13_chapter_machalak et al_01.10.2006.doc

Chapter 13
________________________________________________________________________ Quality of life impairment in bipolar disorder
Erin E Michalak1, Greg Murray2, Allan H Young1 and Raymond W Lam1 1Department of Psychiatry, University of British Columbia 2Faculty of Life and Social Sciences, Swinburne University of Technology This chapter will present an overview of what is currently known about quality of life (QoL) in bipolar disorder (BD). While there is growing consensus that the QoL concept provides an important counterpoint to the objective symptom measures that dominate psychiatry, the implications of this position are yet to be systematically addressed in the BD field. The literature reviewed in this chapter is not informed by any model or theory of QoL as it applies to BD. The data presented are largely empirical in the negative sense of this term, drawn from studies making different assumptions, addressing different questions in BD. In many cases, the measurement of QoL has been incidental to the major thrust of the research design. Indeed, even at the empirical level there is a lack of agreement about the best measure of QoL in this population, and no disorder-specific In this context, the present chapter aims to capture the range of applications of the QoL concept in BD, and highlight any reliable findings. To structure the presentation, it is useful to categorize data into three general areas: studies that have looked at QoL impairment in BD compared with non-clinical and other diagnostic groups, studies that have looked at QoL differences across the states of BD and studies that have looked at QoL changes as an outcome of treatment. We will briefly set the scene for these three investigations by presenting the findings of four manuscripts that have reviewed research The final section of this chapter will make some recommendations about future QoL research in BD, highlighting the need for work at both the theoretical and measurement levels. At the theoretical level, the implications of the vulnerability model of health- related QoL (HRQOL) (e.g., Ritsner, Chapter 1 of this collection) will be briefly reviewed. At the measurement level, we will present some data on the ongoing development of a patient-centred disorder-specific QoL measure for BD. Key words: bipolar disorder, quality of life, functioning. Bipolar disorder is a highly complex and heterogeneous psychiatric condition that is characterised by both a variety of symptoms and marked variability in course. For example, a patient with BD can experience episodes of depression, hypomania, mania, or psychosis, and indeed, can experience a mixture of emotional states, or cycle rapidly between them. Marked variability exists between patients in terms of the length, number and type of episodes, severity and type of symptoms, and the degree of interepisode recovery experienced. Overall, however, patients with BD appear to spend more time in episodes of depression than mania or hypomania1;2, and unsurprisingly, the condition is associated with marked disability. In the year 2000, the World Health Organization estimated that BD was the 6th leading cause of disability worldwide amongst young adults (i.e., 15 44 years of age)3. A woman who develops BD at the age of 25 may lose 9 years in life expectancy (due to cardiovascular and other medical problems), 14 years of productivity, and 12 years of normal health4. While the condition obviously has considerable ramifications at an individual level, it also has a significant impact at a societal level. Bipolar disorder is estimated to affect at least 1% of individuals worldwide5, making it a serious public health concern. The broader category of bipolar spectrum disorders (encompassing, for example, BD type II, which is characterised by episodes of depression and hypomania) has been less extensively studied, but is likely to be more prevalent, affecting up to 8% of the population6. In one widely cited study, the direct and indirect costs associated with BD were estimated to be $45 billion in the United States during 1991, of which only $7 billion was due to actual treatment costs7. Lost productivity within salaried employees and homemakers, however, accounted for Patient outcome in BD has traditionally been determined by the assessment of objectively measured clinical information, such as rates of relapse, the number of times a patient is hospitalised or clinician-rated symptom reduction. In recent years, however, we have seen a shift towards the concomitant assessment of more subjective, patient-centered measures of well-being such as functioning and QoL. As leading researchers Colom and Vieta (2004)8 have stated: “A very important change of paradigm in the treatment of bipolar disorders started a few years ago, when crucial findings on the impact of bipolar disorders on quality of life and social, cognitive and occupational functioning suggested that therapy targets should be changed from symptomatic recovery to functional recovery”. Whilst this statement is laudable, we would go one step further to suggest that restoration of QoL (which encompasses more than restoration of functioning per se) should be a primary goal for treatment, over and above minimizing the symptomatic An overview of QoL research in BD Compared with the study of QoL in unipolar depression, research into QoL in BD has been sparse. To our knowledge, four systematic reviews of previous research in this area have been conducted 9-12. In the first of these, Namjoshi and colleagues (1999)9 assessed all relevant English-language articles published prior to 1999, identifying 10 studies for inclusion. The studies proved to be quite heterogeneous, and used a wide variety of instruments to assess HRQOL. They also tended to be relatively small, most often conducted in depressed or euthymic (rather than hypo/manic) patients, and rarely included descriptions of the psychometric properties of the instruments they utilized. The authors of the review made a number of suggestions for future research, including the need for the development of a disorder-specific measure of QoL for BD, more assessments in manic patients, and more longitudinal research. The second review, conducted by Dean and colleagues (2004)10 examined studies published prior to November 2002 that had assessed HRQOL, work-impairment or healthcare costs and utilization in patients with BD. This review applied a very broad definition of HRQOL, including studies that had assessed social or physical functioning in isolation (for example, the Global Assessment of Functioning (GAF) scale was considered a measure of HRQOL). Using this broad definition, the review identified 65 