This secondary analysis (n=321) of the ESCAPE-TRD trial compared work productivity loss (WPL) and related costs in patients with treatment-resistant depression (TRD) receiving esketamine nasal spray (56mg or 84mg) versus quetiapine (atypical antipsychotic) extended release, both combined with an oral antidepressant. By week 8, WPL decreased by 30.3% with esketamine and 17.3% with quetiapine, leading to a cost savings difference of $156 per week. By week 32, WPL reductions were 45.3% (esketamine) and 32.5% (quetiapine), with a weekly cost savings difference of $153.
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Objective
This post hoc analysis of the ESCAPE-TRD trial compared work productivity loss (WPL) and related costs among patients with treatment-resistant depression (TRD) receiving esketamine nasal spray or quetiapine extended release in combination with an oral antidepressant.
Methods
Adults with TRD randomized to receive esketamine (56/84 mg) or quetiapine (150-300 mg) combined with ongoing antidepressant therapy were included. WPL was assessed using the Work Productivity and Activity Impairment questionnaire. Least squares (LS) mean WPL change versus baseline (treatment initiation date), and LS mean differences (MDs) between esketamine and quetiapine cohorts were reported at weeks 8-32 of treatment using mixed models for repeated measurements. Per patient productivity cost savings were estimated using mean 2021 weekly wages from US Bureau of Labor Statistics.
Results
The esketamine cohort included 165 patients, and quetiapine cohort included 156 patients. At baseline, total WPL was 77.0% and 72.5% in the esketamine and quetiapine cohorts, respectively. By week 8, total WPL decreased from baseline by 30.3 and 17.3 percentage points (pp) in the esketamine and quetiapine cohorts (MD = 13.0 pp; 95% confidence interval [CI], 6.3-19.8 pp), resulting in weekly cost savings of $363 and $207 (MD = $156; 95% CI, $76-$237), respectively. By week 32, total WPL decreased from baseline by 45.3 pp and 32.5 pp in the esketamine and quetiapine cohorts (MD = 12.7 pp; 95% CI, 4.7-20.7 pp), with weekly cost savings of $543 and $390 (MD = $153; 95% CI, $57-$250), respectively.
Conclusion
Among employed adults with TRD, esketamine treatment was associated with significantly larger improvements in WPL and related costs compared to quetiapine, suggesting greater benefits from patient well-being and employer perspectives.
Major depressive disorder (MDD) is a common chronic illness in the United States that disproportionately affects adults of working age, and around a third of treated patients develop treatment-resistant depression (TRD), typically defined as failure to respond to at least two adequate antidepressant courses. Clemens and colleagues note that TRD drives substantial unemployment and work productivity loss (WPL), with prior estimates attributing over 60% of the pharmacologically treated MDD productivity burden to TRD. Esketamine, an intranasal, rapidly acting S‑enantiomer of ketamine approved for TRD in 2019, offers a different treatment profile from oral antidepressants and has shown superior clinical response and remission in prior trials when added to an antidepressant compared with standard augmentation strategies such as second‑generation antipsychotics (SGAs). However, the societal benefits of esketamine, specifically its impact on work productivity and related employer costs, have not been fully characterised. This post hoc analysis of the ESCAPE-TRD trial aimed to compare patient‑reported WPL and estimated productivity costs among employed adults with TRD who received either esketamine nasal spray or extended‑release quetiapine, each combined with an oral antidepressant dosed per US labelling. The investigators evaluated changes in absenteeism, presenteeism, and total WPL over a 32‑week period and translated those changes into weekly and annual cost savings using 2021 US labour market data, with sensitivity analyses to reflect wage differences by sex and employment status.
