(ASPOT19) How many people would be eligible for treatment with nasal esketamine in Denmark? A critical assessment of the definition of treatment-resistant depression

Background: Nasal esketamine was approved to treat treatment-resistant depression (TRD, defined as after having tried >2 antidepressants) in combination with other antidepressants by the European Medical Agency in 2019. Nasal esketamine has not been recommended in Danish guidelines yet, partly because of a small evidence base, safety, and efficacy concerns and additionally because there is no consensus on the definition of TRD for identifying eligible patients.

Objectives: The objective was 1) To describe the characteristics and antidepressant treatment of patients (age 25-64 years) with varying definitions of TRD in clinical practice in Denmark; 2) To compare the identified characteristics with characteristics of participants in randomized controlled trials (RCTs) of esketamine.

Methods: We conducted a population-based cohort study of all individuals who initiated antidepressant treatment in Denmark between 2015-2018. We followed these patients for one year and identified their data on sociodemographics, clinical characteristics, redeemed prescriptions for antidepressants, and psychiatric hospital contacts from the national registers. Patients were classified the by number of different antidepressants redeemed during follow-up to define different levels of TRD.
To compare the identified characteristics with the characteristics of the patients, we conducted a review of relevant RCTs.

Results: During the study period, 68,417 individuals started antidepressant treatment for the first time since 1995. The mean age was 44 years and the sex distribution was in the study 54,3% females. During follow-up, 96.7% of patients used ≤2 antidepressants, 3.3% used 3 or 4 antidepressants, and 0.5% used ≥4 antidepressants. Of all antidepressant users, 4,081 (6.0%) were referred to a psychiatric hospital, including 175 (0.26%), who had tried >2 different antidepressants.
Compared with the participants of the RCTs, individuals from the population-based sample had less than 1-year duration of depression, had depression of unknown severity, and included people with psychotic features, substance abuse, or suicidality.

Conclusions: According to the labeled indication of esketamine for TRD (having tried >2 antidepressants) within a year of treatment initiation, 3.8% of antidepressant users would have been eligible for nasal esketamine, and 0.26% of antidepressant users with psychiatric hospital contacts. Consideration of depression severity, psychotic features, substance abuse, or suicidality to balance the benefit-risk profile of esketamine would decrease the number of eligible patients.