Background
Bipolar disorder is a chronic and debilitating mental illness, characterized by recurrent mood fluctuations between periods of depressive and manic symptoms, with an estimated lifetime prevalence of 1.0 % [
1,
2] and is the 12
th leading cause of disability worldwide [
3]. Frequent episodes of depression represent the most common symptomatic state in individuals with bipolar disorder [
4,
5], where depressive episodes are associated with a greater negative impact on social, occupational, and general functioning than episodes of mania [
4,
6‐
8]. Consequently, health-related quality of life (HRQoL) is also highly compromised in individuals with bipolar depression, where patients with bipolar depression report even greater worsening in their HRQoL and other indicators of functioning than patients with other mood disorders or mental illnesses [
4,
9,
10].
Traditionally, clinical trials of treatment efficacy in patients with bipolar depression have focused on symptom remission (using the Diagnostic and Statistical Manual-IV-TR [DSM-IV-TR] or clinician-reported outcome assessments such as the Montgomery-Asberg Depression Rating Scale [MADRS] score ≤10 to signify remission status [
11]). Increasingly, the ability of the patient to perform activities of daily living, engage and nurture social relationships, and function independently are being considered when evaluating treatment efficacy [
4,
12,
13], as the burden of bipolar depression can persist even in patients considered to be in symptomatic remission [
14,
15]. Given this, HRQoL assessments can provide an additional indicator of improvement in areas valued by the patient beyond symptomatic improvement [
16].
Relatively few clinical trials have incorporated patient-reported outcome (PRO) measures to assess improvement in HRQoL in drug registration trials, although the number of studies incorporating these tools is increasing given the increasingly holistic view of improving patient’s lives in treating chronic illnesses such as bipolar disorder [
4,
17]. A literature review conducted by Revicki et al. in 2005 suggested that HRQoL may improve as a result of treatment, although these studies were limited to a short follow-up duration and small sample size [
18]. More recently, IsHak et al. [
19] expanded on previous reviews to address if various forms of treatment (e.g., drug therapy, behavioral therapy) have an impact on bipolar disorder, demonstrating that several drug and psychotherapeutic treatment regimens were associated with improved HRQoL in this patient population.
Only two medications were approved for the treatment of acute bipolar depression as a monotherapy in the United States until 2013 (e.g., combination of olanzapine-fluoxetine and quetiapine) [
20‐
22]. In two placebo-controlled clinical trials, the atypical antipsychotic lurasidone, approved by the US FDA as a monotherapy and adjunctive to lithium or valproate, was found to significantly improve symptoms of depression, HRQoL, and other PROs in patients with bipolar depression over a 6-week period [
23,
24]. Thus, positive benefits in areas of life valued by the patient were achieved over the trial period. However, it is important to know if PRO improvements were a direct result of lurasidone treatment (a direct effect), or if this HRQoL improvement is achieved due to reductions in symptoms of depression (a completely-mediated indirect effect) or a combination of both, direct and indirect effects. With this information, clinicians and payors will have a much greater understanding of the total effects associated with lurasidone treatment on HRQoL. Thus, the aim of this study was to examine the direct and indirect effects (mediated through improvement in bipolar depression symptoms) of lurasidone in improving patient HRQoL.
Discussion
In this post-hoc analysis of two 6-week, randomized, placebo-controlled clinical trials conducted to assess the efficacy of lurasidone on HRQoL in patients with bipolar depression, lurasidone performed significantly better in comparison to placebo in improving patient-reported HRQoL. In analyses of lurasidone as a monotherapy and adjunctive therapy to lithium or valproate, similar adjusted change in the Q-LES-Q SF was evidenced for all treatment groups receiving lurasidone. The overall findings provide evidence that lurasidone performs similarly as a monotherapy and as an adjunctive therapy, at a range of dosage levels, in improving self-reported HRQoL in patients with bipolar depression.