The ESCAPE-TRD parent trial used an open‑label, rater‑blind, randomised, active‑controlled design across 24 countries. Adults aged 18–74 with TRD (defined here as a score of ≥34 on the 30‑item Inventory of Depressive Symptomatology‑Clinician Rated and failure of 2–6 consecutive treatments in the current episode, including a recent SSRI or SNRI) were randomised to esketamine nasal spray plus their ongoing SSRI/SNRI or extended‑release quetiapine plus their ongoing SSRI/SNRI; randomisation was stratified by age group (18 to ≤64, ≥65) and number of prior treatment failures (2, ≥3). For this post hoc analysis the sample was restricted to trial participants aged 18–64 who received dosing consistent with US labelling: esketamine 56/84 mg twice weekly for the first 4 weeks then every 1–2 weeks, and quetiapine 150–300 mg daily. Participants also had to have usable baseline WPAI (Work Productivity and Activity Impairment) scores at the date of treatment initiation. Work productivity was measured with the WPAI‑depression instrument, a 7‑day recall patient questionnaire. Key WPAI-derived outcomes analysed were absenteeism (hours missed due to depression as a percentage of hours usually worked), presenteeism (self‑rated on a 0–10 scale and converted to percentage impairment), and total WPL (a combined measure computed as absenteeism + (1–absenteeism)×presenteeism). WPAI assessments were collected every 4 weeks during a 32‑week period consisting of an 8‑week initial phase and a 24‑week maintenance phase. Productivity costs were estimated from an employer perspective using 2021 US Bureau of Labor Statistics data: mean annual wage $62,411 and mean hours worked per week 40.5, yielding an hourly wage of $29.6. Costs per patient per week were calculated by multiplying percent WPL by 40.5 hours and the hourly wage; presenteeism costs were derived as the difference between total WPL costs and absenteeism costs. The statistical approach used mixed models for repeated measurements (MMRM) with the baseline WPAI score as a covariate and fixed effects for treatment, age, number of prior treatment failures, visit, and visit‑by‑treatment interaction, using an unstructured covariance matrix. The investigators reported least squares (LS) mean changes from baseline and LS mean differences (MDs) between esketamine and quetiapine cohorts at weeks 8 and 32 and overall (mean of weeks 8, 12, 16, 20, 24, 28, and 32). Cost differences were computed as simple differences in mean weekly savings and were annualised by multiplying weekly differences by 52. Sensitivity analyses reweighted hourly wages to reflect the cohort's female proportion (64.2%, yielding $28.0/hour) and the combined proportions of females and part‑time workers among US adults with a major depressive episode (29.7% part‑time, yielding $26.5/hour).
Patient-reported work productivity was evaluated based on the WPAI scores, which represented a supportive secondary end point in the ESCAPE-TRD trial. The WPAI questionnaire is a patient-filled survey based on a recall period of 7 days 10 and contains the following questions: Q1 = currently employed (yes/no); Q2 = hours missed due to depression-related health problems; Q3 = hours missed due to other reasons; Q4 = hours actually worked; Q5 = degree depressionrelated health affected productivity while working (0-10 rating scale [0: depression had no effect on my work; 10: depression symptoms completely prevented me from working]); and Q6 = degree depression-related health affected regular activities (0-10 rating scale [0: depression had no effect on my regular activities; 10: depression symptoms completely prevented me from my regular activities]). The baseline WPAI scores corresponded to the date of study treatment initiation in the ESCAPE-TRD trial. During a 32-week treatment period comprising an initial treatment phase of 8 weeks and a maintenance phase of 24 weeks, the WPAI outcomes were reported every 4 weeks. The WPAI outcomes included in this post hoc analysis were those for which costs could be estimated from an employer's perspective: absenteeism, defined as the percentage of time absent from work last week due to depression-related health problems (calculated as Q2/(Q2 + Q4) × 100%), presenteeism, defined as the degree health problems affected work productivity in the last week (calculated as (Q5/10) × 100%), and total WPL associated with depression in the prior week, defined as [absenteeism + (1 -absenteeism) * presenteeism] × 100%. The costs associated with total WPL were estimated per patient in 2021 US dollars based on the average US weekly wages obtained from the US Bureau of Labor Statistics (BLS), whereby the mean annual wage in 2021 was $62,411 (based on the BLS Current Population Survey) and the mean number of hours worked per week in 2021 in the United States was 40.5 hours (based on the BLS American Time Use Survey), resulting in a mean hourly wage of $29.6. Sensitivity analyses for hourly wage. Sensitivity analyses were conducted to account for the variation in mean hourly wages between males and females and full-time and parttime employees. This was an important consideration as the majority of patients with TRD are known to be female
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Teeple, A., Zhdanava, M., Pilon, D. et al. · Current Medical Research and Opinion (2023)