HRQOL articles. The authors concluded, (i) that the HRQOL of patients with BD is similar to that of patients with unipolar depression and equal or lower than that observed in patients with chronic medical conditions and, (ii) that treatment interventions for BD have been shown to have a beneficial impact on HRQOL. The third review, conducted by Revicki and colleagues (2005)11 focused on pre-2003 studies measuring HRQOL outcomes of BD treatment and the burden of BD on HRQOL. The authors identified just three clinical trials that had included HRQOL assessments. On the basis of this initial data, they concluded that treatment interventions for BD improve HRQOL, but that there is limited evidence for differences between the mood stabilizers in terms of HRQOL outcomes, and “that the time may be ripe for developing disorder-specific HR-QOL instruments for use in clinical trials” (pg. 592). In the most recent of this series of reviews12, we searched for studies published prior to November 2004 which had examined QoL in BD. This search, which applied slightly more stringent inclusion criteria than some of the earlier reviews, identified 28 studies in total, 7 (25%) of which were published before 1999. The remaining 21 (75%) were published between 2000 and 2004, underscoring the developing interest in this field of research. The studies we identified formed a heterogeneous set. Several undertook to assess QoL during different phases of the disorder, for example, cross-sectional research that compared perceived QoL in euthymic, manic or depressed patients with BD. Other studies compared the QoL of patients with BD to that of other patient populations, both with other psychiatric disorders and with chronic physical conditions. Another area of research examined the psychometric properties of a few HRQOL instruments in BD populations. Finally, we identified a small number of studies that had used a QoL instrument to assess outcome in trials of treatment inventions (mostly pharmacological) for the condition. The studies were also of variable scientific quality. Methodological shortcomings included small sample sizes, cross-sectional designs, idiosyncratic diagnostic methods or poorly differentiated diagnostic groups, use of poorly validated QoL instruments and lack of control for chronicity of illness or the number of previous episodes experienced by the individual. However, the overall scientific quality of the research in this field does appear to be improving. Of the 10 studies identified in the review by Namjoshi and colleagues, only one had a sample size of greater than 100. In comparison, we identified eleven studies that had enrolled more than 100 patients, and it was particularly encouraging to see that some of the large pharmacological trials of treatment interventions for BD are now using QoL measures as secondary outcome The preceding section provides an outline of existing literature on QoL in BD via synopsis of four review studies. As a group, these reviews serve to highlight the significant gaps and deficits in this body of literature. In particular, there appear to be widely held concerns about the valid measurement of QoL in patients with BD, with several reviewers calling for the development of a disorder-specific QoL instrument for this patient population. In the following sections, we will describe this body of literature in more detail, clustering the studies into three subgroups: i) degree of QoL in patients with BD; ii) QoL across mood states within BD; and, iii) QoL as an outcome measure in Several studies have attempted to ascertain the degree of impairment in QoL experienced by patients with BD. Unsurprisingly, QoL in bipolar populations appears to fall far below that observed in general population samples, at least in the realms of emotional or psychosocial well-being. For example, one study utilizing the MOS SF-3613, to date the most widely used HRQOL measure in this patient population, compared scores between patients with BD (N=44) with previously reported norms for a general population sample (N=2,474)14. The SF-36 contains eight sub-scales assessing physical functioning, social functioning, role limitations (physical), role limitations (emotional), pain, mental health, general health and vitality. These yield an overall domain score on a 0-100 scale, where 0 represents worst possible health and 100 best possible health. The results of the study indicated that, compared with the general population, HRQOL was significantly compromised in patients with BD in all SF-36 domains except physical functioning. While the study provided a useful initial comparison, its findings should be interpreted with some caution owing to the disparate sample sizes involved and the fact that it utilised previously published norms for the HRQOL instrument. More recent data was provided by Yatham and colleagues, who reported on SF-36 scores in patients with BD type I (N=920) who were either currently depressed, or had experienced a recent episode of depression15. Scores were significantly lower across all scale domains in the bipolar group compared with norms reported for the US general population, with markedly lower scores in the mental health, vitality, social functioning and role emotional domains. The authors went on to compare these scores with SF-36 scores derived from seven large studies of HRQOL in patients with unipolar depression. Scores on four domains (general health, social functioning, role-physical and role- emotional) were consistently lower than those observed in unipolar depression, however, the unipolar samples tended to exhibit higher scores in the bodily pain domain. Whilst this study was robust in terms of its large sample size and well-described clinical population, it did not control for depression severity or demographic variables in between-group comparisons. Also, diagnosis of BD was made by clinical interview, whereas unipolar depression was diagnosed via a range of subjective and objective methods. A smaller Brazilian study that compared patients with unipolar MDD (N = 89) and with bipolar depression (N = 25) on the WHOQOL-BREF (a carefully developed 26- item scale assessing four domains of wellbeing: physical, psychological, social relationships and environment,16 found poorer psychological functioning in the bipolar Several other studies have compared HRQOL in patients with BD with that of patients with other psychiatric conditions. For example, the NEMESIS study conducted in the Netherlands compared SF-36 scores in 136 adults with DSM-III-R lifetime BD (93 with BD type I and 43 with BD NOS, as diagnosed by the Composite International Diagnostic Interview or CIDI interview) with that observed in a variety of other