This real-world (n=269) analysis of esketamine (Spravato) use finds nearly 50% of patients had their first pharmacy claim approved. Of those approved, 45% had eight or more treatment sessions (as recommended), though spread over 85 days (versus 28 per the label). Patients had lower health utilization, but this could be due to factors outside of the esketamine treatment (e.g. regression to the mean).
Aims
To describe real-world esketamine nasal spray access and use as well as healthcare resource use (HRU) and costs among adults with evidence of major depressive disorder (MDD) with suicidal ideation or behavior (MDSI).
Methods
Adults with ≥1 claim for esketamine nasal spray and evidence of MDSI 12 months before/on the date of esketamine initiation (index date) were selected from Clarivate’s Real World Data product (01/2016-03/2021). Patients initiated esketamine on/after 03/05/2019 (esketamine approval for treatment-resistant depression; later approved for MDSI on 08/05/2020) were included in the overall cohort. Esketamine access (measured as approved/abandoned/rejected claims) and use were described post-index; HRU and healthcare costs (2021 USD) were described over 6 months pre- and post-index.
Results
Among 269 patients in the overall cohort with esketamine pharmacy claims, 46.8% had the first pharmacy claim approved, 38.7% had it rejected, and 14.5% abandoned their claim; 169 patients were initiated on esketamine in the overall cohort (mean age 40.9 years, 62.1% female); 45.0% had ≥8 esketamine treatment sessions (recommended per label) with a mean [median] of 85.0 [58.5] days from index to 8th session (per label 28 days). Among 115 patients with ≥6 months of data post-index, in the 6-month pre- and post-index, respectively, 37.4% and 19.1% had all-cause inpatient admissions, 42.6% and 33.9% had emergency department visits, 92.2% and 81.7% had outpatient visits; mean ± standard deviation all-cause monthly total healthcare costs were $8,371±$15,792 and $6,486±$7,614, respectively.
Limitations
This was a descriptive claims-based analysis; no formal statistical comparisons were performed due to limited sample size as data covered up to 24 months of esketamine use in the US clinical setting.
Conclusions
Nearly half of patients experience access issues with first esketamine nasal spray treatment session. All-cause HRU and healthcare costs trend lower in the 6 months after relative to 6 months before esketamine initiation.
Papers cited by this study that are also in Blossom
Canuso, C. M., Ionescu, D. F., Li, X. et al. · Journal of Clinical Psychopharmacology (2021)
Joshi, K., Pilon, D., Shah, A. et al. · Journal of Medical Economics (2023)
Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
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.
Methods: Adults with ≥1 claim for esketamine nasal spray and evidence of MDSI 12 months before/on the date of esketamine initiation (index date) were selected from Clarivate's Real World Data product (01/2016-03/2021). Patients initiated esketamine on/after 03/05/2019 (esketamine approval for treatment-resistant depression; later approved for MDSI on 08/05/2020) were included in the overall cohort. Esketamine access (measured as approved/abandoned/rejected claims) and use were described post-index; HRU and healthcare costs (2021 USD) were described over 6 months pre-and post-index. Results: Among 269 patients in the overall cohort with esketamine pharmacy claims, 46.8% had the first pharmacy claim approved, 38.7% had it rejected, and 14.5% abandoned their claim; 169 patients were initiated on esketamine in the overall cohort (mean age 40.9 years, 62.1% female); 45.0% had ≥8 esketamine treatment sessions (recommended per label) with a mean A c c e p t e d M a n u s c r i p t plan providers to remove hindrances related to compliance with plan requirements may ensure more timely access to esketamine for MDSI.