The post hoc sample comprised 165 patients in the esketamine cohort and 156 in the quetiapine cohort. Mean ages were 43.1 and 44.4 years, respectively; both cohorts were over 60% female and predominantly white. Participants had lived with depression for about 10 years on average and about one third in each cohort had ≥3 prior treatment failures. Baseline WPAI scores indicated substantial impairment: total WPL 77.0% (esketamine) versus 72.5% (quetiapine), absenteeism 43.4% versus 37.5%, and presenteeism 71.3% versus 66.2%. On the primary WPAI outcomes, the esketamine cohort experienced larger improvements than the quetiapine cohort. At week 8, LS mean total WPL decreased from baseline by 30.3 percentage points (pp) in the esketamine cohort versus 17.3 pp in the quetiapine cohort, an additional improvement of 13.0 pp favoring esketamine (MD = 13.0 pp; 95% CI, 6.3–19.8 pp). By week 32, LS mean total WPL improvements were 45.3 pp (esketamine) and 32.5 pp (quetiapine), corresponding to an MD of 12.7 pp (95% CI, 4.7–20.7 pp). Across all assessed visits (overall), LS mean total WPL improved by 34.8 pp in the esketamine cohort and 24.1 pp in the quetiapine cohort, a between‑group MD of 10.8 pp (95% CI, 5.2–16.3 pp). Both absenteeism and presenteeism improved more in the esketamine group, with presenteeism showing larger absolute improvements than absenteeism within each cohort. Translating WPL changes into monetary terms using the base hourly wage ($29.6), esketamine was associated with greater weekly and annual productivity savings. At week 8, estimated weekly savings per patient due to improved total WPL were $363 in the esketamine cohort versus $207 in the quetiapine cohort (MD = $156; 95% CI, $76–$237). At week 32, weekly savings were $543 versus $390 (MD = $153; 95% CI, $57–$250). Overall weekly savings averaged $417 per patient in the esketamine cohort, which was $128 more than in the quetiapine cohort (95% CI, $62–$194). Annualising the overall weekly difference yielded estimated savings of $21,694 per patient per year for esketamine, $6,670 more than quetiapine. Absenteeism improvements accounted for ≥60% of total cost savings in both cohorts because absenteeism comprised a larger share of baseline WPL costs. Sensitivity analyses that reweighted hourly wages by female proportion and by female plus part‑time proportions produced broadly consistent results. Reweighting by the cohort's female proportion produced overall weekly savings of $392 for esketamine, $121 more than quetiapine (95% CI, $58–$182), or annual savings of $20,384 with a $6,292 advantage versus quetiapine. Reweighting for females and part‑time workers yielded $371 weekly savings for esketamine, $114 more than quetiapine (95% CI, $55–$172), and annual savings of $19,292 with a $5,928 advantage. The authors also considered patient time required for esketamine administration: assuming two weekly sessions during a 4‑week induction and weekly sessions thereafter, 32 weeks of treatment would require 108 hours of patient time. At $29.6/hour this equates to $3,197 of productivity cost, compared with $4,096 of estimated productivity cost savings over 32 weeks, producing a net productivity benefit of $899 under the study assumptions. The extracted text does not report detailed adverse‑event frequencies or other clinical safety data within this post hoc analysis.
Clemens and colleagues interpret the results as showing that, among employed adults with TRD, adding esketamine to an antidepressant was associated with significantly larger reductions in work productivity loss and larger estimated productivity cost savings than adding quetiapine to an antidepressant. The comparative advantage in productivity and cost savings persisted across sensitivity analyses that adjusted hourly wages for female and part‑time employment patterns. The investigators note that, given the substantial national productivity burden of TRD, even treating a modest share of the TRD population with esketamine could materially reduce aggregate productivity losses, although they explicitly did not account for treatment costs in that extrapolation. The discussion highlights methodological points relevant to interpretation. The WPAI absenteeism question instructs respondents not to count time missed to participate in the study; depending on respondent interpretation this could exclude time spent obtaining esketamine treatment. The authors therefore estimated time costs of esketamine administration and concluded that, under their assumptions, esketamine still yielded a net productivity benefit versus quetiapine. They also acknowledge that esketamine treatment may be more expensive than generic antipsychotic augmentation and state that this analysis does not address cost‑effectiveness, which has been assessed elsewhere. The authors position their findings alongside prior real‑world claims research that similarly reported greater reductions in disability days and costs following esketamine initiation versus SGA augmentation, and they suggest that, because SGAs share broadly similar dopamine and serotonin receptor mechanisms, quetiapine findings may be generalisable to other SGA augmentations. Implications raised by the investigators include potential advantages of initiating esketamine earlier after identification of TRD rather than allowing patients to cycle through multiple augmentation strategies, and the importance of continued esketamine treatment for cumulative and durable productivity benefits, given larger improvements observed at 32 weeks than at 8 weeks. The authors emphasise the consistency of their cost estimation approach with methods used in other chronic disease areas. They also acknowledge several limitations: the parent trial's open‑label design could introduce expectation bias and differential discontinuation, the WPAI is subject to recall and response biases, assumptions were made when annualising 32‑week cost data, both treatments have adverse events that may affect productivity, the multinational trial sample may not reflect US labour conditions fully, and racial minorities may have been underrepresented. These limitations are presented as caveats to generalisability and interpretation rather than grounds to overturn the primary comparisons.
