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Characteristics of Real-world Commercially Insured Patients With Treatment-resistant Depression Initiated on Esketamine Nasal Spray or Conventional Therapies in the United States

Open AccessPublished:October 04, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.09.005

      ABSTRACT

      Purpose

      This study aimed to characterize patients with treatment-resistant depression (TRD) initiating esketamine or conventional therapies.

      Methods

      Adults with major depressive disorder (MDD) were selected from the IBM MarketScan Databases. A claims-based algorithm identified patients with evidence of TRD, defined as initiation of a new antidepressant therapy after 2 different antidepressant trials of adequate dose and duration during the most recent major depressive episode. Patients receiving treatment on/after March 5, 2019 (esketamine approval date for TRD), were classified to the esketamine cohort if they newly initiated esketamine (index date) or to the TRD conventional therapies cohorts if they newly initiated electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or pharmacologic therapies (index date was the therapy initiation date, prioritizing ECT, then TMS, then pharmacologic antidepressant therapies). Patient characteristics in the 6 months before therapy initiation were described.

      Findings

      The esketamine cohort included 246 patients (mean age, 46.5 years; 63.0% female), and the TRD conventional therapies cohorts included 104,164 patients (mean age, 46.9 years; 74.8% female; 0.4% initiated ECT, 1.2% initiated TMS). During the 6 months preindex, in the esketamine and TRD conventional therapies cohorts, 77.6% and 41.4% received psychotherapy and 82.9% and 34.2% had a psychiatrist visit, respectively. Most patients had outpatient care for MDD in the esketamine (91.9%) and TRD conventional therapies (63.6%) cohorts; 57.3% and 21.0% received care at specialized mental health care settings. MDD was classified as “severe” among 81.3% and 35.1% of patients in the esketamine and TRD conventional therapies cohorts . Preindex mental health–related (MHR) inpatient admissions and emergency department visits were identified in 12.2% and 16.3% of the esketamine cohort and in 8.2% and 10.3% of the TRD conventional therapies cohort. Before therapy initiation, 34.6% and 17.6% of the esketamine and TRD conventional therapies cohorts received ≥3 unique antidepressants. Suicidal ideation or behavior was observed in 8.5% and 3.6% of the esketamine and TRD conventional therapies cohorts pretherapy initiation. Mean monthly all-cause health care costs in the esketamine cohort were $2532 (58.2% MHR); in the TRD conventional therapies cohorts, costs were $1873 (32.4% MHR).

      Implications

      Among patients with TRD, those initiating esketamine relative to conventional therapies displayed higher MDD severity, used more MHR inpatient/emergency department services and antidepressant treatments, and incurred higher health care costs 6 months pretherapy initiation. These findings suggest potential benefits of identifying and treating patients with TRD earlier with more effective treatments and should inform payers in consideration of esketamine coverage.

      Key words

      Introduction

      Major depressive disorder (MDD) is a recurrent psychiatric condition affecting 7.8% of adults in the United States annually.

      Substance Abuse and Mental Health Services Administration (SAMHSA). Results from the 2019 National Survey on Drug Use and Health: key substance use and mental health indicators in the United States. Available at: https://www.samhsa.gov/data/sites/default/files/reports/rpt29393/2019NSDUHFFRPDFWHTML/2019NSDUHFFR090120.htm#mde. Accessed 2020.

      It is a debilitating disease with heterogeneous symptoms, which may include depressed mood, diminished interest or pleasure, disturbed sleep, and impaired cognition lasting for ≥2 weeks.
      • Otte C
      • Gold SM
      • Penninx BW
      • et al.
      Major depressive disorder.
      Guidelines for treatment choices in MDD use severity of symptoms as a critical factor in their recommendations.
      • Gelenberg AJ
      • Freeman MP
      • Markowitz JC
      • et al.
      The American Psychiatric Association Practice Guideline for the Treatment of Patients With Major Depressive Disorder.
      Patients with mild to moderate symptoms are recommended to initiate antidepressants; depression-focused psychotherapy alone may also be used. Patients with severe symptoms and those who have not responded to initial pharmacologic interventions may receive combined antidepressants or augmentation with non-antidepressant agents (eg, atypical antipsychotics or, less commonly, anticonvulsants)
      • Patkar AA
      • Pae CU.
      Atypical antipsychotic augmentation strategies in the context of guideline-based care for the treatment of major depressive disorder.
      or initiate electroconvulsive therapy (ECT). Furthermore, ECT is recommended for urgent cases; for instance, in patients with significant functional impairment or suicidal risk, or severely ill patients treated in an inpatient setting. Transcranial magnetic stimulation (TMS) may also be used as a subsequent treatment following treatment with antidepressants.
      • Gelenberg AJ
      • Freeman MP
      • Markowitz JC
      • et al.
      The American Psychiatric Association Practice Guideline for the Treatment of Patients With Major Depressive Disorder.
      Among patients with MDD who receive pharmacologic therapy, 30% experience inadequate response to ≥2 different antidepressant treatment courses of adequate dose and duration.
      • Zhdanava M
      • Pilon D
      • Ghelerter I
      • et al.
      The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States.
      This is the most common definition of treatment-resistant depression (TRD), which is also consistent with the definition provided by the US Food and Drug Administration.

      Gaynes BN, Asher G, Gartlehner G, et al. Definition of Treatment-Resistant Depression in the Medicare Population. Technology Assessment Program. Project ID: PSYT0816. (Prepared by RTI–UNC Evidence-Based Practice Center under Contract No. HHSA290201500011I_HHSA29032006T.), 2018; 1-115.

      ,

      US Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Accessed June 7, 2021.

