar disorder, diabetes and pulmonary disorders were particularly common compared to nonpsychiatric controls; within the sample of bipolar patients, being older than age 60 significantly raised risk of hypertension, hyperlipidemia, diabetes, heart disease, pulmonary disease, and thyroid disorder.[18] Poor health habits (e.g., smoking), diminished access to medical care, and side effects of medications could contribute to the high rate of medical problems in this group.

Cognitive functioning. Despite long-held notions that bipolar disorder was relatively free of associated cognitive impairments, a number of recent studies have identified a variety of cognitive impairments in bipolar disorder that persist between depressive and manic states. Existing data suggest that older adults are likely at greater risk.[19] Gildengers, et al., found that approximately 40 to 50 percent of a clinical sample with bipolar disorder older than age 60 showed cognitive impairment on cognitive screening tests.[20]

In a three-group comparison conducted in a sample of community-dwelling outpatients at the University of California, San Diego (UCSD), middle-aged and older adults with bipolar disorder differed from normal comparison subjects by large effect sizes in most neuropsychological domains (particularly verbal memory and processing speed), but differed by only small effect sizes from patients with schizophrenia. These effects were observed despite the fact that patients with bipolar disorder were similar in educational and occupational histories to a normal comparison group. Cognitive deficits in the bipolar group were only weakly related to concurrent psychiatric symptoms, suggesting that these impairments are not completely driven by affective exacerbations.[21] Rather they may be a ‘trait-like’ disturbance in bipolar disorder, especially toward the latter half of life. It remains unclear what causes neurocognitive impairment in bipolar disorder, but neuroimaging studies showing structural and functional differences between the brains of people with bipolar disorder and normal comparison subjects, particularly in brain networks undergirding emotion regulation (e.g., the anterior limbic network).[22]

From what limited data is available, older adults appear to be more at-risk for neurocognitive impairments, and, in cross-sectional mixed-age studies, a longer duration of illness or more severe illness courses (e.g., more manic episodes) appear to relate to greater cognitive impairment.[23] Studies examining the longitudinal trajectory of neurocognition over the lifespan are sorely needed.

Burden of Illness

Health-related quality of life and functioning. In a subset of the UCSD outpatient samples described above, the group with bipolar disorder had better educational and work histories than the schizophrenia group, but similar scores on measures of health-related quality of life (e.g., SF-36) and more medical comorbidity. At particular risk for poor functioning were bipolar patients with cognitive impairment, psychosis, and more severe depression.[24]

Service utilization. Compared to older adults with major depression, older adults with bipolar disorder utilize more mental health services (inpatient, emergency, case management) except for psychotherapy.[25] Mental health service utilization across the life span in bipolar disorder in a VA sample and a public mental health sample indicate lower use of inpatient and emergency services but greater use of “chronic care,” such as case management and conservators[26] and non-psychiatric care.[8]

Suicide. Older people continue to be at risk for suicide, as about 10 to 15 percent of those with bipolar disorder commit suicide and 25 percent attempt suicide during their lifetimes.[27] In a study of 1354 Ontario residents age 66 or older who committed suicide, the presence of bipolar disorder was associated with a higher risk of suicide than any other psychiatric or medical illness.[28]

Treatment Characteristics

Efficacy and treatment options. There have been no placebo-controlled trials specifically targeting this population. Thus, we know little about which medications are best for acute or maintenance treatment of depressive or manic symptoms. The evidence base for mood stabilizers in the treatment of geriatric mania is primarily derived from case reports and secondary analyses of clinical trial data, and even less is published on the treatment of bipolar depression.[29] Open trials for acute geriatric mania[30–32] and valproate[30,33–37] showed similar rate of response as among younger adults. In the one prospective study that tested a standardized treatment among older adults, only 10 percent of 31 patients attained sustained symptomatic recovery after 76 weeks.[38]

Tolerability and side effects. Older adults taking lithium are at risk for toxicity, due to in part to interactions with diuretics and lower renal clearance.[39] In a retrospective analysis of mixed-age placebo controlled trials of lithium and lamotrigine, 85 percent and 82 percent adults over age 55 experienced adverse events (mostly mild to moderate).[40] A recent review estimated that neurocognitive side effects and tremor occur in 30 percent of patients with late-life bipolar disorder.[41]