psychiatric disorders18. Participants with BD showed significantly more impairment in most SF-36 domains compared with other NEMESIS subjects. For example, in the domain of mental health, participants with BD type I experienced significantly lower scores (62.3) than people with other mood (75.2), anxiety (74.0), substance use (80.2) or no psychiatric disorders (85.8). BD type I subjects also reported significantly lower SF-36 scores than patients with BD NOS in the domains of mental health, role limitations (emotional), social functioning and pain. However, there remains some controversy about the accuracy with which the CIDI detects BD NOS, limiting somewhat the inferences that can be made on the basis of these sub-group results. Furthermore, more recent results from the NEMESIS study suggest that the CIDI interview might over-diagnose BD compared to the Structured Clinical Interview for DSM (SCID) interview schedule19. Other research has compared QoL in patients with schizophrenia with that observed in patients with BD. For example, Chand and colleagues in India measured QoL via the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)20 and the WHOQOL-BREF in patients with BD who were in remission and stabilized on lithium prophylaxis (N=50), patients with schizophrenia (N=20) and healthy controls (N=20)21. The Q-LES-Q is a 93-item self-report measure of the degree of enjoyment and satisfaction in various areas of daily living. The questionnaire was developed and validated for use in depressed outpatients and has eight summary scales that reflect major areas of functioning: physical health, mood, leisure time activities, social relationships, general activities, work, household duties and school/coursework. Mean Q-LES-Q scores can be derived from the eight summary scales and range from 0-100, where higher scores indicate better QoL. The bipolar group reported significantly better QoL than the schizophrenia group in all domains of the scale, and in general well-being, physical health and psychological health on the WHOQOL-BREF22. Research findings in this nascent area of research, however, have been inconsistent. For example, Atkinson and colleagues23 used the Quality of Life Index24, to assess QoL in patients with BD (N=37), MDD (N=35) and schizophrenia (N=69). Controversially, the authors found that subjectively reported QoL was lower in patients with BD and MDD than in those with schizophrenia, a trend that was reversed for objectively assessed QoL, which included measures such as medical history, health risk behaviors, educational and financial levels and social functioning. These findings led the authors to speculate about the validity of subjective measures of QoL, particularly in people with affective disorders, and the study became an oft-quoted example of the potential difficulties of using patient-centered outcome assessments in psychiatric conditions that may be characterized by factors such as loss of insight (for example, see 25;26). More recently, Goldberg and Harrow (2005)27 compared subjective life satisfaction and objectively measured functioning in patients following hospitalization for an episode of bipolar mania (N=35), unipolar psychotic depression (N=27) and unipolar nonpsychotic depression (N=95). Both life satisfaction (five major domains, work satisfaction, economic security, satisfaction with social activities and relationships, satisfaction with living situation and perceived mental health were assessed via non-standardised semi- structured interview questions) and functioning (objectively measured via a global outcome scale based on factors such as rehospitalization, psychiatric illness, self-support, role performance and social relationships) were assessed longitudinally in the sample at approximately 2, 4.5 and 7-8 years. Their data indicated, firstly, that subjectively assessed life satisfaction was not significantly different between the bipolar/unipolar groups (although objectively assessed work functioning scores were poorer in the bipolar group compared to the unipolar groups). Secondly, it was found that concordance between subjective and objective measures of functioning was higher in the nonpsychotic depression sample than in the bipolar or unipolar psychotic depression samples, consistent with Atkinson et al.’s earlier finding that more severely ill affective disorder patients’ subjectively assessed life satisfaction may not be equivalent to objectively assessed functioning. The authors posited some tentative explanations for this finding, including the possibility that more severely ill patients may experience diminished insight, insensitivity to changing life circumstances as a consequence of demoralization or desensitization to stress, or altered life expectations. An alternative explanation for these findings is that discrepancies between objective and subjective measures of HRQOL signify a genuine difference rather than an anomaly related to the patient’s psychiatric condition (see Ritsner, Chapter 1 of this collection). Clearly, better designed research is required to help unpack the complex and probably multifaceted relationship between subjective interpretations of life quality and objectively assessed functioning in individuals who are experiencing severe and chronic forms of BD. Finally, other research has applied a ‘health utility’ or ‘health preference’ model to assess health perceptions in patients with BD. The concept of health utility refers to an individual’s preferences for different health states under conditions of uncertainty28. Health preferences are values that reflect an individual’s level of subjective satisfaction, distress or desirability associated with various health conditions, and are frequently assessed by the ‘time tradeoff’ (TTO) and ‘standard gamble’ (SG) approaches29. TTO refers to the years of life a person would be hypothetically willing to exchange for perfect health. For example, patients might be asked to imagine that a treatment exists that would allow them to live in perfect physical and mental health, but reduces their life expectancy. They might then be asked to indicate how much time they would give up for a treatment that would permit them to live in perfect health, if they had ten years to live. SG refers to the required chance for successful outcome to accept a treatment that could result in either immediate death or perfect health. For example, patients might be asked to imagine that they had ten years to live in their current state of health, and that a treatment existed that could either give them perfect health, or kill them immediately. Patients might then be asked to indicate what chance of success the treatment would have to have In a recent