      TRD, representing $43.8 billion in health care, unemployment, and productivity costs annually, is responsible for nearly one half of the total annual burden of medication-treated MDD in the United States.
      • Zhdanava M
      • Pilon D
      • Ghelerter I
      • et al.
      The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States.
      Although TRD is conventionally treated similarly to severe MDD (ie, with antidepressant combinations, non-antidepressant augmentation agents, ECT, TMS),
      • Otte C
      • Gold SM
      • Penninx BW
      • et al.
      Major depressive disorder.
      ,
      • Gelenberg AJ
      • Freeman MP
      • Markowitz JC
      • et al.
      The American Psychiatric Association Practice Guideline for the Treatment of Patients With Major Depressive Disorder.
      novel treatments are emerging.
      • Otte C
      • Gold SM
      • Penninx BW
      • et al.
      Major depressive disorder.
      Esketamine nasal spray is a novel therapy approved by the US Food and Drug Administration in March 2019 for the treatment of TRD in conjunction with an oral antidepressant.

      US Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Accessed June 7, 2021.

      In clinical trials, esketamine reduced depressive symptoms as soon as 24 hours,
      US Food and Drug Administration
      SPRAVATO® (esketamine) Prescribing Information.
      compared with the 4 to 8 weeks typically required by conventional antidepressants to reach full effectiveness.
      • Gelenberg AJ
      • Freeman MP
      • Markowitz JC
      • et al.
      The American Psychiatric Association Practice Guideline for the Treatment of Patients With Major Depressive Disorder.
      Moreover, reduction in the severity of depressive symptoms and in relapse risk were greater with esketamine plus an oral antidepressant compared with placebo plus an oral antidepressant.
      • Popova V
      • Daly EJ
      • Trivedi M
      • et al.
      Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study.
      ,
      • Daly EJ
      • Trivedi MH
      • Janik A
      • et al.
      Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial.
      Given the demonstrated efficacy of esketamine in clinical trials, a better understanding is needed of the characteristics of patients who receive this therapy in the real world. Cepeda et al
      • Cepeda MS
      • Kern DM
      • Canuso CM.
      At baseline patients treated with esketamine have higher burden of disease than other patients with treatment resistant depression: learnings from a population based study.
      recently found that patients with MDD initiated on esketamine had a higher burden of disease before treatment initiation relative to those initiated on conventional MDD therapies, suggesting that in line with the expectations, the real-world use of esketamine is reserved for more severe patients. However, patients included in that study were not required to show evidence of TRD. The present study explored if even among patients with TRD, those who receive esketamine seem more severe than those who receive conventional MDD therapies. Results from this study may inform payer coverage for esketamine and may aid clinicians in better understanding patients’ clinical profiles based on current real-world practice and help tailor treatment decisions accordingly.

      Patients and Methods

      Data Source

      The study used data from the IBM MarketScan Commercial and Medicare Supplemental Databases (January 1, 2010–July 31, 2020). The data contained information on patient demographic characteristics and insurance eligibility as well as medical and prescription drug claims that spanned all US census regions, with a concentration in the South and North Central regions. All data were de-identified and complied with the Health Insurance Portability and Accountability Act.

      Study Design

      This was a descriptive study that used a retrospective cohort design to summarize the characteristics of patients with TRD before treatment initiation. The index window began on March 5, 2019 (esketamine approval date for TRD), or the date on which evidence of TRD was confirmed with a claims-based algorithm (defined in the “Patient Selection Criteria” section), whichever was later. The index date was the date of esketamine initiation (esketamine cohort) or the date of initiation of conventional therapies, prioritizing ECT, followed by TMS, and then by pharmacotherapies. The baseline period was the 6-month period preceding the index date.

      Study Cohorts

      To be representative of treatment modalities recommended in guidelines and used in real-world clinical practice, study cohorts included patients with TRD newly initiated on pharmacologic and nonpharmacologic therapies. Specifically, we identified the following cohorts of patients with TRD: (1) esketamine cohort; (2) conventional therapies cohort, which included patients newly initiating ECT, TMS, or conventional MDD pharmacologic therapies; (3) ECT cohort, which included patients newly initiating ECT who did not initiate esketamine; (4) TMS cohort, which included patients newly initiating TMS who did not initiate esketamine or ECT; and (5) antidepressant pharmacotherapy cohorts, which included patients newly initiating antidepressant pharmacotherapy who did not initiate esketamine, ECT, or TMS. We defined antidepressant pharmacotherapy cohorts based on a benchmark treatment selected as the most commonly used treatment of its type: the adjunctive aripiprazole cohort (aripiprazole was the most common atypical antipsychotic used adjunctively with an antidepressant at index date), the adjunctive bupropion cohort (bupropion was the most common adjunctive antidepressant at index date), the adjunctive gabapentin cohort (gabapentin was the most common adjunctive non-antipsychotic, non-antidepressant agent at index date), and the antidepressant monotherapy cohort (including escitalopram, desvenlafaxine, vortioxetine, or bupropion; all were the most common agents in their class used in monotherapy at index date).

      Patient Selection Criteria

      Patients were included in the esketamine cohort if they newly initiated esketamine on or after March 5, 2019 (ie, patients never had any esketamine prescription before the index date), and on the date of or after evidence of TRD; there were no patients with claims for esketamine before March 5, 2019, observed in this study, and those with claims for esketamine before evidence of TRD were excluded (see Supplemental Figure 1 in the online version at doi:10.1016/j.clinthera.2022.09.005). Patients were included in conventional therapies cohorts if they initiated ECT, TMS, or antidepressant pharmacotherapy on or after March 5, 2019, and on the date of or after evidence of TRD; patients with evidence of the index regimen or any claims for esketamine during the 6-month baseline period were excluded from the conventional therapies cohorts. In addition, all patients met the following inclusion criteria: ≥1 diagnosis for MDD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] or International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM], codes 296.2X, 296.3X, F32.X [excluding F32.8], F33.X [excluding F33.8]) during the major depressive episode (MDE) in which the index regimen was identified; ≥6 months of continuous insurance eligibility before the index date; and aged ≥18 years as of the index date.

