Correlates of subjective and objective burden among caregivers of patients with bipolar disorder

Objective: We examined the relationship between mood symptoms and episodes in patients with bipolar disorder and burden reported by their primary caregivers. Method: Data on subjective and objective burden reported by 500 primary caregivers for 500 patients with bipolar disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP‐BD) were collected using semistructured interviews. Patient data were collected prospectively over 1 year. The relationship between patient course and subsequent caregiver burden was examined. Results: Episodes of patient depression, but not mood elevation, were associated with greater objective and subjective caregiver burden. Burden was associated with fewer patient days well over the previous year. Patient depression was associated with caregiver burden even after controlling for days well. Conclusion: Patient depression, after accounting for chronicity of symptoms, independently predicts caregiver burden. This study underscores the important impact of bipolar depression on those most closely involved with those whom it affects.     

Factors associated with stigma among caregivers of patients with bipolar disorder in the STEP-BD study

OBJECTIVE: Little is known about the factors contributing to mental illness stigma among caregivers of people with bipolar disorder. METHODS: A total of 500 caregivers of patients participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study were interviewed in a cross-sectional design on measures of stigma, mood, burden, and coping. Relatives and friends with bipolar disorder were assessed on measures of diagnosis and clinical status, determined by a days-well measure derived from psychiatrist ratings of DSM-IV episode status. Because patients' clinical status varied widely, separate models were run for patients who were euthymic for at least three-fourths of the past year (well group) and for those who met criteria for an affective episode for at least one-fourth of the previous year (unwell group). Stepwise multiple regression was used to identify patient, illness, and caregiver characteristics associated with caregiver stigma. RESULTS: In the unwell group, greater mental illness stigma was associated with bipolar I (versus II) disorder, less social support for the caregiver, fewer caregiver social interactions, and being a caregiver of Hispanic descent. In the well group, greater stigma was associated with being a caregiver who is the adult child of a parent with bipolar disorder, who has a college education, who has fewer social interactions, and who cares for a female bipolar patient. CONCLUSIONS: Mental illness stigma was found to be prevalent among caregivers of persons with bipolar disorder who have active symptoms as well as for caregivers of those who have remitted symptoms. Stigma is typically associated with factors identifying patients as "different" during symptomatic periods. Research is needed to understand how the stigma experienced by caregivers during stable phases of illness differs from the stigma experienced during patients' illness states.     

Suicidal ideation and depressive symptoms among bipolar patients as predictors of the health and well‐being of caregivers

Objectives: Few studies have addressed the physical and mental health effects of caring for a family member with bipolar disorder. This study examined whether caregivers’ health is associated with changes in suicidal ideation and depressive symptoms among bipolar patients observed over one year. Methods: Patients (N = 500) participating in the Systematic Treatment Enhancement Program for Bipolar Disorder and their primary caregivers (N = 500, including 188 parental and 182 spousal caregivers) were evaluated for up to one year as part of a naturalistic observational study. Caregivers’ perceptions of their own physical health were evaluated using the general health scale from the Medical Outcomes Study 36‐item Short‐Form Health Survey. Caregivers’ depression was evaluated using the Center for Epidemiological Studies of Depression Scale. Results: Caregivers of patients who had increasing suicidal ideation over time reported worsening health over time compared to caregivers of patients whose suicidal ideation decreased or stayed the same. Caregivers of patients who had more suicidal ideation and depressive symptoms reported more depressed mood over a one‐year reporting period than caregivers of patients with less suicidal ideation or depression. The pattern of findings was consistent across parent caregivers and spousal caregivers. Conclusions: Caregivers, rightly concerned about patients becoming suicidal or depressed, may try to care for the patient at the expense of their own health and well‐being. Treatments that focus on the health of caregivers must be developed and tested.     

