Esketamine Nasal Spray vs Quetiapine Extended-Release: Examining Work Productivity Loss and Related Costs in Patients With Treatment-Resistant Depression

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).

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.