      Evidence of TRD

      We identified evidence of TRD during an MDE (Figure 1). The MDE spanned the date of the first observed MDD diagnosis or antidepressant to the date of the last observed MDD diagnosis or last day of supply of an antidepressant followed by a ≥6-month clean period without MDD diagnoses or antidepressant claims. Evidence of TRD was defined as the initiation of a new line of antidepressant therapy of adequate dose after changing 2 different lines of antidepressant therapy of adequate dose and duration. A line of antidepressant therapy comprised either an antidepressant monotherapy or an antidepressant augmented with another antidepressant or non-antidepressant augmentation agent (ie, atypical antipsychotic, psychostimulant, anticonvulsant, thyroid hormone, lithium, buspirone). A change of a line included a switch of an antidepressant or an addition of another antidepressant or non-antidepressant augmentation agent. We defined adequate duration as ≥42 days of continuous treatment without gaps >14 days, and an adequate dose (for antidepressants only) was based on the minimum recommended therapeutic dose in the Antidepressant Treatment Response Questionnaire for geriatric and nongeriatric patients.

      Massachusetts General Hospital (MGH). Antidepressant Treatment Response Questionnaire (ATRQ), Geriatric Population, version 3. 2016.

      ,

      Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), Non-Geriatric Population, version 2. 2015.

      Figure 1
      Figure 1Identification of treatment-resistant depression (TRD). *Adequate dose (for antidepressants [ADs] only) was based on the minimum recommended therapeutic dose in the Antidepressant Treatment Response Questionnaire for geriatric and nongeriatric patients.

      Massachusetts General Hospital (MGH). Antidepressant Treatment Response Questionnaire (ATRQ), Geriatric Population, version 3. 2016.

      ,

      Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), Non-Geriatric Population, version 2. 2015.

      Adequate duration was defined as ≥42 days of continuous treatment without gaps >14 days. A line of therapy comprised either an AD in monotherapy or an AD augmented with another AD or a non-AD augmentation agent. §The line of therapy initiated on the date of evidence of TRD was only required to be of adequate dose, not of adequate duration. Nevertheless, it is possible that it was of both adequate dose and duration. dx = diagnosis; MDD = major depressive disorder; MDE = major depressive episode; tx = treatment.

      Sensitivity Study Populations

      For esketamine to be covered by a health plan, a patient must meet prior authorization criteria, which ensure that esketamine is covered for the intended use.
      Janssen
      Supporting Appropriate Payer Coverage Decisions.
      These criteria vary by health plan, and they may include a requirement of documentation of patient's scoring on a clinical assessment scale such as the 17-item Hamilton Depression Rating Scale or the 10-item Montgomery-Åsberg Depression Rating Scale, as well as history of trial and failure of several antidepressants. Given the prior authorization criteria, it is unlikely for a patient, who does not meet the clinical definition of TRD, to receive coverage for this treatment. Thus, as a sensitivity analysis, we explored characteristics of patients initiated on esketamine or the conventional therapies cohorts in 2 additional populations: (1) all-comers (ie, patients not required to meet the claims-based definition of TRD or have an MDD diagnosis); and (2) patients with MDD (ie, ≥2 MDD diagnoses on different dates during the baseline period but not required to meet the claims-based definition of TRD).

      Patient Characteristics

      Patient characteristics were measured during the 6-month baseline period and included demographic characteristics, MDD severity (based on ICD-10-CM diagnosis codes), diagnoses for other conditions (based on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition,
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders: DSM-5.
      and the Elixhauser list of comorbidities),

      Elixhauser A, Steiner C, Kruzikas D. HCUP Comorbidity Software. Healthcare Cost and Utilization Project (HCUP) 2015. Available at: https://www.hcup-us.ahrq.gov/toolssoftware/comorbidity/comorbidity.jsp#download, Last accessed: August 12, 2020.

      the Quan–Charlson Comorbidity Index,
      • Quan H
      • Sundararajan V
      • Halfon P
      • et al.
      Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.
      treatment patterns (ie, pharmacotherapy and specialized mental health care use), overall health care resource utilization (HRU), and health care costs.
      Antidepressant use (monotherapy and augmentation therapy) was based on days of medication supply in pharmacy claims. Antidepressant augmentation therapy was defined as an overlapping coverage for >6 weeks (42 consecutive days) without gaps >14 days of either ≥2 antidepressant agents, or ≥1 augmentation agent and ≥1 antidepressant agent. Patients with ≥1 claim for an antidepressant agent without evidence of antidepressant augmentation therapy use were considered to be on antidepressant monotherapy.
      Specialized mental health care included specialist visits (eg, psychiatrist, psychologist) identified by using the respective procedure codes. Based on the proportion of claims for specialized mental health care, we categorized outpatient care for MDD as predominantly specialized mental health care or primary care. Patients predominantly involved in specialized mental health care had ≥50% of outpatient MDD claims for specialized mental health care.
      We reported HRU by categories, including inpatient admission, emergency department visits, and outpatient visits. Specifically, we considered inpatient admission and emergency department visits as acute HRU. Health care costs are reported in 2020 US dollars per-patient per-month from the private payer's perspective. Mental health–related HRU and medical costs were identified based on claims with an ICD-10-CM diagnosis between F01 and F99 (inclusive). Mental health–related pharmacy costs were based on pharmacy claims for antidepressants, agents used to augment antidepressants (atypical antipsychotics, anticonvulsants, psychostimulants, thyroid hormone, lithium, or buspirone), and other mental health–related medications (miscellaneous treatments used for attention-deficit/hyperactivity disorder, benzodiazepines, and sleep aids).