study, Revicki et al. (2005)30 assessed health utility values in N = 96 clinically stable outpatients with BD type I. Standard gamble data indicated that the least preferred bipolar state was inpatient mania-related states, on a par with severe depression states (M = 0.26, SD = 0.29 and M = 0.29, SD = 0.28 respectively). Importantly, 96% of their sample was able to complete the SG tasks, indicating that (clinically stable and well- educated) patients with BD are capable of completing these relatively challenging interpretations of health status. In earlier research, Wells and colleagues (1999)31 assessed functioning and health utility in patients with depression or chronic medical conditions within seven managed care organizations in the United States. HRQOL was assessed via the global mental and physical scales of the SF-12 and health utility was measured via TTO and SG. Patients with depression were categorized as those with BD (N=331), MDD (N=3,479), double depression (N=944), dysthymia (N=151) or brief subthreshold depressive symptoms (N=987). In terms of HRQOL, the bipolar group showed levels of impairment second only to patients with double depression. Health utility followed the same pattern. Specifically, patients with BD were willing to give up on average 17% of their life expectancy in return for perfect health, and would accept on average an 11% risk of death in exchange for perfect health. In comparison, patients with MDD were willing to give up 11% of their life expectancy, and accept a 6% risk of death. Tsevat and colleagues32 examined functional status and health utility in 53 outpatients with BD recruited from one site of the multicenter Stanley Foundation Bipolar Network study. The authors aimed to assess how patients with BD rated their current overall health versus their current mental health, and to determine the extent to which health utility correlated with disease state. TTO scores for current overall health were 0.71, but were significantly higher than scores for current mental health, which averaged 0.61. In other words, patients with BD were willing to give up, on average, 39% of their life expectancy in return for perfect mental health. These values are similar to TTO values obtained in the Beaver Dam Health Outcomes Study in patients with depression (0.70) or anxiety (0.77). SF-36 data was also collected in the study, and the authors reported that certain SF-36 domains (general health, vitality and role-emotional) were significantly correlated with mental health TTO and SG scores, but levels of mania were not correlated with utilities for either overall health or mental health. The authors concluded that health utilities may be related to certain health status attributes and to level of depression, but may not be related to level of mania in patients with BD. One advantage of the health utility/preference approach to QoL assessment is that it allows the calculation of quality- adjusted life years (QALYs) (for example,33). QALYs are a commonly used outcome measure in cost-effectiveness studies (for example, see 34), but we are unaware of any studies that have taken advantage of this metric in assessing BD populations at the time In summary, studies using a range of questionnaire and more complex measures have generally confirmed that QoL is, in a range of domains and to a marked extent, lower amongst patients with BD than in the normal population. Beyond this commonsense finding, there is some evidence that QoL is poorer in BD than in other mood and anxiety disorders (perhaps with the exception of double depression). Comparison of BD and psychotic disorders has highlighted a fundamental challenge in comparing QoL across patient groups, namely, that QoL when assessed subjectively in BD might be systematically influenced by the disorder’s varying mood and cognitive symptoms. In the next section, we look more closely at state effects on QoL in BD. Individuals with BD can experience a number of different mood states or episodes (for example, severe depressions through to highly elated mood) during the course of their disorder, or indeed a combination of these mood states (for example, mixed episodes of depression and mania). Bipolar disorder provides a unique window for the QoL researcher to gaze through; it is of significant scientific and clinical relevance to know what impact these mood shifts have upon individuals’ perceived life quality. It is reasonable to expect that QoL would be negatively affected by the depressive episodes of BD. Indeed, as noted above, the large-N study of Yatham et al.35 found remarkably low self-reported QoL amongst BD patients who were either depressed or had experienced a recent episode of depression. The potential relationship between QoL and hypo/mania in BD, however, is not so straightforward. The ‘father of modern psychiatry’ Emil Kraepelin recognized a wide variety of presentations of hypomania and mania, including episodes that were characterised by significant dysphoria or depressive symptomatology. The notion that hypo/mania can be an uncomfortable and unpleasant experience for some individuals, however, lost favour in the mid 20th century, and was almost entirely replaced with an understanding of hypo/mania as a primarily euphoric, positive and driving state. However, more recent research has provided further evidence for Kraepelin’s more flexible conceptualization of mania and both dysphoric mania (which is characterised by significant depressive symptomatology) and mixed episodes (where the patient meets criteria for both manic and depressive episodes simultaneously) The observation that manic states can be accompanied by symptoms of depression led Vojta and colleagues to hypothesize that patients with manic symptoms would report significantly lower QoL than would patients who were euthymic36. To test this theory, the authors administered the SF-12 and the EuroQoL visual analog scale37 in bipolar patients in a manic/hypomanic episode (N=16), depressive episode (N=26), mixed episode (N=14) or who were euthymic (N=30). In keeping with their prediction, patients with mania/hypomania showed significantly lower SF-12 mental health scores than euthymic patients, with depressed or mixed patients showing significantly poorer HRQOL again. Mean EuroQoL scores ran in the same direction, although the difference between euthymic and manic/hypomanic patients was not significant. This research was supported in part by the standard gamble data provided by Revicki and colleagues38 which indicated that the condition least preferred by patients with BD is an inpatient mania-related state, although this was rated in their study as being as unpleasant as being Although the research by Vojta