Barriers to Esketamine Nasal Spray Treatment Among Adults With Treatment-Resistant Depression

Major depressive disorder (MDD) affects a substantial proportion of the US population and a meaningful subset of these patients meet commonly used criteria for treatment-resistant depression (TRD), typically defined as failure to respond to two or more antidepressant trials. Individuals with TRD incur greater health-care utilisation, higher mortality and self-harm risk, and substantial direct and indirect costs. Since October 2019, esketamine nasal spray has been approved for adults with TRD (and for depressive symptoms with suicidal ideation) but under a risk evaluation and mitigation strategy it can only be dispensed in certified treatment centres where patients self-administer the drug and remain under observation; the induction regimen requires repeated visits during the first month. The repeat-travel administration model raises concerns that travel distance, insurance status and other social determinants of health (SDoH) could create barriers to initiating and continuing esketamine treatment. Joshi and colleagues set out to identify factors associated with initiation of esketamine, completion of the induction phase, and interruptions in therapy among US adults meeting TRD criteria. The study aimed to quantify how geographic distance to certified centres, clinical comorbidities, insurance type and county-level SDoH relate to real-world utilisation of esketamine, with the ultimate objective of informing whether alternative care models might be needed to improve access.

This was a retrospective observational comparative cohort study using a large US open medical and pharmacy claims database (Clarivate Real-World Data). The case-finding window ran from October 11, 2017, to February 28, 2022, and the analytic sample included all individuals aged 18–65 who met TRD criteria and either initiated esketamine on or after October 11, 2019 (cases) or met TRD criteria but did not initiate esketamine and instead initiated a new antidepressant after that date (controls). Continuous insurance eligibility was required (at least one medical or pharmacy claim in each 3-month period during the 6-month baseline and 6-month follow-up). A 5% random sample of eligible controls was included. TRD for controls was operationalised using diagnostic claims for MDD (two outpatient claims ≥30 days apart or one primary inpatient claim) plus pharmacy evidence of two antidepressant treatment failures (≥6 weeks’ duration followed by discontinuation, augmentation, or switch) and initiation of a third antidepressant. Individuals with bipolar disorder, schizophrenia, or schizoaffective disorder were excluded. Esketamine users were identified by paid pharmacy claims for 56 mg or 84 mg kits or medical claims for administration. Key covariates included demographics (age, sex, insurance type), clinical comorbidities captured by ICD-10-CM codes (including Charlson Comorbidity Index [CCI] and psychiatric diagnoses such as generalized anxiety disorder, PTSD, substance use disorders, alcohol use disorder and major depressive disorder with suicidal ideation), county-level SDoH measured using the CDC/ATSDR Social Vulnerability Index (SVI) components for socioeconomic status and race/ethnicity, and distance to the nearest certified esketamine treatment centre. Because the claims data only included a ZIP3 for residence, the investigators mapped individuals to counties by matching provider ZIP5s to the patient's ZIP3 and then assigned county-level urban/rural designations and SVI scores. Distance was estimated from county centroid to treatment centre address. Outcomes were: initiation (index esketamine claim), induction (completion of eight esketamine administrations within 45 days of initiation), and interruption (a 30-day gap without esketamine followed by a restart). The analysis compared 966 esketamine users and 39,219 controls on baseline characteristics using significance level P < .01 for univariate comparisons. Multivariate associations between covariates and the three outcomes were estimated using backwards stepwise logistic regression (retention P < .05), yielding adjusted odds ratios (ORs) with 95% CIs. Modelling used SAS v9.4.