      Statistical Analysis

      We described baseline characteristics over the 6-month baseline period using means, SDs, and medians for continuous variables, and frequencies and proportions for binary variables.

      Results

      Demographic Characteristics and Diagnoses for Mental Health and Physical Conditions During the 6-Month Baseline Period

      We identified 246 patients in the esketamine cohort. Table I presents the sample sizes for the TRD conventional therapies cohorts combined and individually. The mean age was 46.5 years in the esketamine cohort and 46.9 years in the TRD conventional therapies cohort, and it ranged from 42.6 years in the antidepressant monotherapy cohort to 52.7 years in the adjunctive gabapentin cohort. The proportion of female patients was 63.0% in the esketamine cohort and 74.8% in the TRD conventional therapies cohort, and it ranged from 64.3% in the ECT cohort to 76.3% in the adjunctive gabapentin cohort.
      Table IDemographic and clinical characteristics during the 6-month baseline period.
      CharacteristicEsketamineTRD Conventional TherapiesECTTMSAdjunctive AripiprazoleAdjunctive GabapentinAdjunctive BupropionAntidepressant Monotherapy
      (n = 246)(n = 104,164)(n = 392)(n = 1202)(n = 9077)(n = 15,905)(n = 9143)(n = 1594)
      Age, mean (SD) [median], y46.5 (14.1) [48.7]46.9 (15.7) [48.2]48.0 (16.1) [50.5]44.4 (15.0) [46.0]45.1 (15.5) [46.7]52.7 (14.1) [54.1]45.9 (14.9) [46.9]42.6 (15.9) [42.7]
      Female155 (63.0%)77,908 (74.8%)252 (64.3%)814 (67.7%)6475 (71.3%)12,130 (76.3%)6715 (73.4%)1178 (73.9%)
      Geographical region
       South119 (48.4%)50,027 (48.0%)160 (40.8%)517 (43.0%)4288 (47.2%)7709 (48.5%)4011 (43.9%)850 (53.3%)
       Northeast54 (22.0%)17,125 (16.4%)97 (24.7%)203 (16.9%)1518 (16.7%)2576 (16.2%)1606 (17.6%)228 (14.3%)
       North central46 (18.7%)24,788 (23.8%)93 (23.7%)222 (18.5%)2261 (24.9%)3631 (22.8%)2442 (26.7%)366 (23.0%)
       West25 (10.2%)11,988 (11.5%)41 (10.5%)258 (21.5%)998 (11.0%)1949 (12.3%)1061 (11.6%)148 (9.3%)
       Unknown2 (0.8%)236 (0.2%)1 (0.3%)2 (0.2%)12 (0.1%)40 (0.3%)23 (0.3%)2 (0.1%)
      Medicare Supplemental17 (6.9%)8343 (8.0%)46 (11.7%)63 (5.2%)529 (5.8%)1979 (12.4%)588 (6.4%)94 (5.9%)
      Type of health care plan
       PPO156 (63.4%)55,855 (53.6%)211 (53.8%)639 (53.2%)4979 (54.9%)8464 (53.2%)4624 (50.6%)857 (53.8%)
       CDHP or HDHP54 (22.0%)22,695 (21.8%)82 (20.9%)273 (22.7%)1946 (21.4%)3224 (20.3%)2169 (23.7%)355 (22.3%)
       HMO or POS  with capitation19 (7.7%)13,897 (13.3%)38 (9.7%)144 (12.0%)1182 (13.0%)2349 (14.8%)1328 (14.5%)210 (13.2%)
       EPO or POS plan13 (5.3%)6530 (6.3%)37 (9.4%)94 (7.8%)539 (5.9%)913 (5.7%)628 (6.9%)113 (7.1%)
       Comprehensive1 (0.4%)3442 (3.3%)19 (4.8%)27 (2.2%)299 (3.3%)681 (4.3%)240 (2.6%)36 (2.3%)
       Unknown3 (1.2%)6 (0.0%)5 (1.3%)25 (2.1%)131 (1.4%)273 (1.7%)154 (1.7%)23 (1.4%)
      1 Mental health–related outpatient visit
      Classified by using ICD-10-CM diagnosis codes between F01 and F99 (inclusive). Physician specialty was reported for the mental health–related outpatient visit prior and closest to index date.
      233 (94.7%)88,086 (84.6%)380 (96.9%)1180 (98.2%)8116 (89.4%)12,569 (79.0%)7666 (83.8%)1301 (81.6%)
      Closest visit to index date
      Specialists were identified by using provider type codes.
       Psychiatrist113 (48.5%)18,840 (21.4%)109 (28.7%)590 (50.0%)2085 (25.7%)2184 (17.4%)1449 (18.9%)198 (15.2%)
       Therapist39 (16.7%)12,236 (13.9%)47 (12.4%)183 (15.5%)1386 (17.1%)1435 (11.4%)1097 (14.3%)188 (14.5%)
       Psychologist15 (6.4%)4754 (5.4%)24 (6.3%)75 (6.4%)461 (5.7%)586 (4.7%)414 (5.4%)68 (5.2%)
       Nurse  practitioner11 (4.7%)4843 (5.5%)14 (3.7%)20 (1.7%)397 (4.9%)647 (5.1%)405 (5.3%)69 (5.3%)
       Primary care  provider8 (3.4%)15,648 (17.8%)22 (5.8%)51 (4.3%)1107 (13.6%)2566 (20.4%)1594 (20.8%)294 (22.6%)
       Other
      Specialists were identified by using provider type codes.
      47 (20.2%)25,494 (28.9%)164 (43.2%)261 (22.1%)2680 (33.0%)5151 (41.0%)2707 (35.3%)484 (37.2%)
      MDD severity available
      MDD severity was based on ICD-10-CM diagnosis codes for MDD excluding patients without MDD diagnoses and patients with “unspecified” disease.
      214 (87.0%)49,638 (47.7%)343 (87.5%)1102 (91.7%)5217 (57.5%)6371 (40.1%)4514 (49.4%)732 (45.9%)
       Severe174 (81.3%)17,417 (35.1%)304 (88.6%)954 (86.6%)2153 (41.3%)1986 (31.2%)1198 (26.5%)214 (29.2%)
       Moderate36 (16.8%)23,575 (47.5%)33 (9.6%)130 (11.8%)2416 (46.3%)3094 (48.6%)2413 (53.5%)370 (50.5%)
       Mild3 (1.4%)5328 (10.7%)6 (1.7%)12 (1.1%)412 (7.9%)775 (12.2%)538 (11.9%)106 (14.5%)
       In remission1 (0.5%)3318 (6.7%)06 (0.5%)236 (4.5%)516 (8.1%)365 (8.1%)42 (5.7%)
      Top 3 DSM-5 comorbidities
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders: DSM-5.
       Anxiety disorders171 (69.5%)57,853 (55.5%)288 (73.5%)872 (72.5%)5448 (60.0%)7879 (49.5%)4868 (53.2%)835 (52.4%)
       Sleep–wake disorders65 (26.4%)23,876 (22.9%)123 (31.4%)336 (28.0%)1971 (21.7%)4469 (28.1%)1787 (19.5%)248 (15.6%)
       Neurodevelopmental disorders55 (22.4%)14,564 (14.0%)52 (13.3%)238 (19.8%)1121 (12.3%)1244 (7.8%)457 (5.0%)104 (6.5%)
      Top 3 physical health conditions