Illness burden and medical comorbidity in the Systematic Treatment Enhancement Program for Bipolar Disorder

Magalhães PV, Kapczinski F, Nierenberg AA, Deckersbach T, Weisinger D, Dodd S, Berk M. Illness burden and medical comorbidity in the Systematic Treatment Enhancement Program for Bipolar Disorder. Objective: Coexisting chronic medical conditions are common in bipolar disorder. Here, we report the prevalence and correlates of medical comorbidity in patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP‐BD). We were particularly interested in associations between variables reflecting illness chronicity and burden with comorbid medical conditions. Method: We used intake data from the open‐label component of the STEP‐BD. History of medical comorbidity was obtained from the affective disorders evaluation, and its presence was the outcome of interest. The sample size in analyses varied from 3399 to 3534. We used multiple Poisson regression to obtain prevalence ratios. Results: The prevalence of any medical comorbidity in the sample was 58.8%. In addition to demographic variable, several clinical characteristics were associated with the frequency of medical comorbidity. Having more than 10 previous mood episodes, childhood onset, smoking, lifetime comorbidity with anxiety, and substance use disorders were independently associated with having a medical comorbidity in the final multivariate model. Conclusion: The results presented here reveal strong associations between variables related to illness chronicity and medical burden in bipolar disorder. This lends further support to recent multidimensional models incorporating medical morbidity as a core feature of bipolar disorder.     

Strategies for improving treatment of bipolar disorder: integration of measurement and management

OBJECTIVE: Bipolar disorder is a common and complex condition associated with high rates of disability and high health care costs. The aim of this article is to provide an overview of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). METHOD: The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to an NIMH request for proposals to study the effectiveness of treatments for Bipolar Disorder. Aspects of this program have been adapted and enriched for presentation in this paper. RESULT: Designed for implementation in routine practice across a variety of settings, STEP-BD offers a disease management program in which standardized assessments are linked to critical decision points in clinical management pathways. CONCLUSION: This paper describes strategies used in STEP-BD to improve the treatment of Bipolar disorder: a simple conceptual model, which integrates assessments and management, and several specialized elements, used in the STEP-BD assessment package.     

Use of mental health and primary care services by caregivers of patients with bipolar disorder: a preliminary study

OBJECTIVES: Caring for a relative with schizophrenia or dementia has been associated with reports of caregiver burden, symptoms of anxiety, depression, poor self-rated health, and elevated health service use; however, comparable data for caregivers of relatives with bipolar disorder are lacking. This study reports preliminary data on the health, psychological distress and health service use of caregivers of patients with bipolar disorder. It additionally evaluates the relationship of the level of burden caregivers report experiencing to their use of health services, controlling for level of psychological distress and health status. METHODS: Subjects were primary caregivers of 264 patients with Research Diagnostic Criteria-diagnosed bipolar disorder and their bipolar relatives. Caregiver mental health and primary care service use were assessed retrospectively for the 7-month period prior to inpatient or outpatient admission of the bipolar patient. Caregiver depression, anxiety, medical conditions and patient symptomatology were assessed as well. RESULTS: Hierarchical logistic regression analysis demonstrated that caregiver burden significantly increased the likelihood of mental health service use (OR = 13.53, p < 0.001) even after controlling for caregiver psychological distress and medical conditions, while anxiety and depression level, but not burden, significantly increased the likelihood of primary care service use, controlling for other variables (OR = 1.72, p = 0.02). CONCLUSIONS: Burdens experienced by family caregivers appear to increase use of health services, and presumably cost, and may be reduced by psychosocial intervention.     

Revisiting depressive-prone bipolar disorder: polarity of initial mood episode and disease course among bipolar I systematic treatment enhancement program for bipolar disorder participants.

BACKGROUND: We examined the hypothesis that a first depressive rather than manic episode in bipolar disorder might herald a subsequent course notable for greater burden of depressive symptoms. METHODS: We analyzed retrospective data on the polarity of first mood episode obtained from 704 bipolar I subjects entering the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. Subjects with an initial manic or depressive episode and those in whom both poles occurred within the same year were compared. RESULTS: Depressive-onset bipolar disorder was more common in women and those with earlier onset of illness. Adjusting for these differences, it was significantly associated with more lifetime depressive episodes and a greater proportion of time with depression and anxiety in the year prior to study entry. CONCLUSIONS: Polarity of first mood episode may be useful in distinguishing subsets of bipolar patients at risk for a more chronic course.     