Major depressive disorder (MDD) is a recurrent psychiatric condition affecting 8.4% of adults in the United States (US). MDD causes considerable impairments in multiple areas of functioning that negatively affect patients' lives. Suicidal ideation and behavior can potentially be a devastating symptom of MDD. Patients with MDD are at increased risk for suicide, particularly during major depressive episodes (MDEs). According to the 2020 National Survey on Drug Use and Health, nearly 50% of adult patients with an MDE in the past year had either serious suicidal ideations or made suicide plans or attempts. Notably, the prevalence of MDD with acute suicidal ideation or behavior (MDSI) is likely underestimated given MDSI is an underdiagnosed condition. Some individuals with MDSI never seek mental health treatment, and hence are never diagnosed, for reasons such as stigma, concerns about being committed to a psychiatric hospital, and lack of insurance coverage. The prevalence of MDSI may have further increased during the COVID-19 pandemic, as quarantine measures and financial losses have placed a substantial strain on the mental health of the general population, leaving individuals vulnerable to mental health issues and suicidal behavior. For patients with existing MDSI, depressive symptoms may worsen, further contributing to increased suicidal risk. MDSI has been shown to be associated with a substantial economic burden. A recent US studyreported that among commercially insured adults with MDSI, the incremental healthcare costs relative to the non-MDD cohort were $7,839 per patient within the first month of a suicide-related event, largely driven by acute hospital care following the event. That study also found that nearly half of patients with MDSI did not receive antidepressants or psychotherapy prior to the suicide-related event. These findings suggest that early identification and treatment of patients with MDSI may reduce the risk of suicidal ideation or A c c e p t e d M a n u s c r i p t behavior, which may in turn prevent the subsequent economic burden associated with acute care. Antidepressants, as monotherapy or combination therapy, have demonstrated efficacy in treating depressive episodes, which supports their use for individuals with MDSI. For patients with MDD at high risk of suicide, electroconvulsive therapy (ECT) may be considered. Esketamine nasal spray is a novel therapy approved by the US Food and Drug Administration (FDA) for treatment-resistant depression (TRD) on 03/05/2019and for MDSI on 08/05/2020. The esketamine MDSI trials were among the first antidepressant global registration studies to enroll patients with MDD at imminent risk of suicide, in which esketamine has demonstrated rapid and significant reduction in depressive symptoms amongst patients with MDSI, when taken in combination with an oral antidepressant. Since suicidal ideation or behavior symptoms may manifest in both MDD and TRD, patients with MDSI could have been initiated on esketamine after its approval for either indication. Consequently, variations in patient profiles related to drug indication approvals may exist in clinical practice. Our previous study using the IBM MarketScan Commercial and Medicare Supplemental Databases has found that most patients with TRD who initiated esketamine nasal spray completed induction treatment at dosing intervals longer than the label recommendation. However, little is known about esketamine use for MDSI in the real world. Notably, TRD and MDSI are two distinct indications for esketamine nasal spray, and that timely access to treatment can be particularly important for patients with MDSI. Therefore, based on just over six months of data available since the approval of esketamine nasal spray for MDSI and up to 24 months since its approval for TRD at the time of the study initiation, the aim of this hypothesis generating study was to understand characteristics of patients with MDSI initiated on esketamine nasal spray and describe their treatment patterns, healthcare resource use (HRU), costs, as well as access to esketamine nasal spray. This new study used Clarivate's Real World Data product, an open claims database containing information on prescription life cycle allowing for an analysis of access to esketamine based on approved, rejected, and abandoned esketamine pharmacy claims and reasons for claim rejection by insurer.
Data were obtained from the Clarivate's Real World Data (RWD) product (01/2016-03/2021), a provider-based open claims database that collects and links information from different pharmacy and clinical networks. The RWD product contains patient demographics, medical claims (including charged amounts, i.e., payment amount for the entire claim as requested by providers), and pharmacy claims (including costs from a private payer's perspective, as well as status of pharmacy claims, i.e., approved, rejected, abandoned [defined below]). The RWD product includes patients from all US regions. Data were de-identified and complied with the patient requirements of the Health Insurance Portability and Accountability Act (HIPAA) of 1996; therefore, no review by an institutional review board was required per Title 45 of CFR, Part 46.101(b)(4).