      Elixhauser A, Steiner C, Kruzikas D. HCUP Comorbidity Software. Healthcare Cost and Utilization Project (HCUP) 2015. Available at: https://www.hcup-us.ahrq.gov/toolssoftware/comorbidity/comorbidity.jsp#download, Last accessed: August 12, 2020.

       Hypertension71 (28.9%)31,712 (30.4%)142 (36.2%)291 (24.2%)2563 (28.2%)6958 (43.7%)2385 (26.1%)349 (21.9%)
       Obesity36 (14.6%)16,512 (15.9%)66 (16.8%)187 (15.6%)1439 (15.9%)3054 (19.2%)1386 (15.2%)205 (12.9%)
       Diabetes25 (10.2%)19,187 (18.4%)90 (23.0%)163 (13.6%)1651 (18.2%)4801 (30.2%)1350 (14.8%)164 (10.3%)
      Quan-CCI
      • Quan H
      • Sundararajan V
      • Halfon P
      • et al.
      Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.
      (SD) [median]
      0.5 (1.1) [0.0]0.7 (1.4) [0.0]0.8 (1.5) [0.0]0.5 (1.2) [0.0]0.6 (1.3) [0.0]1.1 (1.8) [0.0]0.5 (1.2) [0.0]0.4 (1.1) [0.0]
      CDHP = consumer-driven health plan; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; ECT = electroconvulsive therapy; EPO = exclusive provider organization; HDHP = high-deductible health plan; HMO = health maintenance organization; ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification; MDD = major depressive disorder; POS = point-of-service; PPO = preferred provider organization; Quan-CCI = Quan–Charlson Comorbidity Index; TMS = transcranial magnetic stimulation; TRD = treatment-resistant depression.
      Classified by using ICD-10-CM diagnosis codes between F01 and F99 (inclusive). Physician specialty was reported for the mental health–related outpatient visit prior and closest to index date.
      § Specialists were identified by using provider type codes.
      MDD severity was based on ICD-10-CM diagnosis codes for MDD excluding patients without MDD diagnoses and patients with “unspecified” disease.
      The proportion of patients with ≥1 mental health–related outpatient visit during the baseline period was 94.7% in the esketamine cohort and 84.6% in the TRD conventional therapies cohort, and it ranged from 79.0% in the adjunctive gabapentin cohort to 98.2% in the TMS cohort (Table I). In the esketamine cohort, the most common visit closest to the index date was with a psychiatrist (48.5%). Similarly, a visit with a psychiatrist was the most common in the TMS (50%), ECT (28.7%), and adjunctive aripiprazole (25.7%) cohorts. In contrast, the most common visit closest to the index date was with a primary care provider in the adjunctive gabapentin, adjunctive bupropion, and antidepressant monotherapy cohorts (20.4%, 20.8%, and 22.6%, respectively).
      We observed severe MDD during the baseline period among 70.7% of patients in the esketamine cohort. In comparison, the proportion with severe MDD was 16.7% in the TRD conventional therapies cohort and ranged from 12.5% in the adjunctive gabapentin cohort to 79.4% in the TMS cohort. The most common diagnoses of other Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, mental health comorbidities were anxiety disorders (esketamine cohort, 69.5%; conventional therapies cohorts, 49.5%–73.5%) and sleep–wake disorders (esketamine cohort, 26.4%; conventional therapies cohorts, 15.6%–31.4%). The most common diagnoses of physical health conditions were hypertension (esketamine cohort, 28.9%; conventional therapies cohorts, 21.9%–43.7%), obesity (esketamine cohort, 14.6%, conventional therapies cohorts, 12.9%–19.2%), and diabetes (esketamine cohort, 10.2%; conventional therapies cohorts, 10.3%–30.2%) (Table I). The proportion of patients with a suicidal ideation or behavior diagnosis during the 6-month baseline period was 8.5% in the esketamine cohort and 3.6% in the TRD conventional therapies cohort, and it ranged from 1.6% in the antidepressant monotherapy cohort to 30.9% in the ECT cohort (Figure 2).
      Figure 2
      Figure 2Diagnosed suicidal ideation or behavior in the 6-month baseline period. Suicidal ideation or behavior was identified among all patients based on claims with the corresponding International Classification of Diseases, Tenth Revision, Clinical Modification, diagnosis codes: T14.91x (suicide attempt), X71.xx through X83.xx (self-harm due to all mechanisms other than poisoning and asphyxiation), T36.xx through T50.xx with the sixth character of the code = 2 (except for T36.9, T37.9, T39.9, T41.4, T42.7, T43.9, T45.9, T47.9, and T49.9, which are included if the fifth character of the code = 2; self-harm due to poisoning by drugs, medications, and biologic substances), T51.xx through T65.xx with the sixth character of the code = 2 (except for T51.9, T52.9, T53.9, T54.9, T56.9, T57.9, T58.0, T58.1, T58.9, T59.9, T60.9, T61.0, T61.1, T 61.9, T62.9, T63.9, T64.0, T64.8, and T65.9, which are included if the fifth character of the code = 2; self-harm due to toxic effects of nonmedical substances), T71.xx with the sixth character of the code = 2 (self-harm due to asphyxiation, suffocation, hanging) and R45.851 (suicide ideation). ECT = electroconvulsive therapy; TRD = treatment-resistant depression; TMS = transcranial magnetic stimulation.

