Health Care Resource Use and Medical Costs Among Patients With Major Depressive Disorder and Acute Suicidal Ideation or Behavior Initiated on Esketamine Nasal Spray or Traditional Treatments in the United States

Major depressive disorder (MDD) is common in US adults and is associated with an increased risk of suicide, particularly during major depressive episodes. Harding and colleagues note that nearly 50% of adults who experienced a major depressive episode in the past year reported serious suicidal ideation or made suicide plans or attempts. Patients with MDD who have acute suicidal ideation or behaviour (MDSI) carry a substantial humanistic burden and, compared with patients with MDD without suicidal ideation or behaviour, exhibit higher health care resource use (HRU) and costs. Recommended interventions for MDSI after disposition assessment include psychosocial measures and somatic treatments such as antidepressants (monotherapy or with augmentation, for example with second‑generation antipsychotics [SGAs]) and electroconvulsive therapy (ECT). Esketamine nasal spray, in combination with an oral antidepressant, was approved in the United States on 5 August 2020 for depressive symptoms in adults with MDSI; phase 3 trials demonstrated a rapid reduction in depressive symptoms within 24 hours in this population. To address a gap in real‑world evidence comparing esketamine with more traditional treatments, the investigators conducted a retrospective claims‑based study to describe treatment patterns, acute care HRU, outpatient HRU, and medical costs among patients with MDSI who were newly initiated on esketamine, ECT, antidepressant with SGA augmentation, or antidepressant monotherapy, using a large US commercial insurance database. The intent was descriptive: to characterise HRU and payer costs after initiation of these index treatments and to compare post‑initiation outcomes with patients’ own pre‑index (baseline) period.

The study used the Merative® MarketScan® Commercial Database covering 1 January 2016 to 31 January 2022, which contains deidentified employer‑sponsored private insurance medical and pharmacy claims and actual payer costs. Because the data were deidentified, the research was considered exempt from human subjects review under relevant US regulations. A retrospective observational design identified adults (≥18 years) with evidence of MDSI, defined as ≥1 diagnosis code for suicidal ideation or behaviour and ≥1 diagnosis for MDD during the 12‑month baseline period or on the index date. The patient intake window began on 5 August 2020 (the esketamine MDSI approval date) and extended to the end of available data. Patients were required to have ≥12 months of continuous health plan eligibility before the index date and no evidence of the index treatment during that baseline year. Four mutually exclusive cohorts were formed in priority order: (1) esketamine cohort — patients newly initiated on esketamine; among those without esketamine claims, (2) ECT cohort — newly initiated on ECT; (3) SGA augmentation cohort — newly initiated on an antidepressant augmented with an SGA; and (4) antidepressant monotherapy cohort — newly initiated on an antidepressant without overlapping augmenting agents. The index date was the first claim date for the index treatment. Specific code lists for identifying esketamine, ECT, and medication classes were referenced as supplemental material in the article; these supplement tables are not reproduced in the extracted text. Outcomes were described per patient per month (PPPM) to account for variable follow‑up duration; PPPM means average measures standardised to a one‑month rate per patient. Acute care HRU comprised days in inpatient and emergency department settings; outpatient visits were reported separately. Medical costs reported excluded index treatment costs (to assess the impact of the treatments on other health care costs) as well as durable medical equipment and dental/vision care; costs were presented from a private payer perspective and inflated to 2021 US dollars. Analyses were descriptive: means, standard deviations and medians for continuous variables, and frequencies and proportions for categorical variables. No adjusted comparative models are reported in the extracted text.