Phenomenology of rapid-cycling bipolar disorder: data from the first 500 participants in the Systematic Treatment Enhancement Program

OBJECTIVE: This study compared demographic and phenomenological variables between bipolar patients with and without rapid cycling as a function of bipolar I versus bipolar II status. METHOD: The authors examined demographic, historical, and symptomatic features of patients with and without rapid cycling in a cross-sectional study of the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health designed to evaluate the longitudinal outcome of patients with bipolar disorder. RESULTS: Rapid-cycling bipolar disorder occurred in 20% of the study group. Rapid-cycling patients were more likely to be women, although the effect was somewhat more pronounced among bipolar I patients than bipolar II patients. In addition, rapid-cycling bipolar patients experienced onset of their illness at a younger age, were more often depressed at study entry, and had poorer global functioning in the year before study entry than nonrapid-cycling patients. Rapid-cycling patients also experienced a significantly greater number of depressive and hypomanic/manic episodes in the prior year. A lifetime history of psychosis did not distinguish between rapid and nonrapid-cycling patients, although bipolar I patients were more likely to have experienced psychosis than bipolar II patients. CONCLUSIONS: Patients with rapid-cycling bipolar disorder demonstrate a greater severity of illness than nonrapid-cycling patients on a number of clinical measures. This study highlights the need to refine treatments for rapid cycling to reduce the overall morbidity and mortality of patients with this illness course modifier.     

Rumination,gender, and depressive symptoms associated with caregiving strain in bipolar disorder

Perlick DA, Gonzalez J, Michael L, Huth M, Culver J, Kaczynski R. Calabrese J. Miklowitz DJ. Rumination, gender, and depressive symptoms associated with caregiving strain in bipolar disorder. Objective: To evaluate the associations between indices of caregiving strain, ruminative style, depressive symptoms, and gender among family members of patients with bipolar disorder. Method: One hundred and fifty primary caregivers of patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP‐BD) participated in a cross‐sectional study to evaluate the role of ruminative style in maintaining depressive symptoms associated with caregiving strain. Patient lifetime diagnosis and current episode status were evaluated by the Affective Disorder Evaluation and the Clinical Monitoring Form. Caregivers were evaluated within 30 days of the patient on measures of family strain, depressive symptoms, and ruminative style. Results: Men and women did not differ on depression, caregiver strain, or ruminative style scores. Scores suggest an overall mild level of depression and moderate caregiver strain for the sample. Greater caregiver strain was significantly associated (P < 0.05) with rumination and level of depressive symptoms, controlling for patient clinical status and demographic variables. Rumination reduced the apparent association between strain and depression by nearly half. Gender was not significantly associated with depression or rumination. Conclusion: Rumination helps explain depressive symptoms experienced by both male and female caregivers of patients with bipolar disorder. Interventions for caregivers targeted at decreasing rumination should be considered.     

Family‐focused treatment for caregivers of patients with bipolar disorder

Perlick DA, Miklowitz DJ, Lopez N, Chou J, Kalvin C, Adzhiashvili V, Aronson A. Family‐focused treatment for caregivers of patients with bipolar disorder.
Bipolar Disord 2010: 12: 627–637. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Family members of patients with bipolar disorder experience high rates of subjective and objective burden which place them at risk for adverse physical health and mental health outcomes. We present preliminary efficacy data from a novel variation of Family Focused Treatment [Miklowitz DJ. Bipolar Disorder: A Family‐Focused Treatment Approach (2^nd ed.). New York: The Guilford Press, 2008] that aimed to reduce symptoms of bipolar disorder by working with caregivers to enhance illness management skills and self‐care. Methods: The primary family caregivers of 46 patients with bipolar I (n = 40) or II (n = 6) disorder, diagnosed by the Structured Clinical Interview for DSM‐IV Axis I Disorders, were assigned randomly to receive either: (i) a 12–15‐session family‐focused, cognitive‐behavioral intervention designed to provide the caregiver with skills for managing the relative’s illness, attaining self‐care goals, and reducing strain, depression, and health risk behavior [Family‐Focused Treatment‐Health Promoting Intervention (FFT‐HPI)]; or (ii) an 8‐ to 12‐session health education (HE) intervention delivered via videotapes. We assessed patients pre‐ and post‐treatment on levels of depression and mania and caregivers on levels of burden, health behavior, and coping. Results: Randomization to FFT‐HPI was associated with significant decreases in caregiver depressive symptoms and health risk behavior. Greater reductions in depressive symptoms among patients were also observed in the FFT‐HPI group. Reduction in patients’ depression was partially mediated by reductions in caregivers’ depression levels. Decreases in caregivers’ depression were partially mediated by reductions in caregivers’ levels of avoidance coping. Conclusions: Families coping with bipolar disorder may benefit from family interventions as a result of changes in the caregivers’ ability to manage stress and regulate their moods, even when the patient is not available for treatment.     