      Use of Antidepressant Therapy During the Baseline Period

      During the 6-month baseline period before initiation of the cohort-defining therapy, 34.6% of patients in the esketamine cohort received ≥3 unique antidepressants compared with 17.6% in the TRD conventional therapies cohort; among the individual conventional therapies cohorts, this proportion ranged from 3.4% in the antidepressant monotherapy cohort to 40.1% in the ECT cohort (Figure 3). In the esketamine cohort, 65.4% of patients had an antidepressant augmentation therapy regimen compared with 56.4% in the TRD conventional therapies cohort; among individual conventional therapies cohorts, this proportion ranged from 16.6% in the antidepressant monotherapy cohort to 67.1% in the TMS cohort (Figure 4). The proportion of patients with antidepressant monotherapy use was 32.1% in the esketamine cohort and 41.3% in the TRD conventional therapies cohort, and it ranged from 30.6% in the TMS cohort to 66.5% in the adjunctive bupropion cohort.
      Figure 3
      Figure 3Patients with ≥3 unique antidepressant agents received during the 6-month baseline period. ECT = electroconvulsive therapy; TRD = treatment-resistant depression; TMS = transcranial magnetic stimulation.
      Figure 4
      Figure 4Patients with antidepressant therapy during the 6-month baseline period: unobserved, monotherapy alone, and augmentation therapy. Antidepressant augmentation therapy (Aug) was defined as an overlapping coverage for >6 weeks (42 consecutive days) without gaps >14 days of either ≥2 generic antidepressant agents, or ≥1 augmentation agent and ≥1 antidepressant agent. Antidepressant monotherapy (Mono) was defined as patients with ≥1 claim for an antidepressant agent who did not meet the criteria for antidepressant augmentation therapy. ECT = electroconvulsive therapy; TRD = treatment-resistant depression; TMS = transcranial magnetic stimulation; Unobserved = no antidepressant use observed.

      Use of Specialized Mental Health Services and Outpatient Care for MDD During the Baseline Period

      During the 6-month baseline period, 77.6% of patients in the esketamine cohort had at least 1 psychotherapy visit compared with 41.4% in the TRD conventional therapies cohort; among the individual conventional therapies cohorts, this proportion ranged from 32.5% in the adjunctive gabapentin cohort to 77.4% in the TMS cohort (Figure 5A). The proportion of patients who had at least 1 psychiatrist visit during the baseline period was 82.9% in the esketamine cohort and 34.2% in the TRD conventional therapies cohort, and it ranged from 22.1% in the antidepressant monotherapy cohort to 83.7% in the TMS cohort (Figure 5B). The proportion of patients who had at least 1 outpatient visit for MDD during the baseline period was 91.9% in the esketamine cohort and 63.6% in the TRD conventional therapies cohort, and it ranged from 57.4% in the adjunctive gabapentin cohort to 93.9% in the TMS cohort (Figure 5C). Most patients in the esketamine cohort (57.3%) and in the TMS cohort (54.3%) received predominantly specialized mental health care as outpatient care for MDD. In contrast, most patients in the ECT and pharmacotherapy cohorts received predominantly primary care as outpatient care for MDD.
      Figure 5
      Figure 5Psychotherapy visits during the 6-month baseline period (A), psychiatrist visits during the 6-month baseline period (B), and outpatient care with a diagnosis of major depressive disorder (MDD) during the 6-month baseline period: unobserved, predominantly primary care, or predominantly specialized mental health care‡,§ (C). *Psychotherapy visits were identified based on procedure codes. Psychiatrist visits were identified based on provider type codes. Predominantly primary care was defined as having <50% of outpatient claims with an MDD diagnosis with a provider type, place of service or revenue code identifying mental-health specialists. §Predominantly specialized mental health care was defined as having ≥50% of outpatient claims with an MDD diagnosis with a provider type, place of service, or revenue code identifying mental health specialists. ECT = electroconvulsive therapy; MH = predominantly involved in mental health care; PC = predominantly involved in primary care; TRD = treatment-resistant depression; TMS = transcranial magnetic stimulation; Unobserved = no antidepressant use observed.