Cohort sizes were 122 patients in the esketamine cohort, 336 in the ECT cohort, 9,958 in the SGA augmentation cohort, and 4,496 in the antidepressant monotherapy cohort. Mean ages varied across cohorts (esketamine 36.1 years; ECT 41.2 years; SGA augmentation 33.1 years; antidepressant monotherapy 29.1 years). The majority were female in all cohorts (range 57.2% to 65.6%). The mean time from the most recent suicidal ideation or behaviour diagnosis to the index date ranged from 36.7 days in the ECT cohort to 102.5 days in the esketamine cohort. Treatment‑resistant depression (TRD) prevalence during the episode containing the index date was highest in the esketamine cohort (59%), followed by ECT (45%), SGA augmentation (27%), and antidepressant monotherapy (3%). During baseline, the esketamine and ECT cohorts had received, on average, more prior antidepressant agents (mean 3) than the SGA augmentation (mean 2) and antidepressant monotherapy (mean 0.5) cohorts. Mean follow‑up durations were 6.5 months (esketamine), 7.9 months (ECT and SGA augmentation), and 7.5 months (antidepressant monotherapy). Esketamine treatment patterns among the 122 patients in that cohort showed a mean of 10.9 treatment sessions during follow‑up; 51.6% of patients completed ≥8 sessions and 45.9% completed ≥9 sessions. The mean time to complete 8 sessions was 56.5 days, and mean intervals between consecutive sessions ranged from 8.1 to 13.6 days between session 1 and session 8. On the index date 33.6% of esketamine patients received an 84‑mg dose; by the eighth session 85.7% were receiving 84 mg. (The paper references the per‑label recommendation of 8 sessions and twice‑weekly administration, but the observed timing exceeded that schedule.) Acute care HRU (days in inpatient and emergency department) and outpatient visits PPPM are reported for baseline and follow‑up. Baseline mean all‑cause acute care HRU PPPM was 1.42 days (esketamine), 2.20 days (ECT), 1.16 days (SGA augmentation), and 0.51 days (antidepressant monotherapy). During follow‑up, mean acute care HRU PPPM was 0.59 days (esketamine), 3.17 days (ECT), 0.92 days (SGA augmentation), and 0.32 days (antidepressant monotherapy). Relative to baseline, mean acute care HRU decreased by 58% in the esketamine cohort, 37% in the antidepressant monotherapy cohort, and 21% in the SGA augmentation cohort; by contrast, it increased by 44% in the ECT cohort. All‑cause outpatient visits PPPM increased from baseline to follow‑up in all cohorts. Baseline outpatient visit means were 4.32 (esketamine), 3.61 (ECT), 2.23 (SGA augmentation), and 1.11 (antidepressant monotherapy). Follow‑up means were 5.69 (esketamine), 5.16 (ECT), 2.92 (SGA augmentation), and 1.76 (antidepressant monotherapy). Medical costs PPPM (all‑cause, excluding index treatment costs) during baseline were $3,746 (esketamine), $5,926 (ECT), $2,615 (SGA augmentation), and $1,260 (antidepressant monotherapy). During follow‑up, corresponding costs PPPM were $1,869 (esketamine), $4,624 (ECT), $2,163 (SGA augmentation), and $863 (antidepressant monotherapy). The reduction in mean medical costs from baseline was 50% in the esketamine cohort (a decrease of $1,877 PPPM reported in 2021 US dollars, which the authors convert to $2,118 PPPM in 2024 US dollars), 32% in the antidepressant monotherapy cohort, 22% in the ECT cohort, and 17% in the SGA augmentation cohort. The reported cost results exclude the costs of the index treatments themselves.

Harding and colleagues interpret the descriptive findings to suggest that initiation of esketamine nasal spray in patients with MDSI was associated with larger post‑initiation reductions in acute care HRU and medical costs (excluding index treatment costs) than initiation of ECT or antidepressant with SGA augmentation. They also note that esketamine recipients often did not adhere exactly to the per‑label treatment schedule: although just over half completed ≥8 sessions, the mean time to complete those sessions and the intervals between sessions exceeded the recommended twice‑weekly schedule. The authors position these results alongside prior clinical trial evidence showing rapid symptom reduction with esketamine and a previous claims‑based study; they report a higher proportion completing the full esketamine course in the current analysis than in the earlier real‑world study (51.6% vs 38.3%), attributing this to a longer observation window. They further observe that decreases in HRU and costs from baseline are expected to some degree because baseline measurement captured the period around a suicidal ideation or behaviour event, when costs are typically concentrated, and that the magnitude of post‑treatment cost reduction appeared correlated with the type of index treatment. The authors acknowledge several limitations. Generalisability is restricted to commercially insured populations because the database reflects employer‑sponsored private insurance; findings may not apply to Medicaid, Medicare, or uninsured populations. The analysis is descriptive and unadjusted, so between‑cohort differences in demographics and clinical history could confound comparisons; formal adjusted comparative analyses are recommended. The study period overlapped with the COVID‑19 pandemic, which could have influenced HRU and costs, although the authors note similar index date distributions across cohorts. Finally, underreporting of suicidal ideation or behaviour in claims data due to stigma or patient concerns could bias case ascertainment. As reported by the investigators, these results complement clinical trial evidence and may help inform positioning of esketamine in the treatment algorithm for MDSI; they suggest cost‑effectiveness analyses and further research across broader payer populations as useful next steps. The authors refrain from causal claims, noting the descriptive nature of the study and calling for future adjusted analyses.

Among commercially insured US patients with MDSI, mean all‑cause acute care HRU and medical costs after treatment initiation trended lower among those initiated on esketamine nasal spray compared with those initiated on ECT or on antidepressant with SGA augmentation. Reductions from the pretreatment period in acute care HRU and medical costs were larger following esketamine initiation than following ECT, SGA augmentation, or antidepressant monotherapy initiation.