A retrospective observational descriptive study design was used. The index date was defined as the date of initiation of esketamine nasal spray on or after the date of evidence of MDSI, and on or after 03/05/2019 (the date of esketamine nasal spray approval for TRD, its first indication, was used to preserve sample size). The baseline period was defined as the 12-month period of continuous clinical activity before the index date. Clinical activity was based on the first and last patient-level activity flags in the data, with flags defined as either a pharmacy or a medical claim. The follow-up period spanned from the index date until the earliest of the end of continuous clinical activity or end of data availability.
To increase sample size, patients with MDSI initiated on esketamine on or after 03/05/2019 (esketamine approval date for TRD in the US) were included in the overall cohort. Given the esketamine approval date for MDSI in the US was on 08/05/2020, a subgroup analysis among patients with MDSI initiating esketamine only on or after 08/05/2020 (i.e., the 2020-initiator subgroup) was also conducted to validate trends observed in the overall cohort.
Among patients in the overall cohort, patients with ≥6 months of clinical activity following the index date comprised another subgroup (i.e., the 6-month subgroup), in which outcomes were described during the most recent 6 months of the baseline period and during the first 6 months of the follow-up period. Since the recommended treatment course of esketamine for MDSI is 8 treatment sessions in 1 month, a sensitivity analysis was also conducted among patients in the overall cohort who had ≥1 month of clinical activity following the index date (i.e., the 1-month subgroup); in this analysis, outcomes were described during the last month of the baseline and the first month of the follow-up periods.
Patients were included in the study if they met the following criteria: had ≥1 pharmacy claim Patients were excluded from the study if they initiated esketamine before evidence of MDSI, before the approval date of esketamine for TRD (03/05/2019), and/or had ≥1 claim with a diagnosis for schizophrenia spectrum or other psychotic disorders during the baseline period (ICD-10-CM: F06.0, F06.1, F06.2, F20.81, F20.9, F21, F22, F23, F25.0, F25.1, F28, F29).
Esketamine nasal spray access and use were reported for the overall cohort and the 2020initiator subgroup. Specifically, access to esketamine was assessed among patients with A c c e p t e d M a n u s c r i p t pharmacy claims for esketamine of any status (i.e., approved, rejected, or abandoned), as claim status information was available only for pharmacy claims. Approved claims are claims submitted by a pharmacy and approved for payment by health plans after claims adjudication. Rejected claims are adjudicated claims for prescriptions denied by health plans. Abandoned claims are adjudicated claims for prescriptions, approved by health plans that patients decided to abandon, usually due to cost or non-compliance. Only the final status of each claim was reported. For esketamine use, esketamine treatment sessions (number, frequency, and dose) were assessed among patients with approved pharmacy or medical claims for esketamine. Esketamine treatment sessions were identified based on claims observed on unique days. The dose of esketamine treatment sessions was based on NDC and HCPCS codes for esketamine pharmacy and medical claims (i.e., the dose of 56 mg was identified using NDC code 50458-0028-02 and HCPCS code G2082, and the dose of 84 mg was identified using NDC code 50458-0028-03 and HCPCS code G2083; dose for HCPCS code S0013 was dependent on number of units). The following outcomes were reported among the 6-month subgroup of the overall cohort during the 6 months pre-and post-index: severity of depressive symptoms based on the most recent diagnosis for MDD among patients with ≥1 MDD diagnosis both pre-and post-index (ICD-10-CM codes for severe: F32.2, F32.3, F33.2, F33.3; moderate: F32.1, F33.1; mild: F32.0, F33.0; unspecified: F32.9, F33.9; in remission: F32.4, F32.5, F33.4), all-cause and mental healthrelated per-patient-per-month (PPPM) HRU and healthcare costs. All-cause and mental healthrelated PPPM HRU and healthcare costs were also reported for the sensitivity analysis, in the 1month subgroup during the 1 month pre-and post-index. Healthcare costs, which included pharmacy costs from a private payer's perspective and medical costs reported as charged amounts were adjusted for inflation using the medical care component of the US Consumer Price Index and presented in 2021 US dollars.
