Access and real-world use patterns of esketamine nasal spray among patients with treatment-resistant depression covered by private or public insurance

Major depressive disorder (MDD) affects a substantial proportion of US adults and, when pharmacological treatment fails on two or more adequate antidepressant courses, patients are commonly classified as having treatment-resistant depression (TRD). Esketamine nasal spray, approved in the US in 2019 in combination with an oral antidepressant for adult TRD, has shown rapid reductions in depressive symptoms in clinical trials and efficacy in relapse prevention. However, access to esketamine in routine care is constrained by payer prior-authorisation processes and by in‑office administration requirements: dosing must occur in Risk Evaluation and Mitigation Strategy (REMS)-certified centres with at least two hours of post‑administration monitoring and restrictions on driving, factors that may impede patient attendance and adherence to the recommended dosing schedule. Teeple and colleagues aimed to describe real‑world patterns of access to and use of esketamine nasal spray among adults with TRD covered by private or public insurance in the United States. Using an open claims database, the study sought to quantify pharmacy claim approval rates for treatment sessions, characterise reasons for claim rejection or abandonment, and describe how patients actually received and continued esketamine over time compared with label‑recommended induction and maintenance schedules. The intention was to identify potential barriers to initiation and sustained use in routine clinical practice.

The investigators performed a retrospective observational study using Clarivate's Real World Data (RWD) open claims product covering January 2016 to March 2021. This database links pharmacy and medical claims across multiple provider networks; it does not capture services rendered outside the network and lacks explicit health‑plan enrolment periods. De‑identified data included patient demographics, medical and pharmacy claims, claim payment amounts and pharmacy claim adjudication status (approved, rejected, abandoned). No institutional review board review was required due to the de‑identified nature of the data. The index window began on 05 March 2019 (the US approval date for esketamine) and ran to March 2021. The index date was the date of esketamine initiation. A six‑month baseline period of clinical activity (any pharmacy or medical claim) preceded the index date; follow‑up extended from index to the earlier of end of clinical activity or end of data availability. Inclusion required at least one pharmacy or medical claim for esketamine on/after 05 March 2019, evidence of TRD during the major depressive episode (MDE) that led to esketamine initiation, at least one claim with an MDD diagnosis during that MDE, a minimum of six months of clinical activity pre‑index, and age 18 or older at index. Evidence of TRD was operationalised using treatment‑line algorithms: TRD required initiation of an antidepressant treatment line of adequate dose after changing two prior antidepressant treatment lines of adequate dose and duration. A treatment line could be antidepressant monotherapy or an antidepressant augmented with another antidepressant or a non‑antidepressant augmentation agent. Adequate duration was ≥42 days of continuous therapy with no gaps >14 days; adequate antidepressant dose was based on minimum recommended therapeutic doses from the Antidepressant Treatment Response Questionnaire. Pharmacy claim approval rates were assessed for each of the first eight esketamine treatment sessions (the induction phase per label), excluding patients with medical‑only claims due to small numbers. Pharmacy claims were adjudicated per session; final statuses were approved, rejected, or abandoned. Reasons for rejection could include multiple causes per claim. Esketamine treatment sessions were identified by unique claim dates; dose was inferred from drug and procedure codes. Treatment interruption was defined as a gap >60 days between sessions (twice the four‑week maintenance interval used in long‑term safety studies). A pre‑specified subgroup comprised patients with ≥42 days of follow‑up who completed ≥8 sessions within the first 42 days (an allowance of an extra two weeks was permitted to accommodate claim/adherence variability). Descriptive statistics (means, SDs, medians, frequencies, proportions) summarised characteristics and patterns, and Kaplan–Meier methods described time to first interruption >60 days.