Usage of multiple medications. Older adults with bipolar disorder commonly receive complex medication regimens, including mood stabilizers, antipsychotics, and anti-depresssants. There has been a recent shift away from lithium toward use of valproic acid in pharmaco-epidemiological study of for older adults.[42] In a prospective study that tested the feasibility of a standard treatment pathway in 31 geriatric patients with bipolar disorder,[43] antipsychotic, antidepressant, and sedative medication were each used in over 30 percent of the population in addition to mood stabilizers. These multiple psychiatric medications are coupled with a high number of non-psychiatric prescriptions in aging people, as the average person older than age 60 takes approximately seven medications.

Role of Medication Adherence

As stated by former US Surgeon General C. Everett Koop, “medications don’t work in people who don’t take them,” leading many to refer to medication adherence as the “sixth vital sign.” Medication nonadherence has been called the single greatest impediment to effective long-term treatment in bipolar disorder, and therefore it is a central aspect of clinical management.

Prevalence and consequences. There is little data about whether older adults with bipolar disorder are more or less adherent than their younger counterparts,[44] although one study in a large administrative sample of veterans indicated that the rate of self-reported adherence to antipsychotic medications was better compared to younger groups.[45] In mixed-aged samples with bipolar disorder, at any given time about 40 percent of those with bipolar disorder are not fully adherent, and one third take less than 30 percent of their medication.[46] The consequences of nonadherence are substantial, as patients with bipolar disorder who are nonadherent are at higher risk of relapse, recurrence, and hospitalization.[47,48]

Measurement of medication adherence. Although seemingly simple, medication adherence is exceedingly difficult to measure, and is associated with a complex set of interacting risk factors. Nonadherence may occur only with specific medications, it can be intermittent, or it may be continuous.[49] There are multiple ways of measuring medication adherence, yet there remains no single “gold standard” assessment procedure. Table 1 provides a description of the procedures and their advantages and disadvantages in measuring medication adherence. In general, the best measure is one that combines multiple sources of information.

Causes of nonadherence in older adults. There are many contributors to nonadherence in bipolar disorder, including such factors as comorbid substance abuse, denial of need for medications, cognitive impairment, and many others (see Berk, et al.,[49] for an excellent review). Thus, there is no single risk profile for nonadherence in bipolar disorder. Lacro and colleagues have provided a framework for understanding the causes of nonadherence in severe psychiatric disorders, divided into patient-related (e.g., negative attitude about medications, forgetting, poor medication management ability), provider-related (e.g., poor therapeutic alliance), and medication-related (e.g., side effects, complexity of medication regimens).[50] Very little data exists that allows for understanding the interaction between these categories of risk factors and aging among patients with bipolar disorder.

However, a particularly relevant distinction for aging and adherence is between intentional nonadherence (i.e., actively deciding not to take medication) and unintentional nonadherence (i.e., forgetting or difficulty following instructions). Among younger adults with bipolar disorder, attitudes and beliefs about medications are considered the primary contributors to nonadherence,[51,52] particularly the denial of need for medications;[53] thus, intentional nonadherence is of primary concern among younger people.

Older adults have a number of practical challenges in staying adherent to medications, leading to potentially higher rates of unintentional nonadherence. Aging appears to be correlated with higher rates of unintentional nonadherence with medications for depression,[54] hypertension,[55] and respiratory disorders,[56] and, when asked, the older adults cite “forgetting” as the most common cause of nonadherence.[57,58] Unintentional nonadherence may occur in concert with greater medication burden, as some (but not all) studies indicate that adherence declines as the number of medications and frequency of dosing increases.[59]