      Acute All-Cause and Mental Health–Related Resource Utilization During the Baseline Period

      During the 6-month baseline period, the proportion of patients with at least 1 all-cause inpatient admission was 13.0% in the esketamine cohort and 10.6% in the TRD conventional therapies cohort, and it ranged from 5.4% in the antidepressant monotherapy cohort to 38.5% in the ECT cohort. Those with at least 1 all-cause emergency department visit comprised 27.6% in the esketamine cohort and 30.8% in the TRD conventional therapies cohort, and it ranged from 24.9% in the adjunctive bupropion cohort to 42.9% in the ECT cohort (Table II). The proportion of patients with at least 1 mental health–related inpatient admission during the baseline period was 12.2% in the esketamine cohort and 8.2% in the TRD conventional therapies cohort, and it ranged from 4.0% in the antidepressant monotherapy cohort to 36.7% in the ECT cohort. The proportion of patients with at least 1 mental health–related emergency department visit during the baseline period was 16.3% in the esketamine cohort and 10.3% in the TRD conventional therapies cohort, and it ranged from 6.3% in the adjunctive bupropion cohort to 26.8% in the ECT cohort.
      Table IIAll-cause and mental health–related inpatient admissions and emergency department (ED) visits during the 6-month baseline period.
      VariableEsketamineTRD Conventional TherapiesECTTMSAdjunctive AripiprazoleAdjunctive GabapentinAdjunctive BupropionAntidepressant Monotherapy
      (n = 246)(n = 104,164)(n = 392)(n = 1202)(n = 9077)(n = 15,905)(n = 9143)(n = 1594)
      All-cause
       Inpatient admissions
      Had ≥1 inpatient admission32 (13.0%)11,027 (10.6%)151 (38.5%)139 (11.6%)1134 (12.5%)2337 (14.7%)526 (5.8%)86 (5.4%)
      No. of admissions (SD) [median]0.03 (0.07) [0.00]0.02 (0.08) [0.00]0.11 (0.17) [0.00]0.03 (0.09) [0.00]0.03 (0.09) [0.00]0.03 (0.09) [0.00]0.01 (0.05) [0.00]0.01 (0.05) [0.00]
      No. of days (SD) [median]0.20 (0.67 [0.00]0.14 (0.71) [0.00]0.91 (2.26) [0.00]0.19 (0.86) [0.00]0.18 (0.81) [0.00]0.20 (0.83) [0.00]0.06 (0.47) [0.00]0.07 (0.62) [0.00]
       ED visits
      Had ≥1 ED visit68 (27.6%)32,067 (30.8%)168 (42.9%)383 (31.9%)2764 (30.5%)5671 (35.7%)2275 (24.9%)398 (25.0%)
      No. of ED visits (SD) [median]0.09 (0.20) [0.00]0.10 (0.22) [0.00]0.19 (0.40) [0.00]0.10 (0.21) [0.00]0.10 (0.24) [0.00]0.12 (0.26) [0.00]0.07 (0.16) [0.00]0.08 (0.19) [0.00]
      Mental health–related
      Mental health–related resource utilization was identified based on claims with an International Classification of Diseases, Tenth Revision, Clinical Modification, diagnosis between F01 and F99 (inclusive).
       Inpatient admissions
      Had ≥1 inpatient admission30 (12.2%)8515 (8.2%)144 (36.7%)128 (10.6%)988 (10.9%)1583 (10.0%)394 (4.3%)64 (4.0%)
      No. of admissions (SD) [median]0.02 (0.07) [0.00]0.02 (0.07) [0.00]0.10 (0.16) [0.00]0.02 (0.08) [0.00]0.02 (0.08) [0.00]0.02 (0.08) [0.00]0.01 (0.04) [0.00]0.01 (0.05) [0.00]
      No. of days (SD) [median]0.17 (0.63) [0.00]0.09 (0.54) [0.00]0.84 (2.18) [0.00]0.17 (0.84) [0.00]0.14 (0.74) [0.00]0.10 (0.51) [0.00]0.04 (0.32) [0.00]0.04 (0.31) [0.00]
       ED visits
      Had ≥1 ED visit40 (16.3%)10,777 (10.3%)105 (26.8%)152 (12.6%)1075 (11.8%)1853 (11.7%)578 (6.3%)107 (6.7%)
      No. of ED visits (SD) [median]0.05 (0.13) [0.00]0.03 (0.11) [0.00]0.11 (0.32) [0.00]0.03 (0.11) [0.00]0.03 (0.12) [0.00]0.03 (0.13) [0.00]0.01 (0.07) [0.00]0.02 (0.09) [0.00]
      ECT = electroconvulsive therapy; TMS = transcranial magnetic stimulation; TRD = treatment-resistant depression.
      low asterisk Mental health–related resource utilization was identified based on claims with an International Classification of Diseases, Tenth Revision, Clinical Modification, diagnosis between F01 and F99 (inclusive).