and colleagues produced some interesting preliminary data, the study did not control for confounding variables such as psychiatric comorbidity, sociodemographic factors, personality type or other psychosocial variables. The complex issue of QoL across clinical states in BD has recently been addressed more comprehensively in a cross-sectional study of the first 2000 participants enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, or STEP-BD39. STEP-BD, a large multicentre prospective, naturalistic study that features several embedded randomized-controlled trials is measuring QoL via the long version of the Q- LES-Q and the SF-3640. In addition, the study is assessing a comprehensive battery of possible confounders, including demographic and socioeconomic factors, family history, psychiatric comorbidity, clinical characteristics (including age of onset), personality (as assessed by the 60-item NEO-Five Factor Inventory), social support, negative life events and attributional style. The primary finding from the analysis was that depressive symptoms were strongly associated with poorer emotional QoL, even after relevant confounding variables were controlled for. Conversely, apparent “supranormal” QoL reported in patients with hypo/mania (compared to that of euthymic patients) disappeared after statistical control. These results represent early data from a study that has the potential to address several important questions regarding QoL in BD. The above sections have summarized our current understanding of how episodes of depression and hypo/mania impact upon HRQOL. However, it is also of interest for us to know how patients function between these episodes, or when they are considered to be in remission. The notion that patients with BD usually achieve complete functional recovery between episodes has been brought into question by a growing body of evidence indicating that inter-episode functioning in the condition often remains compromised, with marked residual functional deficits often remaining after symptomatic recovery41. Available research indicates that 25-35% of patients continue to experience partial impairment in their occupational and social functioning; a similar proportion will exhibit extreme functional problems42-45. Furthermore, degree of functional impairment appears to be strongly correlated with residual depressive symptoms (for example, 46,47) during Several studies have now assessed QoL in inter-episode patients with BD. For example, a Canadian research group generated a series of interrelated reports on QoL in euthymic patients with BD. Three publications48-50 describe various aspects of QoL in a single sample of outpatients (N=∼68) with BD type I or II who had been clinically euthymic for at least one month. First, Cooke and colleagues48 examined levels of HRQOL using the MOS SF-20, a short version of the SF-36. Mean scores on the scale were comparable to those reported for patients with MDD by Wells and colleagues in the large RAND Corporation MOS Study51. Analysis of SF-20 scores by type of BD showed that patients with BD type II reported significantly poorer HRQOL than BD type I in the areas of social functioning and mental health. Robb and colleagues49 then reported on QoL in the context of the ‘Illness Intrusiveness Model’52;53, which addresses the impact a disorder and/or its treatment has upon an individual’s activities across 13 life domains: health, diet, active/passive recreation, work/financial status, self expression/improvement, family relations, relations with spouse, sex life, other relationships, religious expression and community involvement. Illness intrusiveness occurred in several life areas, with more intrusion being associated with higher Hamilton Depression Rating Scale (Ham-D)54 scores, patients having experienced a recent episode of depression and having BD type II. In a separate sample of euthymic BD type I patients (N=62), MacQueen and colleagues55 reported that SF-20 scores did not appear to be impacted by whether or not the patient had experienced psychosis during their index episode of mania, although the psychotic sample may have been too small (N=16) to detect statistically significant differences between sub-groups. Finally, MacQueen and colleagues56 focused upon the effect of number of manic and depressive episodes on SF-20 and GAF scores in euthymic patients (N=64), finding that number of past episodes of depression was a stronger determinant of HRQOL than number of previous manic episodes. In this study, good correlation was reported between subjective (SF-20) and objective (GAF) ratings. A study by Ozer and colleagues57 assessed 100 interepisode patients with BD in Turkey with the aim of examining the impact of ‘history of illness’ and ‘present symptomatology’ factors upon a variety of outcome measures including the Schedule for Affective Disorder and Schizophrenia (SADS) and Q-LES-Q. Using multivariate analysis, Ozer and colleagues found that none of the historical variables (including age at first episode, number of previous depressive/manic episodes, duration of illness, number of hospitalizations, age at first hospitalization, or number of symptoms during first episode) were predictive of mean Q-LES-Q scores. Of the current symptoms assessed, only the depression subscale of the SADS interview significantly predicted lower Q-LES- Q scores, accounting for only 13% of the observed variance. When the patient population was subdivided into three groups (low, moderate and high) according to severity of SADS depression scores, mean Q-LES-Q scores were 39%, 38% and 35%, respectively. In comparison, mean Q-LES-Q scores have been reported to be 42% in hospitalized psychiatric inpatients58, 42% in outpatients with MDD59, 44% in patients with seasonal affective disorder (SAD)60, 53% in patients with chronic MDD61, and 83% in the general One potential problem with existing research addressing HRQOL in euthymic patients with BD concerns the differing research methodologies used to determine euthymia. Whereas clinical trials of maintenance treatment interventions for BD tend to apply rigorous determinants of euthymia on the basis of standardized psychiatric rating scales such as the Young Mania Rating Scale (YMRS)62 and Ham-D, many of the studies in the HRQOL arena have applied less stringent criteria, such as clinician impression of functioning. Given that even mild residual symptoms (particularly of depression) appear to be strongly associated with impaired QoL, it is important for future research to use more sophisticated and thorough assessments of residual symptomatology and more In summary, a number of studies have attended to the QoL implications of the different syndromes that