Neuropsychological deficits and medication adherence. Adherence, particularly in a person taking multiple medications, is actually a fairly complex cognitive task. Park and colleagues[60–62] developed a model that breaks medication taking into a series of cognitive processes: 1) working memory in transferring data from pill bottle labels, 2) prospective memory and executive functioning in organizing and planning to take medications, and 3) long-term memory in recalling medication dosage times. This model has been applied to adherence and interventions for medically ill older adults,[62,63] although not to late-life psychiatric disorders. However, there is reason to suspect that the model could be useful, as cognitive impairment has been identified as a risk factor for nonadherence in bipolar disorder[49,52] and among older adults in general.[64] In a study of older adults prescribed antidepressants, cognitive impairment was the greatest risk factor for unintentional nonadherence.[54] from the larger body of literature on cognitive abilities and adherence in other chronic illnesses (e.g., HIV), evidence suggests that memory deficits are not the sole cognitive ability implicated in nonadherence.[65] Deficits in executive function and attention relate to worse adherence[65,66] and medication management ability.[67,68] instructions of medications, which may also contribute to problems with adherence.[62] In two studies, older adults with bipolar disorder performed worse on tests of knowledge about the properties of mood stabilizers compared to younger adults.[69,70]

Psychosocial Interventions for Bipolar Disorder

Psychosocial interventions, in general, have not been a widely accepted intervention for bipolar disorder until the past decade. Much work has been completed over the past 10 years in developing and assessing the effectiveness of psychosocial interventions for bipolar disorder. These interventions are intended to complement, not supplant, medication treatment, and there are a variety of modalities that now have empirical support in bipolar disorder, including cognitive-behavioral,[71] psychoeducational,[72] interpersonal,[73] and family therapy.[74] These interventions range from brief, fixed educational approaches discussing medication adherence and relapse prevention[75] to more intensive individualized approaches.[74] Importantly, psychotherapy can be particularly useful for addressing bipolar depression, as suggested by the findings from the recently completed multisite Systematic Treatment Effectiveness Program for Bipolar Disorder study.[76]

Psychosocial interventions targeting medication adherence. The enhancement of medication adherence is a central therapeutic target in many psychosocial interventions for bipolar disorder.[77] In a review of the effectiveness of psychotherapy for enhancing medication adherence in bipolar disorder, seven of 11 clinical trials reviewed showed positive effects on medication adherence,[78] with greater effect found for multicomponent interventions that focused on medication adherence versus interventions that covered a broad set of problems or those that only included education.

The goal of psychosocial interventions focusing on medication adherence enhancement is typically to alter attitudes toward bipolar illness and need for medication, thus targeting intentional adherence. An implicit assumption is that once the participant is willing to take the medication, he or she will manage medications and become adherent. However, examining the broader spectrum of interventions that have been evaluated in older adults with schizophrenia[79] or other chronic illnesses,[80] multicomponent interventions include training in medication management skills as well.

The following is a description of some specific strategies that may be useful in older adults with bipolar disorder:

1. Education. Here the primary goal is to increase knowledge about the properties of medications and awareness of the patient’s role in managing medication. At minimum, educational interventions should include printed information about the basic properties of mood stabilizer, antipsychotic, and anti-depressants, such as their purposes, dosages and instructions, and factors that affect medication effectiveness. It is essential to provide education about the causes and consequences of bipolar disorder, and particularly useful to draw parallels to other chronic medical illnesses, such as diabetes. Education should also strive to highlight the personal impacts of the illness, in order to make information more salient to the individual. An effective method of increasing personal awareness of bipolar disorder symptoms is to have participants complete mood charts.

2. Motivational interviewing and working with medication attitudes. The goal of motivational enhancement interventions is to increase the probability of behavior change (i.e., taking medications consistently) by highlighting the advantages of adherence, develop strategies to counteract the drawbacks, and, in general, increase participant activation in developing a treatment plan. A useful tool is the “decisional balance” activity, which solicits perceived benefits and drawbacks of taking medications, a technique commonly employed in motivational interviewing.[81] To address the primary drawback of side effects, the use of a side effect tracking form may assist in recognizing side effects, and subsequently a personalized plan can be developed to counteract chronic side effects. For example, goal setting with respect to behavioral strategies to counteract weight gain or fatigue can be employed.[82] Standardized lifestyle interventions designed for people with mood disorders are available, although their effectiveness in clinical practice is unclear.[83]

3. Compensatory skills training. The general goals here is to reduce the amount of effortful cognitive processing in daily adherence behaviors, by encouraging consistent medication taking habits and by simplifying the act of organizing medications. Interventions in this category are primarily intended to address unintentional nonadherence. A wide variety of strategies are available to increase the ease of taking medications, including medication tracking forms and external reminders/tools (e.g. pillboxes, electronic medication reminders). These external cues are best coupled with behavioral strategies that facilitate recalling medication, including pairing activities with medication taking, developing routines around medication taking, and placing cues in the environment to trigger medication taking behavior. It is vital that these strategies be personalized, and that the emphasis is on making the process of medication taking easier and less effortful.