The study identified 1,914 certified esketamine treatment centres in the US during the study period, present in 42 states and 619 counties. The analytic sample comprised 966 individuals who initiated esketamine and 39,219 controls who met TRD criteria but did not receive esketamine. Compared with controls, esketamine users were younger (mean 41.5 vs 45.1 years), had lower mean CCI (0.3 vs 0.8), were more often male (36.7% vs 25.1%), more likely commercially insured (80.6% vs 62.6%) and more likely to reside in urban counties (72.8% vs 60.3%) (all P < .01). Psychiatric comorbidities such as generalized anxiety disorder (55.3% vs 29.1%), sleep-wake disorders (34.1% vs 26.0%), PTSD (23.4% vs 11.6%), major depressive disorder with suicidal ideation (14.7% vs 9.0%), and OCD (5.4% vs 2.1%) were more frequent among esketamine users, whereas substance use disorder (14.0% vs 21.2%) and alcohol use disorder (6.2% vs 7.0%) were less common. Esketamine users were also more likely to be seen by psychiatrists (83.1% vs 37.9%) and less likely to have recent inpatient admissions or emergency visits. Distance to care differed markedly: esketamine users resided a mean 8.9 miles from the nearest treatment centre versus 20.4 miles for controls. Nearly half (49.9%) of controls lived more than 8.9 miles from a centre; this proportion rose to 91.6% among rural residents. Compared with living within 0–9 miles, the study reported initiation rate declines of 11.9% (10–19 miles), 50.8% (20–29 miles), 68.1% (30–39 miles), 75.9% (40–49 miles) and 92.8% (50+ miles). In adjusted models, factors associated with higher odds of initiating esketamine included PTSD (OR 2.52; 95% CI 2.15–2.96), major depressive disorder with suicidal ideation (OR 1.76; 95% CI 1.45–2.13), sleep-wake disorders (OR 1.62; 95% CI 1.41–1.87) and GAD (OR 1.46; 95% CI 1.23–1.62). Male sex was associated with greater initiation (OR 1.75; 95% CI 1.53–2.01). Increasing distance from a treatment centre showed a near-linear reduction in adjusted odds of initiation for each 5-mile increment: for example, compared with residence within 5 miles, the 5–9 mile band had OR 0.74 (95% CI 0.62–0.87) and 60+ miles had OR 0.04 (95% CI 0.02–0.10). A nonzero CCI score reduced the odds of initiation (OR 0.47; 95% CI 0.39–0.56). Regarding induction, 33.3% completed eight administrations within 30 days and 41.4% within 45 days. Higher adjusted odds of completing induction were observed for those with “other” insurance (OR 2.39; 95% CI 1.31–4.40) and with sleep-wake disorders (OR 1.37; 95% CI 1.03–1.82). Lower odds of induction completion were seen for individuals with higher CCI (OR 0.61; 95% CI 0.42–0.88), residents of counties in the highest-risk socioeconomic vulnerability category (OR 0.43; 95% CI 0.26–0.69), and residents of counties with higher proportions of Hispanic populations (OR 0.64; 95% CI 0.47–0.85). Fifteen point seven percent of esketamine users experienced an interruption in treatment. Adjusted odds of interruption were higher for individuals with alcohol use disorder (OR 3.0; 95% CI 1.64–5.47), those living 30+ miles from a treatment centre (OR 2.32; 95% CI 1.10–4.88), and those residing in counties with higher proportions of African American (OR 1.58; 95% CI 1.04–2.38), multirace (OR 1.56; 95% CI 1.03–2.37) or Hispanic residents (OR 1.49; 95% CI 1.03–2.17). Lower odds of interruption were observed among Medicaid beneficiaries (OR 0.39; 95% CI 0.20–0.78) and individuals with GAD (OR 0.53; 95% CI 0.36–0.76).

Joshi and colleagues interpret their findings as consistent with broader evidence that travel distance, rural residence and SDoH negatively influence mental health service utilisation. Distance to the nearest certified esketamine centre was associated with a near-linear decline in initiation, with residence 20–24 miles away linked to more than a 50% reduction in likelihood of starting treatment. Insurance status and medical comorbidity also related to initiation: individuals insured by Medicaid and those with greater physical comorbidity were less likely to start esketamine. The authors note that distance did not predict completion of the induction phase, but induction completion was lower among Medicaid beneficiaries, those with higher CCI, and residents of counties with high Hispanic proportions or the lowest SES. Interruptions in treatment were more likely with alcohol use disorder, greater distance and residence in counties with larger racial and ethnic minority populations; by contrast, Medicaid insurance and GAD were associated with fewer interruptions. The reduced likelihood of interruption among Medicaid-covered patients is discussed as possibly reflecting differences in prior authorisation, documentation requirements for continued treatment, or lower out-of-pocket costs under some plans; the authors caution these are plausible explanations rather than established causal mechanisms. Further interpretation highlights that esketamine users had more psychiatric comorbidities and greater contact with psychiatry providers, which may reflect referral patterns and diagnostic opportunities. The lower prevalence of substance use disorder among users may reflect prescriber caution given addiction concerns and sobriety requirements used in clinical trials. The authors emphasise that racial and ethnic disparities in initiating and maintaining esketamine treatment mirror longstanding inequities in US mental health care access and retention. The paper expands prior research by analysing a broader nonuser comparator group without restricting by distance to centres, by assessing demographic, insurance and comorbidity factors together, and by including treatment interruption as an outcome. The investigators suggest that alternative care delivery models — including provision in physician offices or supervised home-based administration — warrant study to address access barriers. Key limitations acknowledged include possible missing or misclassified data inherent to open claims sources; ecological assignment of distance and SDoH at county level using a ZIP3-to-ZIP5 mapping algorithm and county centroids rather than individual addresses; and limited sensitivity/specificity of claims-based methods for identifying suicidal ideation. The authors conclude that demographic, geographic and social determinants were strongly associated with initiation and continuation of esketamine therapy and argue that alternative models of care may be needed to improve equitable access for people with TRD.

Demographic, geographic and social determinants of health were strongly associated with whether individuals with TRD initiated and continued esketamine treatment. Most US counties lack a certified esketamine centre and increasing distance to the nearest centre was a consistent barrier to initiation, with nearly linear declines in uptake for each 5-mile increment. Independent of distance, people with medical comorbidities, residents of counties with high proportions of racial and ethnic minorities, and rural residents faced higher risk of not starting and not continuing treatment. Given the substantial clinical and economic burden of TRD and the therapeutic role of esketamine, the authors recommend exploring alternative models of care delivery to mitigate travel and other access barriers.