fall under the rubric of BD. In terms of the degree of QoL impact, there is evidence to suggest that both the depressive and hypo/manic syndromes are associated with reduced QoL relative to euthymic states. However, further investigation of QoL in euthymic states within BD highlights the importance of considering the course by which the patient arrived at euthymia (past episodes of depression, hypomania versus mania) and the current features of the euthymic state (especially the quasi-ubiquitous presence of depressive symptoms). Bipolar disorder is a heterogeneous condition both between and within individuals: not surprisingly, then, the QoL consequences of BD are measurably impacted by both current state and individual course of the disorder. QoL as an outcome measure in BD treatment research In a review of clinical trials published prior to 2002, Revicki and colleagues11 identified three that had included HRQOL assessments. In our more recent literature review12 that included studies published prior to 2005, we identified eight studies that had incorporated a QoL outcome measure: five clinical trials that examined pharmacological interventions for BD and three studies that assessed non-pharmacological interventions. At the time of writing1, a Medline search reveals that results from two further large clinical trials have been published that included a HRQOL assessment63;64. The following section will provide an overview of this nascent body of research. Namjoshi and colleagues from a Lilly research group have conducted a series of studies examining the efficacy of olanzapine as a treatment intervention for BD65-69. In the first of these, Namjoshi et al., (2002)65 evaluated the impact of acute (3-week) treatment with olanzapine or placebo and long-term (49-week open label) treatment of BD type I (manic/mixed). During the acute-phase treatment period, treatment-related 1 June 2006 improvements in HRQOL were only apparent for the physical functioning domain of the SF-36. Improvement in other aspects of HRQOL (specifically, bodily pain, vitality, general health and social functioning) occurred during the open label treatment period, indicating that olanzapine may have a relatively rapid effect in terms of improving physical functioning in patients with acute mania, but other HRQOL domains may be Shi and colleagues compared the treatment effects of olanzapine and haloperidol in patients with acute mania (N=453)66,67. During the acute treatment phase of the study, significantly greater improvement in five of the SF-36 domains (general health, physical functioning, role limitations – physical, social functioning and vitality) was apparent in the olanzapine group. Superiority of olanzapine over haloperidol persisted over the study’s 6-week continuation phase, during which time improvements in work and household functioning also became apparent. Other research has examined the effects of adding olanzapine to lithium or valproate in patients with BD (N=224)68. Combination therapy was associated with better outcome in several Quality of Life Interview (QOLI69) domains compared to lithium or valproate monotherapy. The SF-36 and Quality of Life in Depression Scale (QLDS70) have been used in a study comparing the benefits of olanzapine alone versus an olanzapine-fluoxetine combination or placebo71. Compared with placebo, patients who received olanzapine showed greater improvement at 8 weeks in SF-36 mental health summary scores, and in mental health, role-emotional and social functioning domain scores. The combination group fared significantly better in terms of HRQOL improvement than the olanzapine-alone group, showing improvement in five of the SF-36 domain scores and in QLDS total score. The Q-LES-Q has been administered at baseline (hospital discharge), 6 and 12 weeks in a comparison of divalproex sodium and olanzapine in the treatment of acute mania72. No significant treatment effects were detected in Q-LES-Q scores in the study, although only 52 (43%) of the 120 patients randomized to either divalproex or olanzapine completed the QoL instrument. The authors reported an association between weight gain being reported as an adverse event and poorer change scores in the physical, leisure, and general activities domains of the Q-LES-Q at 6 weeks (but not at 12 weeks). Negative correlations were reported between increased weight (at 6 weeks) and overall life satisfaction, physical health, mood, general activities and satisfaction with medication on the Q-LES-Q. In a more recent study, Revicki and colleagues (2005)73 reported on data from a pragmatic, randomized clinical trial of divalproex versus lithium in 201 patients hospitalized for a BD type I manic or mixed episode. Life quality was assessed via the SF-36 at 1, 3, 6, 9 and 12 months, with no significant differences emerging between intervention groups in HRQOL outcome. An analysis of HRQOL in patients who continued mood stabilizing therapy beyond 3 months versus those who did not found no significant between group differences in SF-36 physical functioning scores, although there was a non-significant trend towards improved mental functioning scores in the continuation group at the 6 and 12 month assessment points. Finally, some initial HRQOL data has recently been published from the BOLDER study74. BOLDER is a large, 8-week, multicenter, double-blind, randomized, fixed-dose, placebo-controlled monotherapy study of quetiapine (600 or 300 mg/day) versus placebo in outpatients with DSM-IV bipolar I or bipolar II disorder, with or without rapid cycling, in a major depressive episode. The study administered the 16-item short form of the Q- LES-Q at baseline, weeks 4 and 8 to assess QoL, finding 12 and 11 point increase in Q- LES-Q scores at last assessment in the high and low dose groups respectively, compared to a 7-point change in the placebo group (i.e. significantly greater improvement in QoL in both groups after 8 weeks of treatment compared to placebo). These data are encouraging; elsewhere, the Q-LES-Q has been used to assess outcome in the treatment of dysthymia with sertraline, imipramine or placebo, where after 12 weeks of treatment an 8-point change was reported in the two active intervention arms, with a 4-point change in the placebo arm75. In another study of the treatment of chronic depression with either sertraline or imipramine, a 9-point change was seen after 4 weeks of treatment, and a 14- point change after 12 weeks76. The 12-point change in Q-LES-Q score observed in the BOLDER study is in keeping, then, with outcome data from other studies in unipolar depression, indicating that QoL in patients with BD is also amenable to relatively rapid change, even when study inclusion criteria