Esketamine nasal spray for major depressive disorder with acute suicidal ideation or behavior: description of treatment access, utilization, and claims-based outcomes in the United States

Major depressive disorder (MDD) affects a substantial proportion of US adults and can include suicidal ideation or behaviour (MDSI), a condition that is often underdiagnosed and may have risen during the COVID-19 pandemic. Previous work has documented the high clinical and economic burden associated with MDSI, including costly hospital care after suicide-related events, and highlighted gaps in prior treatment before such events. Esketamine nasal spray received US Food and Drug Administration approval for treatment-resistant depression (TRD) on 03/05/2019 and for MDSI on 08/05/2020; clinical trials showed rapid reductions in depressive symptoms when esketamine was combined with an oral antidepressant, but real-world evidence on access, utilisation, and outcomes in MDSI is limited. Zhdanava and colleagues set out to describe real-world access to and use of esketamine nasal spray among adults with evidence of MDSI, and to characterise healthcare resource use (HRU) and costs before and after treatment initiation. The study used an open claims database that allows inspection of pharmacy claim lifecycles (approved, rejected, abandoned), enabling an analysis of administrative barriers to treatment as well as patterns of dosing, session frequency, clinical severity, HRU, and costs in routine US practice shortly after esketamine's regulatory approvals.

The investigators performed a retrospective, descriptive analysis using Clarivate's Real World Data (RWD) product covering January 2016 to March 2021. The RWD database is a provider-based open claims dataset that links pharmacy and medical claims, captures claim adjudication status for pharmacy prescriptions (approved, rejected, abandoned), and reports charged medical amounts and pharmacy costs from a private payer perspective. Data were de-identified and HIPAA-compliant. The study population comprised adults with at least one esketamine pharmacy claim and evidence of MDSI in the 12 months before or on the date of esketamine initiation (the index date). To preserve sample size, the overall cohort included patients who initiated esketamine on or after 03/05/2019 (the date of FDA approval for TRD); a subgroup of patients initiating on or after 08/05/2020 (the MDSI approval date) was analysed separately (the 2020-initiator subgroup). Additional subgroup analyses included a 6-month subgroup (patients with ≥6 months of clinical activity after index) for pre/post comparisons over six months, and a 1-month subgroup (≥1 month of activity) as a sensitivity analysis for 1-month pre/post comparisons. Continuous clinical activity was defined using patient-level activity flags derived from pharmacy or medical claims. Key exclusions were initiation of esketamine prior to documented evidence of MDSI or prior to 03/05/2019, and any baseline diagnosis for schizophrenia-spectrum or other psychotic disorders. Outcomes described for the cohort(s) included esketamine access (final pharmacy claim status: approved, rejected, abandoned), reasons for claim rejection when available, treatment use (number, frequency and dose of treatment sessions identified by unique claim dates and NDC/HCPCS codes), HRU (all-cause and mental health-related per-patient-per-month [PPPM]) and healthcare costs (medical charges and pharmacy costs adjusted to 2021 US dollars using the medical care component of the US Consumer Price Index). Severity of depressive symptoms was proxied by most recent ICD-10-CM MDD diagnosis codes categorised by severity. The analysis was descriptive only: means, standard deviations, medians, frequencies and proportions were reported; no formal inferential statistics were performed.