Among employed adults with TRD receiving adjunctive treatment, esketamine plus an antidepressant was associated with a significantly larger reduction in work productivity loss and greater annual estimated productivity cost savings compared with quetiapine plus an antidepressant. The authors conclude that, from patient well‑being and employer perspectives, initiating esketamine shortly after evidence of TRD rather than pursuing additional antipsychotic augmentation may yield larger productivity benefits; however, they do not claim to assess overall cost‑effectiveness within this analysis.
employed adults with TRD, treatment with esketamine was associated with significantly greater improvements in total WPL compared to quetiapine, both in combination with an antidepressant, which translated to significantly larger cost savings. The comparative advantage of esketamine versus quetiapine in terms of cost savings remained robust in sensitivities accounting for variation in mean hourly wages between males and females and full-time and part-time employees. In 2021, the annual prevalence of TRD was estimated at 2.8 million adults,and the annual productivity burden of TRD was estimated at $9.3 billion in the United States.Based on the annual cost savings per patient due to improved productivity associated with esketamine in this study, treating even 15% of the population with TRD with esketamine could potentially offset the total productivity burden of TRD, not accounting for the cost of treatment. In the WPAI questionnaire, absenteeism is reported based on the question "during the past seven days, how many hours did you miss from work because of problems associated with depression?" and it is specified that respondents should not include time missed due to participating in the study in this measure. Depending on how the question is understood, the hours of absenteeism may not include hours spent obtaining treatment for depression. Each esketamine dose may require 3 hours of patient time for administration, monitoring, and travel to and from a treatment center.Thus, 32 weeks of treatment will require 108 hours of patient time, assuming treatment sessions twice per week for the first 4 weeks (induction) and weekly sessions afterward. With the mean hourly wage of $29.6, this would translate into $3,197 of productivity loss over 32 weeks vs $4,096 of productivity cost savings due to treatment for net savings of $899. Therefore, even if the measure of absenteeism did not originally account for patient time necessary to receive esketamine treatment, there are still productivity benefits in using esketamine versus quetiapine, both in combination with an antidepressant. It should be noted that the cost of esketamine may be higher than generic augmentation medications; however, this analysis does not make any claims about the cost-effectiveness of esketamine, which was previously assessed elsewhere.This post hoc analysis used WPL data from the ESCAPE-TRD trial; costs associated with WPL were estimated using US labor market conditions, based on mean weekly wages and mean number of hours worked per week obtained from the US BLS.Similar methodology has been commonly used in published work across multiple chronic disease areas, including atopic dermatitis, irritable bowel syndrome, and psoriasis.The demographic characteristics of patients with TRD included in this post hoc analysis were largely consistent with those of patients included in prior real-world studies conducted in the US.The results from this study complement findings of a recent real-world claims-based study among patients with TRD in the US which showed greater reduction in disability days and costs 6 months after initiation of esketamine versus a SGA in combination with an antidepressant.SGAs, such as quetiapine, work across the class by blocking D2 dopamine receptors as well as serotonin receptor antagonist action. Thus, given the somewhat comparable mechanisms of action, it may be reasonable to expect comparable effects relative to augmentation with other SGAs. Together, the findings suggest that esketamine treatment is associated with greater benefits from patient's well-being and employer's perspectives compared to the standard of care, antipsychotic augmentation treatment. In the real-world setting, patients undergo at least 2 lines of treatment on average, often with antipsychotic augmentation, after evidence of TRD and before they initiate esketamine.Some patients may also receive antipsychotic augmentation along with esketamine. The findings of this study suggest potential gains of initiating patients on esketamine earlier after evidence of TRD instead of letting them cycle through additional lines of antidepressants augmented with antipsychotics. Further, although esketamine is a rapidly acting medication, the results of this study highlight the importance of continued esketamine treatment according to the label for a cumulative durable treatment effect, as greater improvements in WPL were observed after 32 weeks of treatment relative to 8 weeks.