Analysis was descriptive with means, standard deviations (SDs), and medians reported for continuous variables and frequencies and proportions reported for binary variables.
A total of 269 patients in the overall cohort and 78 patients in the 2020-initiator subgroup had pharmacy claims of esketamine nasal spray. When the claim for the first treatment session was a pharmacy claim, 46.8% and 39.7% of patients had the claim approved, 38.7% and 47.4% had the claim rejected, and 14.5% and 12.8% abandoned their claim, in the overall cohort and 2020initiator subgroup, respectively (Figure). The main reasons for rejections were "claim errors" (overall cohort: 52.9%; 2020-initiator subgroup: 54.1%), "not covered by plan" (overall cohort: 52.9%; 2020-initiator subgroup: 45.9%), and "prior authorization required" (overall cohort: 26.9%; 2020-initiator subgroup: 37.8%). The approval rate of esketamine nasal spray treatment sessions was lowest for the first session and increased to 90.7% and 81.3% by the 8th session in the overall cohort and 2020-initiator subgroup, respectively (Figure). The mean [median] number of attempts to submit a claim before receiving a final decision from health plans was 4.8
A total of 169 patients in the overall cohort and 47 in the 2020-initiator subgroup were initiated on esketamine nasal spray (i.e., had ≥1 approved pharmacy claim or a medical claim for esketamine). Overall, patients had similar baseline characteristics (Table). Patients in the 2020-initiator subgroup were slightly younger than patients in the overall cohort (mean age of 37.7 vs 40.9 years). Nearly all patients had a diagnosis of suicidal ideation or behavior during the baseline period (99.4% of the overall cohort and 97.9% of the 2020-initiator subgroup), with the The mean [median] number of months of follow-up was 10.3in the overall cohort and 3.2in the 2020-initiator subgroup.
In the overall cohort and 2020-initiator subgroup, respectively, 39.6% and 36.2% of patients had claims for ≥1 unique antidepressant agent during the follow-up period; the most frequently observed antidepressants are presented in Table. Also, 37.9% of the overall cohort and 27.7% of the 2020-initiator subgroup had a psychotherapy visit; and 16.6% in the overall cohort and 8.5% in the 2020-initiator subgroup received a psychiatric diagnostic evaluation. The proportion of patients who received care in an inpatient psychiatric facility during the follow-up period was 7.7% in the overall cohort and 2.1% in the 2020-initiator subgroup. The proportion of patients who received electroconvulsive therapy during the follow-up period was 5.9% in the overall cohort and 2.1% in the 2020-initiator subgroup.
During the follow-up period, patients in the overall cohort had a mean [median] of 11.1esketamine nasal spray treatment sessions, while patients in the 2020-initiator subgroup had a mean [median] of 7.9 [4.0] sessions. The proportion of patients completing ≥8 esketamine A c c e p t e d M a n u s c r i p t treatment sessions (recommended treatment course per label)was 45.0% in the overall cohort and 38.3% in the 2020-initiator subgroup (Figure). The mean [median] time from the index date to the 8th session was 85.0 [58.5] days in the overall cohort and 50.8 [49.0] days in the 2020-initiator subgroup; per label, esketamine is indicated as 8 doses in 4 weeks (28 days) for patients with MDSI. Most patients initiated esketamine with a dose of 56 mg (overall cohort: 74.6%; 2020-initiator subgroup: 61.7%) and titrated to the dose of 84 mg by the 2nd session (overall cohort: 58.8%; 2020-initiator subgroup: 70.0%); per label, the recommended dose of esketamine for MDSI is 84 mg and may be reduced to 56 mg based on tolerability.
Among 169 patients initiated on esketamine nasal spray, 115 (68.0%) had ≥6 months of followup after the index date. The mean [median] age of this 6-month subgroup was 42.0 [42.5] years and 65.2% were female.
A total of 67.8% of patient in the 6-month subgroup had ≥1 diagnosis for MDD during both the 6-month pre-and post-index periods. The proportion of patients with severe MDD was 76.9% in the 6 months pre-index and 60.3% in the 6 months post-index (Supplementary Figure).