are broadened to include greater diagnostic heterogeneity, such as rapid cycling and BD type II patients. It will be interesting to see the impact of treatments upon long-term QoL outcomes in the BOLDER trial, and other well-designed pharmacological intervention studies. Although pharmacology forms the bedrock of treatment for BD77, there is a clear need for other treatment modalities that augment the effects of medication in this complex psychiatric condition. Over the last decade, we have seen an upsurge of interest in examining the role of psychological interventions as an adjunct to the pharmacological treatment of BD78;79. Most of this research has concentrated upon examining the efficacy of psychotherapy (in a variety of guises) as a treatment intervention. Several multi-modal psychotherapeutic interventions for BD have been developed, such as Family Focused Treatment (FFT)80;81, Interpersonal and Social Rhythm Therapy82 and Cognitive- Behavioural Therapy (CBT)83. Surprisingly few studies of psychosocial treatment interventions for BD, however, have used QoL measures to assess outcome. In one study, Patelis-Siotis and colleagues84 used the SF-36 in a feasibility study of group cognitive behavior therapy (CBT) in patients with BD. Although baseline SF-36 data was available for 42 patients, pre and post intervention data was only available for a proportion of participants (N=22) as completion of the QoL questionnaires was optional. Nevertheless, SF-36 vitality and role emotional scores were significantly improved following CBT, with an accompanying trend towards improved social functioning. A more recent study examined the effects of providing three sessions of psychoeducation (PE) about lithium treatment to patients (N=26) with BD85. In addition to assessing the effects of PE upon medication adherence, the authors examined the impact of the intervention upon QoL, as measured by the WHOQOL-BREF. Following PE, patients in the intervention arm of the study showed significant improvement in two of the WHOQOL-BREF’s four domains (physical health and social functioning) and in overall perceived health. Patients in the control arm of the study, in comparison, showed no significant changes in their perceived QoL. The results of the study indicate that even relatively brief psychosocial treatment interventions can have a positive impact upon HRQOL – a finding supported by our own non-randomised study of the effects of PE upon Q-LES-Q scores in euthymic or mildly symptomatic outpatients (N=57) with BD In summary, research using QoL as an outcome measure attests to the fact that QoL measures provide additional important information over that provided by symptom measures. Although based on a small number of studies, there is some evidence that QoL improves relatively slowly after treatment (perhaps paralleling functional recovery). Emerging research into adjunctive psychosocial treatments suggests that even relatively brief interventions may have effects on QoL. Over the past decade, we have seen an upsurge of interest in examining QoL in BD. This emerging body of research has provided some initial evidence that it is both feasible and important to assess life quality in this complex psychiatric condition. Our own qualitative data garnered from in-depth interviews with patients diagnosed with BD suggests that QoL is a meaningful indicator of well-being in this patient population87. Importantly, when measuring outcome in response to treatment, QoL assessment scales hold the potential to provide information over and above that provided by traditional outcome measures. However, this chapter has also served to illustrate that the existing literature on QoL in BD is relatively immature, lagging well behind the study of QoL in relation to other psychiatric conditions such as schizophrenia. In particular, there is no current consensus about which QoL instruments are most appropriate for use in this patient population, very little replication of core findings across research studies, and as yet there is no disorder-specific measure to assess QoL in patients with BD. How, then, should the field progress? At a theoretical level, it is useful to draw direction from the substantial research into QoL in other psychiatric disorders. Ritsner’s Distress/Protection Vulnerability model, for example, is based on a number of studies showing that immediate illness factors are only one aspect of the QoL picture. His model is framed around two groups of factors – distress (e.g., negative symptoms of schizophrenia) and protective (e.g., social support). Most importantly, perhaps, his model parallels the prominent diathesis-stress model of psychopathology, in positing a primary role for stable temperamental traits that act as vulnerabilities (e.g., neuroticism, emotion-focused coping), or protective factors (e.g., extraversion, high self-esteem) for QoL. He suggests, therefore, that QoL is not usefully seen as an outcome of illness, but as a stable feature of the person that is impacted by illness (as well as other features of the environment). The evidence he presents to support this framing of QoL is the generally low correlations between illness-related variables and QoL, the absence of progressive alteration of QoL over time in patients with serious mental disorders, and the presence of QoL impairments in patients who ultimately will, but are not currently, exhibiting signs In Chapter 1 of this collection, Ritsner also discusses the potential interface between neurobiological and quality of life research. Numerous neurobiological factors may conceivably be related to QoL in BD. These include genetic polymorphisms, structural brain abnormalities (e.g., white matter lesions), hypothalamic-pituitary adrenal (HPA) axis function and neurocognition. Although little work has been done relating these factors to QoL in BD there is particular interest in the latter two factors at present. HPA axis function is now understood to be abnormal in patients with BD and it has also been shown that this abnormality persists into euthymia88. In cancer patients pilot studies have shown enhanced QoL and decreased stress symptoms with possibly beneficial changes in HPA axis functioning after stress reduction programs89. We await the application of such an approach to BD with interest. Neurocognitive impairment has also been described in euthymic BD, including widespread impairments in executive function90. Such deficits may clearly contribute to impaired QoL particularly in the euthymic phase and indeed are commonly a source of complaint in patients with BD. However the temporal relationship between HPA axis function, cognition and QoL in BD remains to be fully established and is an