Stability of symptoms across major depressive episodes in bipolar disorder

Objective: Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated. Methods: We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow‐up. Across‐episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression. Results: A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes. Conclusion: While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.     

Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

OBJECTIVE: The authors provide a detailed perspective on the correlates of comorbid anxiety in a large, well-characterized sample of bipolar disorder patients. METHOD: Anxiety and its correlates were examined in a cross-sectional sample from the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health designed to evaluate the longitudinal outcome of patients with bipolar disorder. RESULTS: Lifetime comorbid anxiety disorders were common, occurring in over one-half of the sample, and were associated with younger age at onset, decreased likelihood of recovery, poorer role functioning and quality of life, less time euthymic, and greater likelihood of suicide attempts. Although substance abuse disorders were particularly prevalent among patients with anxiety disorders, comorbid anxiety appeared to exert an independent, deleterious effect on functioning, including history of suicide attempts (odds ratio=2.45, 95% CI=1.4-4.2). CONCLUSIONS: An independent association of comorbid anxiety with greater severity and impairment in bipolar disorder patients was demonstrated, highlighting the need for greater clinical attention to anxiety in this population, particularly for enhanced clinical monitoring of suicidality. In addition, it is important to determine whether effective treatment of anxiety symptoms can lessen bipolar disorder severity, improve response to treatment of manic or depressive symptoms, or reduce suicidality.     

Retrospective age at onset of bipolar disorder and outcome during two-year follow-up: results from the STEP-BD study

Objective:  Symptoms of bipolar disorder are increasingly recognized among children and adolescents, but little is known about the course of bipolar disorder among adults who experience childhood onset of symptoms.
Methods:  We examined prospective outcomes during up to two years of naturalistic treatment among 3,658 adult bipolar I and II outpatients participating in a multicenter clinical effectiveness study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Age at illness onset was identified retrospectively by clinician assessment at study entry.
Results:  Compared to patients with onset of mood symptoms after age 18 years (n = 1,187), those with onset before age 13 years (n = 1,068) experienced earlier recurrence of mood episodes after initial remission, fewer days of euthymia, and greater impairment in functioning and quality of life over the two-year follow-up. Outcomes for those with onset between age 13 and 18 years (n = 1,403) were generally intermediate between these two groups.
Conclusion:  Consistent with previous reports in smaller cohorts, adults with retrospectively obtained early-onset bipolar disorder appear to be at greater risk for recurrence, chronicity of mood symptoms, and functional impairment during prospective observation.     

Aims and results of the NIMH systematic treatment enhancement program for bipolar disorder (STEP-BD)

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.     

Complicated grief and its correlates in patients with bipolar disorder

BACKGROUND: While the recent loss of a loved one has been identified as a risk factor for suicide in patients with bipolar disorder, and complicated grief (CG) has been associated with elevated rates of suicidality compared with loss without CG, little is known about the frequency or impact of CG in bipolar disorder. We investigated the frequency and implications of loss of loved ones in an ongoing study of bipolar disorder. METHOD: We conducted a survey of 120 patients with well-characterized DSM-IV bipolar disorder participating in Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a large naturalistic study, in order to identify frequency of loss and to examine the presence of CG and its clinical correlates. Survey data were gathered from October 2003 to March 2004. RESULTS: A lifetime history of a significant loss was reported by 86% (103/120) of participants; 24.3% (25/103) of those met criteria for CG, defined as a score > or = 25 on the Inventory of Complicated Grief (ICG), with a mean +/- SD ICG score of 33.7 +/- 6.9. The presence of CG was associated with elevated rates of panic disorder and alcohol abuse comorbidity, as well as other measures of panic symptoms and phobic avoidance. CG was also associated with a higher rate of lifetime suicide attempts, greater functional impairment, and poorer social support. CONCLUSION: Our findings suggest the presence of a substantial burden of comorbid grief-related illness and impairment in patients with bipolar disorder. Further research is needed to understand the overlap of anxiety disorders and phobic avoidance in bipolar patients with complicated grief.     

