Review articleThe burden of treatment-resistant depression: A systematic review of the economic and quality of life literature
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.
References (67)
- et al.
Economic evaluation of duloxetine versus serotonin selective reuptake inhibitors and venlafaxine XR in treating major depressive disorder in Scotland
J. Affect. Disord.
(2010) - et al.
What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies
J. Affect. Disord.
(2009) - et al.
Cross-validation of item selection and scoring for the SF-12 Health Survey in nine countries: results from the IQOLA Project. International Quality of Life Assessment
J. Clin. Epidemiol
(1998) - et al.
Treatment-resistant depression increases health costs and resource utilization
Rev. Bras. Psiquiatr.
(2012) - et al.
Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach
J. Affect. Disord.
(2014) - et al.
Cost-effectiveness of repetitive transcranial magnetic stimulation versus antidepressant therapy for treatment-resistant depression
Value Health
(2015) Assessment of clinical guidelines for continuation treatment in major depression
Value Health
(2001)- et al.
The economic burden of treatment-resistant depression
Clin Ther
(2013) - et al.
Should pharmacogenetics be incorporated in major depression treatment? Economic evaluation in high- and middle-income European countries
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2012) - et al.
Challenging sequential approach to treatment resistant depression: cost-utility analysis based on the Sequenced Treatment Alternatives to Relieve Depression (STAR( )D) trial
Eur. Neuropsychopharmacol
(2013)
Patient-assigned health state utilities for depression-related outcomes: differences by depression severity and antidepressant medications
J. Affect. Disord.
Health-related quality of life measured with EQ-5D in patients treated for depression in primary care
Value Health
Core discrete event simulation model for the evaluation of health care technologies in major depressive disorder
Value Health
Cost of depression: effect of adherence and treatment response
Eur Psychiatry
Intensive Short-Term Dynamic Psychotherapy of treatment-resistant depression: a pilot study
Depress Anxiety
Cost-effectiveness analysis of pharmaceutical treatment options in the first-line management of major depressive disorder in Belgium
Pharmacoeconomics
Challenging the myth of an "epidemic" of common mental disorders: trends in the global prevalence of anxiety and depression between 1990 and 2010
Depress Anxiety
Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy
Neuropsychopharmacology
Health-related quality of life and symptom severity in Chinese patients with major depressive disorder
Asia Pac Psychiatry
Health-related quality of life in depression: a STAR*D report
Ann. Clin. Psychiatry
Clinical and functional outcomes of patients who experience partial response to citalopram: secondary analysis of STAR*D
J. Psychiatry Pract.
Improvement of health-related quality of life in depression after transcranial magnetic stimulation in a naturalistic trial is associated with decreased perfusion in precuneus
Health Qual. Life Outcomes
Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression
J. Clin. Psychiatry
Medicare patient experience with vagus nerve stimulation for treatment-resistant depression
J. Med. Econ.
Randomised Controlled Trial of Antiglucocorticoid augmentation (metyrapone) of Antidepressants in Depression (ADD Study)
US norms for six generic health-related quality-of-life indexes from the National Health Measurement study
Med. Care
Treating depression after initial treatment failure: directly comparing switch and augmenting strategies in STAR*D
J. Clin. Psychopharmacol
Cost burden of treatment resistance in patients with depression
Am. J. Manag. Care
Economic implications of treatment-resistant depression among employees
Pharmacoeconomics
The economic burden of adults with major depressive disorder in the United States (2005 and 2010)
J. Clin. Psychiatry
The excess cost of depression in South Australia: a population-based study
Aust. N Z J. Psychiatry
Cost-effectiveness of combinatorial pharmacogenomic testing for treatment-resistant major depressive disorder patients
Am. J. Manag. Care
Direct and indirect costs of employees with treatment-resistant and non-treatment-resistant major depressive disorder
Curr. Med. Res. Opin.
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