A total of 269 patients in the overall cohort and 78 in the 2020-initiator subgroup had esketamine pharmacy claims whose adjudication status was observable. When the first treatment-session claim was a pharmacy claim, 46.8% of patients in the overall cohort had that claim approved, 38.7% had it rejected, and 14.5% abandoned it; corresponding figures for the 2020-initiator subgroup were 39.7% approved, 47.4% rejected, and 12.8% abandoned. Commonly recorded reasons for rejected claims included claim errors (about 53% overall), treatment not covered by the plan (about 53% overall), and prior authorisation requirements (26.9% overall). Approval rates rose across sessions, reaching 90.7% by the 8th session in the overall cohort and 81.3% in the 2020-initiator subgroup. On average, 4.8 attempts were made to submit a claim before a final decision was received. Among patients with at least one approved pharmacy claim or a medical claim for esketamine, 169 were initiated in the overall cohort and 47 in the 2020-initiator subgroup. The overall cohort had a mean age of 40.9 years and 62.1% were female; the 2020-initiator subgroup was slightly younger (mean 37.7 years). Mean [median] follow-up was 10.3 [not stated] months in the overall cohort and 3.2 months in the 2020-initiator subgroup. Treatment patterns during follow-up showed that patients in the overall cohort had a mean [median] of 11.1 esketamine sessions, while the 2020-initiator subgroup had 7.9 [4.0] sessions. The proportion completing at least the label-recommended eight sessions was 45.0% in the overall cohort and 38.3% in the 2020-initiator subgroup. Time from index to the 8th session had mean [median] 85.0 [58.5] days overall and 50.8 [49.0] days in the 2020 subgroup; by contrast, the label recommends eight doses in 28 days for MDSI. Most patients initiated at 56 mg (overall: 74.6%; 2020 subgroup: 61.7%) and many titrated to 84 mg by the second session (overall: 58.8%; 2020 subgroup: 70.0%), consistent with the recommended 84 mg dose for MDSI with possible reduction to 56 mg for tolerability. Concomitant care in the follow-up period included observed claims for at least one antidepressant in 39.6% of the overall cohort and 36.2% of the 2020-initiator subgroup, psychotherapy visits in 37.9% and 27.7% respectively, psychiatric diagnostic evaluations in 16.6% and 8.5%, inpatient psychiatric care in 7.7% and 2.1%, and electroconvulsive therapy in 5.9% and 2.1%. Among the 6-month subgroup (115 patients, 68.0% of those initiated), mean [median] age was 42.0 [42.5] years and 65.2% were female. Of patients with at least one MDD diagnosis in both pre- and post-periods (67.8% of the subgroup), the proportion coded as severe MDD fell from 76.9% in the 6 months pre-index to 60.3% in the 6 months post-index. All-cause HRU also trended lower post-initiation: the share with any all-cause inpatient admission fell from 37.4% pre-index to 19.1% post-index, emergency department visits from 42.6% to 33.9%, and outpatient visits from 92.2% to 81.7%. Mental health-related HRU components showed similar declines. Total mean ± SD all-cause PPPM healthcare costs in the 6-month subgroup decreased from $8,371 ± $15,792 in the pre-index period to $6,486 ± $7,614 [median $3,906] in the post-index period. The proportion of medical healthcare charges attributable to mental health was 65.9% pre-index and 65.8% post-index. In the 1-month sensitivity analysis (155 patients), inpatient admissions decreased from 11.0% pre-index to 3.2% post-index and outpatient visits from 62.6% to 58.1%. However, mean all-cause PPPM total costs rose from $6,941 ± $15,346 [median $918] in the month pre-index to $8,546 ± $10,622 in the month post-index; the extracted text for some 1-month medical-charge details is truncated and not fully clear.

Zhdanava and colleagues interpret these findings as evidence that patients with MDSI face substantial barriers to timely access to prescribed esketamine nasal spray in routine US practice, particularly for the first treatment session. The investigators identify administrative obstacles—physician claim errors, lack of plan coverage, and prior authorisation requirements—as frequent reasons for initial claim rejection, and note that some insurers may require inpatient admission before initiation. Practical burdens related to the treatment regimen and Risk Evaluation and Mitigation Strategy (REMS) requirements were also emphasised: twice-weekly visits, monitoring time that precludes driving, and the need to attend a REMS-certified centre may complicate adherence to the label-recommended schedule, especially for working-age adults; this may help explain why fewer than half of treated patients completed the eight-session course within the guideline time frame and why median time to the 8th session exceeded the label-recommended 28 days. Among patients who accessed esketamine, the authors report numerical reductions in indicators of disease severity, HRU and healthcare costs over the 6 months following initiation, consistent with clinical-trial evidence of rapid symptomatic improvement. At the same time they caution that pre/post changes may reflect regression toward the mean or other time-varying factors rather than a causal treatment effect. The authors acknowledge under-capture of some concomitant care in the dataset (for example, drug samples and out-of-network services), and they highlight several limitations that temper interpretation: pharmacy claims do not guarantee medication administration or adherence and exact administration dates may be uncertain; findings may not generalise to the uninsured; requiring continuous activity periods may introduce immortal-time bias; the dataset covered only up to 24 months of esketamine use at the time of analysis; pre/post comparisons are vulnerable to confounding by time-varying events; and the study period overlapped with the COVID-19 pandemic so pandemic-related effects could not be disentangled from treatment-associated patterns. Given these caveats, the authors suggest that health-plan providers and care systems should consider strategies to reduce administrative hurdles and support patients and caregivers with logistical barriers so that timely access to esketamine is not impeded. They also note that further studies with more recent data, longer follow-up and analytic designs capable of testing causal hypotheses are needed to confirm and extend these descriptive observations.