Adaptations of psychosocial interventions for older adults. In general, empirically based psychotherapies work about as well as they do in younger adults, provided a few adaptations are made. Psychoeducational interventions in older adults typically use briefer sessions, accompanying manuals that reinforce session content, and greater repetition of content.[84] A particularly useful set of strategies is live or in-person practice with skills, such as exemplified by the Functional Adaptation Skills Training program for schizophrenia.[82] Training in medication management skills, for example, involves breaking medication management into small steps that are first demonstrated to, then practiced by, the group participant. Tracking measures and homework assignments are used to determine whether these skills generalize to the participants’ home environment. More extensive recommendations for adapting psychotherapy protocols for older adults are available.[84]

Provider level interventions. Interventions aimed at improving the delivery systems of care for older adults with bipolar disorder may also have an effect in improving adherence. As reviewed above, later-life bipolar disorder often involves cognitive impairments, medical comorbidities, and functional limitations, which, together, demand greater coordination among providers than commonly occurs in mental healthcare systems. The chronic care model is a flexible approach that combines centralized electronic records, a care manager to help coordinate aspects of care, and standardized psychoeducation. A model of chronic care for bipolar disorder has been successfully implemented in a large health maintenance organization and in the Veterans’ administration.[85,86]

Medication errors and dangerous interactions between medications prescribed by different providers (e.g., lithium and ACE inhibitors) can be reduced by such approaches. Furthermore, chronic care can facilitate proactive response to symptom exacerbation and recognition of medical comorbidities. Furthermore, this kind of chronic care directly addresses the organizational barriers to care that often hinder adherence.

Support groups. The availability of psychoeducation and chronic care for bipolar disorder remains fairly limited. A more widely available option are support groups provided by consumer-run organizations, such as the Depression and Bipolar Alliance (www.dbsalliance.org) and the National Alliance on Mental Illness (www.nami.org). These support groups can provide much needed education and support about bipolar disorder. Participation in these groups may indeed improve adherence, although systematic research on the effect of support groups in bipolar disorder is limited. It is important to note that older adults typically underutilize support groups in many illnesses, and it is likely that bipolar disorder is not an exception.

Family involvement. Family involvement in care and care planning can also be of great benefit to adherence. In other chronic illness, such as HIV, living with a family member or partner is one of the most potent facilitators of adherence.[87] There is an evidenced-based family-focused therapy for bipolar disorder that was evaluated favorably in the recent STEP-BD trial,[76] but it has yet to be adapted to older adults. Among older adults with bipolar disorder, family members can help to facilitate medication management and they can also recognize symptom exacerbations or adverse events as they occur. Clinicians should also be aware that caregivers of individuals with bipolar disorder often experience considerable strain themselves,[88] and that many older adults with bipolar disorder may not have family members who are able or willing to participate in their care.

Summary

Clearly, empirical understanding of later-life bipolar disorder is a “frontier” in geriatric psychiatry, and much more needs to be done to understand the strategies that work best to encourage adherence. Among the best ways the improve adherence would be to understand which medication or medication combinations are safest and most effective, yet there is presently little data available to guide clinicians in this regard. Older adults likely possess different risk factors in terms of nonadherence, and the presence of cognitive deficits, medical comorbidities, and functional impairments may contribute to higher rates of unintentional nonadherence. Psychosocial interventions that reduce effortful cognitive processing in managing medications, along with increasing patient knowledge and activation in treatment, can be beneficial in enhancing adherence in this population. Even greater gains in adherence may stem from comprehensive “chronic care” approaches to delivering mental health services to older adults with bipolar disorder. There remains much that needs to be learned about, and learned from, this vulnerable group of patients.

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