The analysis of access included 535 patients with any pharmacy claim for esketamine (any final status). Among these, the mean age was 49.1 years, 65.4% were female, and most (81.1%) had commercial insurance (12.5% Medicare, 4.3% Medicaid). A subset of 273 patients had at least one approved pharmacy or medical claim and thus were counted as initiated on esketamine; their mean age was 49.3 years and 66.3% were female, with a similar insurance distribution. Access findings showed that among patients whose first esketamine claim was a pharmacy claim (N = 534), only 34.6% of first‑session claims were finally approved, 46.3% were rejected, and 19.1% were abandoned. The most common documented reasons for rejection were “not covered by plan” (57.1% of rejected claims), claim errors (52.6%), and “prior authorisation required” (22.7%). Approval rates rose sharply after the first session to 85.2% for the second session and remained stable across subsequent induction sessions. Of patients with a first‑claim rejection, 16.2% (40/247) later obtained approval via a re‑submitted pharmacy claim and 2.0% (5/247) had an esketamine medical claim. Mean time from first claim submission to final plan decision was 7.0 ± 17.0 days for the first session and decreased to 1.3 ± 4.0 days by the second session. Regarding prior treatments, among those who initiated esketamine the mean interval from MDE start to esketamine index was 58.2 months and from evidence of TRD to index was 27.6 months. Patients had an average of 4.0 antidepressant treatment courses since MDE start and 2.1 since evidence of TRD. Augmentation with non‑antidepressant agents was frequent (91.9% since MDE start; 74.4% since TRD evidence), most commonly second‑generation antipsychotics (57.0% since MDE; 52.7% since TRD evidence). Treatment‑pattern results among the 273 initiators showed a mean follow‑up of 11.8 ± 6.4 months and a mean of 11.8 ± 13.3 esketamine sessions per patient. Forty‑seven point six percent completed eight sessions (the labelled induction count); 43.2% had ≥9 sessions (entered maintenance phase I), 34.8% had ≥12 sessions (completed induction and maintenance phase I), and 32.6% had ≥13 sessions (entered maintenance phase II). Most patients started at the label‑recommended 56 mg dose (78.0%) and titrated to 84 mg by the third session (68.1%); by the 12th session 87.4% were on 84 mg. The mean time from index to the eighth session was 80.1 ± 71.9 days (label induction is 28 days). Median interval between the first and second sessions was eight days, then a median seven days between subsequent sessions up to the eighth. Kaplan–Meier analysis estimated the median time to first treatment interruption (>60 days) as 4.1 months; by six months, 64.9% had experienced such an interruption. Among 188 patients with an interruption, 21.3% later restarted treatment. A subgroup of 48 patients (17.6% of initiators) completed ≥8 sessions within 42 days; in this subgroup mean total sessions were 24.4 ± 27.2 over 10.9 ± 5.8 months. For them, mean time to the eighth session was 28.2 ± 5.0 days, 93.8% reached ≥9 sessions and 70.8% reached ≥13 sessions. Dosing patterns in the subgroup showed 95.8% started at 56 mg and a majority were on 84 mg by later sessions.

The authors interpret these findings as evidence that initial access to esketamine via pharmacy benefits is frequently impeded in real‑world US practice, with nearly half of first pharmacy claims rejected and common rejection reasons being non‑coverage, claim errors and prior‑authorisation requirements. Approval rates and adjudication speed improved substantially after the first session, which the authors suggest is consistent with obtaining prior authorisation that covers the induction phase and with a reduction in administrative errors after initial approval. In terms of use patterns, less than half of patients completed the eight‑session induction phase and only 17.6% completed induction within the approximate label‑recommended time window. The study team highlights practical barriers that may contribute: the twice‑weekly visits during induction combined with two hours of post‑dosing observation, inability to drive the same day, travel and caregiver needs, and the limited geographic availability of REMS‑certified centres. The authors note that adherence challenges are common in depression more broadly and add that the long mean interval observed between TRD evidence and esketamine initiation (about 27.6 months) could reflect provider, payer and patient‑level factors, or incomplete capture in the open claims data. Teeple and colleagues compare their findings with prior reports: an early‑access French cohort showed shorter, induction‑centred exposure, while a separate US closed‑claims study by the authors found broadly similar proportions completing induction and maintenance stages, supporting the external consistency of observed patterns. The investigators acknowledge important limitations: reliance on an open claims database that does not capture care outside network providers and lacks health‑plan enrolment information, potential underestimation or misclassification of treatment exposures, pharmacy claim dates that may not match administration dates, use of prescription‑fill algorithms that cannot confirm medication ingestion, lack of generalisability to the uninsured, and absence of data on reasons for treatment interruptions. Finally, the authors suggest that the findings point to opportunities for interventions to improve access and adherence, proposing collaborative efforts among manufacturers, healthcare providers, payers and patients and recommending future research to elucidate the drivers of the real‑world use patterns and to identify ways to enhance TRD care.

The study concludes that initial access to esketamine nasal spray can be hindered by prior authorisation requirements and claim filing errors, and that many patients who start treatment do not follow the label‑recommended induction schedule. Nevertheless, most patients who complete induction proceed to maintenance, which the authors interpret as indicative of therapeutic benefit for those who can access and adhere to treatment. They recommend collaborative strategies to improve both initial access and ongoing treatment compliance.