area of active research at present. Ritsner further highlights that, in contrast to QoL research in schizophrenia, the BD QoL field is still driven by a strongly medical model conception, with the illness itself dominating explanations of QoL. No studies in QoL of BD have yet measured the psychological variables (specifically, personality, coping style, cognitive style) that are components of Ritsner’s more holistic model of HRQL. In a fundamental way, QoL research in the field of BD still starts with the disorder, while QoL research as championed by Ritsner starts with the person. Following the lead of schizophrenia research, future research into QoL in BD should include important “third variables”, such as measures of normal personality, which are almost certain to moderate and/or mediate the effect of life events (including mental disorder) on QoL. At an empirical level, the widespread adoption of a disease-specific QoL instrument for BD is critical for the advancement of the field. Although some existing QoL instruments are likely to capture key aspects of QoL in this condition, they may be less sensitive to some of the more unique aspects of this complex psychiatric disorder. QoL scales developed for patients with unipolar depression (such as the QLDS) or for unspecified psychiatric populations (such as the Q-LES-Q) will overlap in content somewhat with a scale developed specifically for patients with BD. However, there are likely to be some bipolar symptoms (for example, financial indiscretion, hypersexuality, interpersonal behaviour when hypo/manic) that have a unique impact upon QoL that existing scales do not tap. Indeed, part of the rationale for developing disorder-specific measures lies in the understanding that such scales can be more sensitive to change in response to treatment than their more generic counterparts91. However, the validity of disorder-specific scales should be maximized through thorough consultation with individuals with the condition themselves, a core part of the development of our own disorder specific scale for BD, the Quality of Life in Bipolar Disorder (QoL.BD). In order to generate an initial set of items for the QoL.BD, we performed a series of in- depth qualitative interviews, aiming a priori to garner the viewpoints of a fairly representative sample of people diagnosed with the disorder (for example, BD type I and II, low functioning versus high functioning individuals). We also aimed to interview caregivers of people severely affected by BD (in the belief that the individuals themselves might be unable to undergo a lengthy qualitative interview), healthcare workers with expertise in BD (in the belief that they would be able to describe the impact of BD upon QoL at a broader group level) and international experts in the BD research. In total, we conducted 52 interviews with people with BD (N=35), their caregivers (N=5) and healthcare professionals or experts (N=12) identified by both convenience and purposive sampling. Clinical characteristics of the affected sample ranged widely between individuals who had been clinically stable for several years through to inpatients who were recovering from a severe episode of depression or mania. The results of this initial study provided some interesting initial data concerning the impact of BD upon QoL87;93. The majority of the affected individuals we interviewed described how the condition had had a profoundly negative effect upon their QoL, often having serious and enduring effects on their ability to have good education, meaningful vocation, financial independence and healthy social and intimate relationships. Having said this, we also interviewed a number of people who were functioning exceptionally well despite their diagnosis; a minority of people even espoused the view that their condition had opened up new doors of opportunity for them, for example, in terms of positively changing their career paths or social networks. On the whole, however, even these individuals described having undergone several years of hardship and adjustment before getting ‘back on track’. Respondents described a wide variety of factors that influenced their QoL, including but not limited to: side effects of medications, occupation, education, physical functioning, environment, healthcare factors, leisure activities, routine and sexuality. Some of the factors discussed (for example, independence, stigma and disclosure, identity, and spirituality) are not frequently examined in relation to QoL; yet, they appear to have a significant impact upon peoples’ ability to live their lives to the full in the context of BD. We are continuing to develop the QoL.BD in close consultation with both individuals with BD and healthcare professionals in the hope of maximizing the validity of the resulting scale. In terms of empirical findings to date, and recognizing the limitations described above, it a) QoL is seriously affected in BD. The QoL impacts of BD might be more serious than seen in other mood and anxiety disorders (except perhaps double depression), and may even be comparable to the consequences of the deteriorating b) Consistent with recent thinking and epidemiological data, there is little support for the notion that there are states of BD that have purely positive QoL implications. Both euthymia and mania are commonly flavoured with depression, and the depressed states and depressive symptoms of BD are clearly negative c) Consistent with an emphasis on broader outcome measures in psychiatry generally, and a more patient-centred perspective, the small number of studies with relevant data have found that symptom variables and QoL variables respond differently to both pharmacotherapy and psychotherapy. Consistent with the definition of QoL, there is some evidence that effective treatment is measured d) Future QoL research in BD is likely to benefit from adopting a broader focus, and including measures of the range of variables that undoubtedly interact with life events (including disorder) to produce individual differences in QoL. e) Pace the prescription above to be less disorder-centric, the field also requires a disorder-specific measure that is sensitive to the range of quality of life impacts that result from the interaction between predispositions (both vulnerabilities and strengths), positive and negative features of the present environment and the specific symptoms of BD. Given the immature state of the literature, such an instrument is best developed “bottom-up”, with the raw data being descriptions of QoL deriving from patients, carers and relevant others. The challenge of investigating QoL in BD is sizeable but worthwhile. 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