All-cause and mental health-related HRU in the 6-month subgroup appeared lower in the 6 months after relative to the 6 months before esketamine initiation. During the 6-month preand post-index periods, 37.4% and 19.1% of patients had ≥1 all-cause inpatient admission, 42.6% and 33.9% had ≥1 all-cause emergency department visit, and 92.2% and 81.7% had ≥1 all-cause outpatient visit, respectively. Similar trends were observed for all mental healthrelated HRU components (Supplementary Figure).
The total mean ± SD [median] all-cause PPPM healthcare costs (i.e., medical charges and pharmacy costs) incurred by patients in the 6-month subgroup were $8,371 ± $15,792in the 6 months pre-index and $6,486 ± $7,614 [$3,906] in the 6 months post-index (Figure).). The proportion of mental health-related medical healthcare charges among all-cause medical healthcare charges were 65.9% in the 6 months pre-index and 65.8% in the 6 months post-index.
Among 169 patients initiated on esketamine nasal spray, 155 (91.7%) patients had ≥1 month of follow-up after the index date and were included in the sensitivity analysis.
All-cause inpatient and outpatient HRU appeared to be lower in the month after esketamine initiation relative to the month before initiation. Specifically, 11.0% and 3.2% of patients had ≥1 all-cause inpatient admission, and 62.6% and 58.1% of patients had ≥1 all-cause outpatient visit during the 1-month pre-and post-index periods, respectively. Moreover, reductions in all mental health-related HRU components were observed (Supplementary Figure).
The total mean ± SD [median] all-cause PPPM healthcare costs incurred by patients in the 1month subgroup were $6,941 ± $15,346 [$918] in the month pre-index and $8,546 ± $± 10,622in the month post-index (Supplementary Figure). The mean ± SD [median] all-cause PPPM medical healthcare charges decreased from $6,786 ± $15,330 [$748] in the month pre-). The proportion of mental health-related medical healthcare charges among all-cause medical healthcare charges were 79.4% in the month pre-index and 59.6% in the month post-index.
This real-world observational study highlights that patients with MDSI face challenges when accessing prescribed esketamine nasal spray in the real world, particularly for the first treatment session. At the same time, it suggests potential benefits of esketamine nasal spray in mitigating the clinical and economic burden of MDSI among those who manage to gain access to the drug. Barriers to esketamine adoption in clinical practice, such as administrative requirements of prior authorization from payers, have been recognized; however, studies specifically evaluating patient access to prescribed esketamine treatment are limited. The current claimsbased analysis revealed that a large portion of patients with MDSI had difficulty accessing their initial esketamine treatment due to physician claim errors, treatment not covered by patient's insurance, and prior authorization requirement. Patients may also be reluctant to be treated in hospitals due to stigma, but some insurance companies may require an inpatient admission prior to initiation of esketamine treatment. Notably, timely access to treatment is crucial for patients with MDSI because of the serious consequences if the condition is left untreated, as the functional and social impairments associated with the suicidal ideation or behavior of patients with MDSI can pose a negative impact on patients' daily living. In this study, among those who had access to the esketamine nasal spray, less than half completed the label-recommended treatment course, and the median time to completing the treatment was longer than the label recommendation. This may be due to the organizational challenges patients and their caregivers face complying with the treatment schedule. Esketamine is indicated for MDSI twice a week for four weeks, needs to be administered in a Risk Evaluation Management Strategy (REMS)-certified treatment center, and patients cannot drive after a treatment session. For working-age adults and their caregivers, a twice-a-A c c e p t e d M a n u s c r i p t week commute to a treatment center during the working hours with two additional hours of monitoring after each session could be burdensome. Of note, more than 95% of patients in this study were at the working age of under 65 years old. While the REMS requirements are intended to ensure the safe use of medications, support programs are warranted to help patients and caregivers manage the time and logistics related to the treatment. Esketamine nasal spray was approved by the FDA for the treatment of MDSI in August 2020, and clinical trials of esketamine have demonstrated rapid reduction in depressive symptoms in patients with