Are antidepressants associated with new-onset suicidality in bipolar disorder? A prospective study of participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

OBJECTIVE: Depressive episodes are common in bipolar disorder, and the disorder is characterized by high suicide rates. Recent analyses indicate a possible association of antidepressant treatment and suicidality in children and adults with depressive or anxiety disorders. However, few data are available to inform the suicidality risk assessment of antidepressant use specifically in bipolar disorder. METHOD: Of the first 2000 participants followed for 18 months in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 425 experienced a prospectively observed, new-onset major depressive episode without initial suicidal ideation. Standardized ratings of suicidality and antidepressant exposure at index depressive episode and next evaluation were used to investigate the primary hypothesis that new-onset suicidality was associated with increased antidepressant exposure (antidepressant initiation or dose increase). Secondary analysis investigated correlates of new-onset suicidality and antidepressant exposure. Data were collected from November 8, 1999, to April 24, 2002. RESULTS: Twenty-four participants (5.6%) developed new-onset suicidality at follow-up, including 2 suicide attempts. There was no association of new-onset suicidality with increased antidepressant exposure or any change in antidepressant exposure, and no association with initiation of antidepressant treatment. New-onset suicidality was associated with neuroticism, prior attempt, and higher depressive or manic symptom ratings at index episode. Increased antidepressant exposure was negatively associated with higher manic symptom rating at index episode; control for this sole empirically identified confound did not alter the primary results. CONCLUSIONS: Although careful monitoring for suicidality is always warranted in bipolar disorder, this cohort study provides no evidence that increased antidepressant exposure is associated with new-onset suicidality in this already high-risk population. Correlates of both suicidality and antidepressant exposure indicate directions for further research.     

Lamotrigine treatment of bipolar disorder: data from the first 500 patients in STEP-BD

Objective:  To describe the frequency and correlates of lamotrigine therapy among the first 500 patients enrolled into the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.
Method:  Systematic recording of psychiatric history and medication data at intake into the STEP-BD project.
Results:  Of the participants with bipolar disorder type I or II (n = 483), 77 (15.4%) were currently taking lamotrigine (mean dose: 258.12 mg/day) and 52 (10.4%) reported prior lamotrigine use. The groups were comparable with regard to duration of illness and mood state at study entry. Compared with participants who had never taken lamotrigine, those currently treated with lamotrigine were significantly more likely to have a prior history of rapid cycling (62.5% vs. 43.1%; p < 0.01) and an antidepressant-induced switch to (hypo)mania (49.3% vs. 33.3%; p < 0.01). In contrast, only 16.9% of lamotrigine-treated participants were taking an antidepressant at study intake, as compared with 29.1% of participants with no history of lamotrigine therapy (p < 0.03).
Conclusions:  While noting the limitations of a cross-sectional assessment, these data suggest that lamotrigine therapy was commonly used in these academic centers for patients with bipolar disorder several years before it was recommended in the American Psychiatric Association practice guidelines, particularly in patients with a history of rapid cycling or antidepressant-induced mania.     

Comparisons of perceived quality of life across clinical states in bipolar disorder: data from the first 2000 Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) participants

BACKGROUND: Evidence indicates that quality of life is subnormal in patients with bipolar disorder and that it differs across mood states. However, the pattern of specific deficits has not been well studied, and the role of potential confounders has received no attention. METHOD: We investigated the self-reported quality of life, Medical Outcomes Study 36-Item Short Form (SF-36), and Quality of Life Enjoyment and Satisfaction (QLESQ) at baseline across the clinical states of the first 2000 participants enrolled in Systematic Treatment Enhancement Program for Bipolar Disorder. RESULTS: Bivariate analyses indicated significant differences across mood state, with depressive symptoms predicting lower SF-36 mental and physical scores and QLESQ overall score. However, adjustment for relevant clinical and demographic variables erased the difference in the SF-36 physical score. Notably, covariate adjustment removed the apparently "supranormal" SF-36 mental and QLESQ scores among those with mania/hypomania compared with those euthymic. CONCLUSION: Depressive symptoms are a strong predictor of quality of life, yet covariate adjustment has an impact as well. Clinically, this indicates the need for addressing these factors if quality of life is to be maximized. Such factors should also be taken into account in future naturalistic and clinical trials research on quality of life in bipolar disorder.