Elsevier

Journal of Affective Disorders

Volume 242, 1 January 2019, Pages 195-210
Journal of Affective Disorders

Review article
The burden of treatment-resistant depression: A systematic review of the economic and quality of life literature

https://doi.org/10.1016/j.jad.2018.06.045Get rights and content

Highlights

  • In a systematic review of the published literature, 35 studies were identified.

  • Increasing treatment resistance was associated with higher costs.

  • Increasing treatment resistance was associated with reduced HRQoL and health status.

  • Varied definitions of treatment resistance made comparisons challenging.

  • Substantial geographic variability was observed in economic burden.

Abstract

Background

Major depressive disorder (MDD) is a global public health concern. In particular, treatment-resistant depression (TRD) represents a key unmet need in the management of MDD. A systematic review of the epidemiological and economic literature on the burden associated with an increasing number of treatment steps due to TRD/non-response within an MDD episode was performed to quantify the burden of TRD.

Methods

Studies were identified in the PubMed/Medline databases through April 27th, 2017. Articles were limited to full-length peer-reviewed journal publications with no date restrictions. Economic and patient health-related quality of life (HRQoL) data on non-response by the number of treatment steps were quantified and, where appropriate, compared across studies; otherwise, comparative data within studies were reported.

Results

The 12 studies on economic burden found an association between increasing levels of TRD/non-response and elevations in direct and indirect costs. Likewise, the 19 studies studying HRQoL burden found that increasing levels of TRD/non-response correlated with reduced patient HRQoL and health status.

Limitations

TRD is defined inconsistently, which results in notable heterogeneity between published studies and poses methodological challenges for between-study comparisons. It is unknown if the increased economic and patient HRQoL burden are due to factors associated with TRD/non-response in addition to those due to depression persistence or severity.

Conclusions

A consistent trend was observed such that medical costs increased and patient HRQoL and health status decreased by increasing level of TRD/non-response within an MDD episode. These findings highlight the need for improved therapies for TRD to help reduce disease burden.

Introduction

Major depressive disorder (MDD) is an important worldwide public health concern. The global prevalence of MDD in 2010 was 4.4% (Baxter et al., 2014). Depression is a leading cause of years of life lost due to disability (YLD) in World Health Organization (WHO) member states and corresponds to 10.3% of the total YLD across all diseases (World Health Organization, 2012). Approximately 6.7% of adults aged 18 or older had a least one major depressive episode (MDE) in the United States (US) in 2015. The overall economic burden of MDD in the US is estimated to be greater than $200 billion (Greenberg et al., 2015), and in 2012, the annual incremental direct medical cost for an MDD patient was approximately $6,400 (2012 USD) compared to an individual without MDD (Greenberg et al., 2015). MDD has a substantial impact on patient health-related quality of life (HRQoL). Among MDD patients enrolled in large-scale trials for depression and anxiety disorders, 63% had severely impaired HRQoL, as defined by two standard deviations (SDs) below the community norm (Daly et al., 2010, Rapaport et al., 2005).

First-line pharmacological treatment for MDD typically consists of selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) monotherapy (Kupfer, 2005). However, it is estimated that 53% and 67% of patients with MDD show non-response and non-remission, respectively, to first-line depression treatment (Warden et al., 2007). Failure to respond to first-line pharmacotherapy for MDD is associated with multiple negative health outcomes, including increased emergency room utilization and hospitalization (Knoth et al., 2010), greater risk of unemployment, reduced work productivity, and poorer patient HRQoL compared to responders (Knoth et al., 2010). Treatment failure and rates of relapse in patients with MDD increase with the number of treatment steps (McIntyre et al., 2014)

Treatment-resistant depression (TRD) refers to difficult-to-treat or refractory depression. Although inconsistently defined (Souery et al., 2006), the most common definition of TRD is non-response to two or more adequate courses of consecutive antidepressant treatment in a single MDE (McIntyre et al., 2014). TRD affects 20%−30% of all individuals with MDD (Fekadu et al., 2009) and contributes substantially to the burden of disease; TRD has been associated with poorer patient HRQoL, increased mortality, and higher rates of relapse relative to non-TRD within one year of remission (Fekadu et al., 2009). Although these data demonstrate the potential benefits of effective treatments for TRD, and may be supplemented with non-pharmacological and exploratory interventions, individuals with TRD currently have limited therapeutic options, as fluoxetine/olanzapine is the only therapy specifically approved for TRD in the US, and no therapies are licensed for TRD in other regions.

A comprehensive understanding of the impact of TRD on economic and patient HRQoL outcomes will demonstrate the value of new therapies to physicians and patients and identify the cost drivers of disease for payers. Previously conducted reviews on the burden of TRD are outdated or limited by methodological approach (Mauskopf et al., 2009, Mrazek et al., 2014). The current study builds on these prior reviews and addresses gaps in the literature. The objective of this study is to present a systematic review and synthesis of the literature on the economic and humanistic burden associated with an increasing number of treatment steps due to TRD/non-response within an MDD episode. Economic and patient HRQoL data are quantified and, where appropriate, compared across studies; otherwise, comparative data within studies are reported.

Section snippets

Search strategy

Literature related to the economic and patient HRQoL burden associated with an increasing number of treatment steps due to TRD/non-response within an MDD episode was reviewed (Table S1, S2). PubMed/Medline databases were searched from inception to April 27th, 2017, using the following medical subject headings (MeSH), key words, and free-text search terms: major depressive disorder, MDD, treatment-resistant depression, depressive disorder, treatment-resistant, economics, costs, cost of illness,

Results

The search strategy yielded a total of 1381 abstracts, of which 304 were eligible for full-text screening. Of these, 134 full-text articles were reviewed for assessment of economic outcomes (Fig. 1A), and 170 full-text articles were reviewed for assessment of patient HRQoL outcomes (Fig. 1B). After applying the inclusion and exclusion criteria, 13 studies were included in the economic burden review, and 22 studies were included in the patient HRQoL burden review. A variety of definitions were

Discussion

In this study, the published literature was systematically reviewed to identify observational and modeling studies related to the economic and humanistic burden of TRD. Across all identified studies, a strong relationship was observed between an increasing number of treatment steps due to TRD/non-response within an MDD episode and increasing costs (both direct medical and indirect). This is consistent with the notion that morbidity increases with depression that requires additional treatment

Conclusion

Our review demonstrates that TRD represents an economic and humanistic burden to healthcare systems, patients, and their families. Hospitalization costs appear to be the largest driver of overall economic burden, and depression severity may contribute to reduced patient HRQoL and health status. Despite these observations, TRD continues to represent a substantial unmet need in the treatment of depression. Treatments specifically targeting TRD have the potential to address the substantial

Acknowledgments

All authors contributed equally to the study design, data collection, analysis and interpretation as well as the writing of the manuscript. The authors wish to acknowledge the medical writing support of Jane Kondejewski, PhD of Snell Medical Communication.

Funding

This work was supported by Takeda Pharmaceuticals International, Inc.

Author contributions

All authors contributed equally to the study design, data collection, analysis and interpretation as well as the writing of the manuscript. The authors wish to acknowledge the medical writing support of Jane Kondejewski, PhD of Snell Medical Communication.

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