While morbidity and mortality is high in patients with bipolar depression and HRQoL is often greatly compromised, improvement in HRQoL in clinical treatment trials for bipolar depression is often understudied. However, the relatively few studies that have been published provide support for the assertion that treatment can improve HRQoL in patients with bipolar depression. Using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) as a measure of HRQoL in an 8-week randomized, controlled trial of olanzapine or olanzapine-fluoxetine combination, Shi and colleagues [
33] found that patients receiving either olanzapine or olanzapine-fluoxetine reported significantly greater improvement on the mental and physical component scores of the SF-36. More recently, Endicott and colleagues [
34] conducted a secondary analysis of two 8-week randomized, controlled clinical trials of quetiapine. Using a mixed model for repeated measures analysis, they found that patients taking 300 and 600 mg/day significantly improved on the Q-LES-Q SF with adjusted least squares mean (SE) change scores of 10.89 (0.59) and 12.14 (0.62), respectively, by Week 8. These findings parallel earlier work where Q-LES-Q SF scores were significantly improved in patients taking quetiapine in comparison to placebo at Week 4 and Week 8 [
35]. The present study demonstrated that in controlled analyses, lurasidone was even more effective in improving HRQoL as measured by the Q-LES-Q SF, where mean (SD) change scores were 22.5 (16.9) and 23.3 (18.7) in the monotherapy and adjunctive therapy studies, respectively.
The HRQoL improvement in patients receiving lurasidone parallel the reduction in MADRS depression scores in this sample [
23,
24]. Specifically, both as a monotherapy and an adjunctive therapy, lurasidone treatment had a significantly greater effect in reducing depression over 6 weeks in comparison to placebo as measured by the MADRS and the Clinical Global Impressions-Bipolar scale. Path analysis revealed that MADRS total score improvement was a partial (monotherapy) and almost-complete mediator (adjunctive therapy) on the relationship between treatment and improvement in the Q-LES-Q SF. Thus, improvement in HRQoL in lurasidone-treated patients largely occurred through improvements in depression symptoms. This finding of partial (rather than full) mediation in the monotherapy trial could be due to larger mean Q-LES-Q SF improvement resulting from lurasidone administered as a monotherapy in comparison to an adjunctive therapy. These findings are supported by previous investigations comparing the effects of monotherapy and combination therapy on HRQoL using the investigator-rated global assessment of functioning (GAF) in patients with bipolar disorder [
36,
37]. However, future research assessing the incremental benefit of monotherapy over adjunctive therapy on HRQoL improvement is needed in patients with bipolar depression.
This knowledge of both the direct and indirect effects of lurasidone treatment on improvement in HRQoL provides a more holistic view of the complex effect of treatment on the magnitude and level of improvement in how a patient feels or functions. Whereas the primary goal of treatment for patients with bipolar depression is often the alleviation of depression symptoms, improved HRQoL is often critical to patients and their clinicians [
4], and could potentially shape long-term recovery. For example, improved HRQoL has been associated with greater adherence to treatment [
38], which has been shown to be a great barrier to effective long-term treatment in patients with bipolar depression [
39].
The results of the present study are supported by previous investigations that have demonstrated that a strong relationship exists between a depressed clinical state and reduced HRQoL in patients with bipolar disorder [
34,
40‐
42]. For example, using data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) multicenter trial, researchers sought to determine the unique contribution of clinical states (e.g., depression, mania/hypomania, mixed) in relation to HRQoL. Bipolar patients with depression had significantly lower HRQoL scores in comparison to recovered, recovering, and patients with mania/hypomania, controlling for sociodemographic and health characteristics. Similar conclusions were drawn by Saarni et al. [
43] and Vojta [
41], concluding that in bipolar patients, depressive symptoms are the strongest predictors of reduced HRQoL. Also using the Q-LES-Q SF and MADRS to assess HRQoL and depression, respectively, Endicott [
34] found that improvement in HRQoL across an 8-week period was most strongly correlated with improvements in MADRS scores. In the current study, we expanded on these analyses using path analysis, finding that not only is change in these constructs correlated across time, but that change in MADRS is predictive of change in Q-LES-Q SF, thus providing an assessment of the mediating effect of depression on the treatment-HRQoL relationship.