MDSI receiving esketamine and concomitant oral antidepressant, compared with those receiving placebo plus oral antidepressant. However, MDSI has been associated with high HRU and healthcare costs, likely attributable to care in a hospital setting. In this study patient's mean age and sex ratio were comparable to those in the esketamine MDSI trials; a numerical decrease was observed in inpatient and emergency department visits and total healthcare costs 6 months following esketamine initiation, signaling a potential reduction in disease severity after treatment. The relatively higher healthcare costs in the 6 months pre-esketamine initiation could be due to the occurrence of SI events, which often result in hospitalizations and could be costly. The currently observed reductions in HRU and costs were consistent with the apparent reduction in MDD severity post-esketamine based on diagnosis codes. While lower HRU, costs and MDD severity could be associated with esketamine initiation, it is important to note that these changes in the post-esketamine period may be subject to regression towards the mean, as patients with a suicidal ideation or behavior event at baseline may have spontaneous remission from this extreme symptom. Nonetheless, the presence and severity of depressive symptoms, as well as the time spent depressed, have been shown to increase suicidal risk in patients with MDD, highlighting that early access to effective treatment may not only prevent symptom escalation but also reduce the associated economic burden among patients with MDSI. As rapid access to effective treatment for the underlying depression, such as esketamine, is crucial in MDSI care, health plan providers should ensure that timely access to esketamine is not hindered by compliance issues with plan requirements. Strategies to help patients with MDSI reach timely and effective care may prevent the devastating consequences of delayed treatment in this vulnerable population.
Esketamine nasal spray is indicated in conjunction with an oral antidepressant. The American Psychiatric Association guideline also recommends long-term use of antidepressants for suicidal patients with recurrent depressive disorder and highlights the central role of psychotherapies in the clinical care of suicidal patients. In the current study, about 40% of patients with MDSI in the overall cohort had observed claims for antidepressants during the follow-up period and about one-third of patients were observed to receive psychotherapy. This lower than anticipated utilization of antidepressants and psychotherapies may be at least partially explained by the limitations of the data, as drug samples and drugs and medical services paid out-of-pocket or received from providers outside of the Clarivate's RWD product network are not being captured. For the same reasons, the proportion of patients with TRD identified with a claims-based algorithm may be underreported.
The findings of this study should be considered in light of certain additional limitations. First, pharmacy claims do not guarantee that the medication dispensed was taken as prescribed; with respect to esketamine pharmacy claims, the exact date of the esketamine administration may be unknown. Second, the results may not be generalizable to individuals without health insurance. Third, the requirement for patients to have ≥1 and ≥6 months of continuous clinical activity post-index may have introduced immortal-time bias. Fourth, at the time this analysis was conducted, the data covered only 24 months of esketamine use in the US clinical setting. While HRU and costs were compared during 6-month baseline and follow-up periods to preserve sample size, studies with more recent data and longer follow-up are needed to confirm the trends in this descriptive analysis and test hypotheses related to outcomes of esketamine use. Fifth, in pre/post analyses, time-varying events may influence the association of treatment initiation with observed outcomes. Lastly, since the study period covers the COVID-19 era, it is not possible to separate the impact on treatment patterns, HRU, and costs caused by this pandemic from those associated with esketamine treatment. b. Suicide attempt or intentional self-harm as described by Hedegaard et al.c. Reported for patients with ≥1 code for suicidal ideation or behavior during the baseline period or on the index date.
Create a free account to open full-text PDFs.
Ionescu, D. F., Qiu, X., Lane, R. et al. · International Journal of Neuropsychopharmacology (2020)
Papers in Blossom that reference this study
Samalin, L., Rothärmel, M., Mekaoui, L. et al. · Journal of Psychiatric Research (2026)
Harding, L., Zhdanava, M., Teeple, A. et al. · Clinical Therapeutics (2025)