Several study limitations should be noted. The study duration was only 6 weeks, and a longitudinal study is needed to determine if patients maintain the demonstrated improvement or continue to improve over a longer period of time. However, a 6-week trial length is a standard for acute depression clinical trials [
44,
45]. In addition, HRQoL was assessed based on patient-reported data, and not direct observation of patient behavior or functioning, and the assessment was conducted with only one assessment of HRQoL. The findings from the current study could be different if an alternative PRO of HRQoL was selected. Finally, we used path analysis in a limited sample to determine if depression mediated the treatment-HRQoL relationship. A replication of these analyses in a larger population is needed to confirm our findings. Although mediation analysis allows for the interpretation of causal relationships from correlational data, additional research using a causal study design is necessary to validate these findings.
Acknowledgements
The authors thank the participants of this study, as well as the members of the Lurasidone Bipolar Disorder Study Group (Czech Republic: Drs. J. Drahozal, E. Herman, M. Klabusayova, and Z. Solle; France: Dr. M. Zins Ritter; India: Drs. M. Chudgar, H. Gandhi, M. Gowda, V. Indla, U. Nagapurkar, J. Trivedi, P. Thatikonda, M. Vaishnav, and R. Yadav; Romania: Drs. M.G. Badescu, D. Cozman, G. Oros, and D. Vasile; Russia: Drs. M. Ivanov, V. Kozlovsky, V. Tochilov, and V. Vid; South Africa: Drs. K. Botha, G. Jordaan, L. Nel, J. Schronen; Ukraine: Drs. V. Abramov, V. Bitenskyy, S. Rymsha, A. Skrypnikov, and V. Verbenko; United States: Drs. S. Aaronson, M. Alam, S. Atkinson, P. Bhatia, R. Brenner, J. Calabrese, A. Cutler, G. Dempsey, D. Garcia, E. Gfeller, H. Hassman, R. Knapp, R. Manning, J. Miller, N. Rosenthal, R. Hidaldo, T. Tran-Johnson, N. Vatakis, D. Walling, R. Weisler, K. Yadalam, M. Allen, J. Kunovac, and S. Potkin).
Ethics and consent to participate
List of IRB/ECs for NCT00868699
• CEC
• Cedars-Sinai Medical Center
• Copernicus Group
• Comisia Nationala de Etica pentru Studiul Clinic al Medicamentului
• Cosmos Independent Ethics Committee
• CPP OUEST IV
• Ethics Committee MITR Hospital
• Ethics Committee-Sheth V.S. General Hospital
• Eticka komise BIALBI, s.r.o
• Eticka komise pro multicentricka kinicka hodnocen FN Motol
• IBIOME Independent Ethics Committee
• Independent Ethics Committee
• Institutional Ethics Committee
• Komisja Bioetyczna
• Landesamt fur Gesundheit und Soziales Berlin
• LEC at SPSRI named after V.M. Bekhterev
• MetroHealth Institutional Review Board
• Ministry of Health of Ukraine
• North Maharashtra Ethics Committee
• Pharma-Ethics
• Spandana Ethics Committee
• Stanford University IRB
• State Pharmacological Center
• University of CA – Irvine
• University of Cape Town
• University Hospitals Case Medical Center IRB
• VIMHANS Hospital Ethic Committee
• Western Institutional Review Board
List of IRB/ECs for NCT00868452
• CEC
• Central Ethics Commission
• Copernicus Group
• Comisia Nationala de Etica pentru Studiul Clinic al Medicamentului
• CPP OUEST IV
• The Ethics Committee
• Ethics Committee MITR Hospital
• Ethics Committee-V.S. General Hospital
• Eticka komise BIALBI, s.r.o
• Eticka komise NZZ Clinitrial, s.r.o.
• Eticka komise pro multicentricka kinicka hodnocen FN Motol
• IBIOME Independent Ethics Committee
• Independent Ethics Committee
• Institutional Ethics Committee
• LEC at SPSRI named after V.M. Bekhterev
• MetroHealth Institutional Review Board
• North Maharashtra Ethics Committee
• Pharma-Ethics
• Spandana Ethics Committee
• State Pharmacological Center
• University of CA – Irvine
• University Hospitals Case Medical Center IRB
• VIMHANS Hospital Ethic Committee
• Western Institutional Review Board