      All-Cause and Mental Health–Related Health Care Costs During the Baseline Period

      During the baseline period, mean monthly all-cause total health care costs were $2532 in the esketamine cohort and $1873 in the TRD conventional therapies cohort, and they ranged from $923 in the antidepressant monotherapy cohort to $5063 in the ECT cohort (Figure 6). In the esketamine cohort, 58.2% ($1473) of the all-cause total health care costs were mental health related; this proportion ranged from 25.2% ($724) in the adjunctive gabapentin cohort to 69.8% ($3532) in the ECT cohort.
      Figure 6
      Figure 6Mean monthly all-cause (AC) and mental health–related (MH) total health care costs during the 6-month baseline period. Mean AC health care costs were reported in 2020 US dollars per-patient per-month from the private payer's perspective. MH medical costs were identified based on claims with an International Classification of Diseases, Tenth Revision, Clinical Modification, diagnosis between F01 and F99 (inclusive). MH pharmacy costs were based on pharmacy claims for antidepressants, agents used to augment antidepressants (atypical antipsychotics, anticonvulsants, psychostimulants, thyroid hormone, lithium, or buspirone), and other MH medications (miscellaneous treatments used for attention-deficit/hyperactivity disorder, benzodiazepines, and sleep aids). ECT = electroconvulsive therapy; TRD = treatment-resistant depression; TMS = transcranial magnetic stimulation.

      Characteristics in Sensitivity Study Populations

      Characteristics in sensitivity study populations are presented in Supplemental Table 1 (all-comers cohorts) (see the online version at doi:10.1016/j.clinthera.2022.09.005) and in Supplemental Table 2 (MDD cohorts) (see the online version at doi:10.1016/j.clinthera.2022.09.005). Characteristics of patients in the all-comers esketamine and MDD esketamine cohorts were largely consistent with those of patients in the TRD esketamine cohort.

      Discussion

      This retrospective cohort study found that commercially insured adults with evidence of TRD exhibited high disease burden before being initiated on esketamine. This was evidenced by a high prevalence of severe MDD and high utilization of care relative to adults with TRD initiating conventional therapies. We observed similar results in the all-comers and MDD esketamine cohorts. Based on characteristics before therapy initiation such as prevalence of diagnosed suicidal behavior, acute mental health–related resource use, and costs, adults with observed TRD subsequently initiated on esketamine seemed largely comparable to those initiated on TMS, and more severe than those initiated on benchmark oral pharmacologic therapies for MDD, while seeming to be less severe than those initiated on ECT.
      Our findings are largely consistent with a recent study by Cepeda et al
      • Cepeda MS
      • Kern DM
      • Canuso CM.
      At baseline patients treated with esketamine have higher burden of disease than other patients with treatment resistant depression: learnings from a population based study.
      assessing characteristics of commercially insured patients initiated on esketamine or conventional MDD therapies, which similarly reported a high prevalence of severe MDD and burden of disease among patients before initiation of esketamine therapy. These findings remain robust despite design differences between the 2 analyses. Specifically, patients included in the study of Cepeda et al who initiated esketamine had a diagnosis of MDD but were not required to show evidence of TRD; this was similar to our MDD esketamine cohort but less stringent than our TRD esketamine cohort. Similar pretreatment characteristics in the esketamine cohorts (ie, patients exhibited high disease burden at baseline), regardless of meeting the claims-based definition of TRD or even having observed MDD diagnoses, suggest that in the real world, it is likely that patients must have shown evidence of severe disease or impairment before being initiated on esketamine. This may not be surprising because health care providers are required to justify the intended use of esketamine when obtaining prior authorization from payers to ensure the treatment is covered.
      Janssen
      Supporting Appropriate Payer Coverage Decisions.
      Furthermore, the distribution of esketamine must comply with the Risk Evaluation and Mitigation Strategy program, which supports the safe use of medication and aims to mitigate the risk of serious adverse outcomes resulting from sedation and dissociation caused by esketamine administration and abuse and misuse of esketamine by requiring additional monitoring by the service providers.

      US Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Accessed June 7, 2021.

      ,

      U.S. Food and Drug Administration. Risk Evaluation and Mitigation Strategies REMS. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems. Accessed June 11, 2021.

      In our study, patients included in the all-comers esketamine cohort and/or MDD esketamine cohort but excluded from the TRD esketamine cohort could have been covered by plans with less stringent prior authorization criteria, or could have received some antidepressants without going through the insurance claiming process. The former explanation might suggest that even with less stringent prior authorization criteria, esketamine would likely be reserved for severe patients with a clinical need for it.
      Reserving esketamine as a later treatment line in patients with TRD, despite the demonstrated reduction in the severity of depressive symptoms and lower risk of relapse associated with esketamine relative to antidepressants, may lead to poorer long-term outcomes.
      • Popova V
      • Daly EJ
      • Trivedi M
      • et al.
      Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study.
      ,
      • Daly EJ
      • Trivedi MH
      • Janik A
      • et al.
      Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial.
      The landmark STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial reported lower remission rates and higher relapse rates with increasing lines of treatment.
      • Rush AJ
      • Trivedi MH
      • Wisniewski SR
      • et al.
      Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.
      To this end, physicians and payers may consider the benefits of using esketamine earlier in the TRD disease course to improve outcomes.
      The present study found that among all cohorts, the ECT cohort had the highest prevalence of diagnosed suicidal ideation or behavior, the highest proportions of all-cause and mental health–related inpatient and emergency department utilization, and the highest all-cause and mental health–related health care costs at baseline. Suicidal ideation and behavior are commonly diagnosed in an inpatient setting,
      • Zhdanava M
      • Voelker J
      • Pilon D
      • et al.
      Cluster analysis of care pathways in adults with major depressive disorder with acute suicidal ideation or behavior in the USA.
      and ECT is commonly used among patients with suicidal risk due to its ability to achieve a more rapid response compared with conventional antidepressants.
      • Gelenberg AJ
      • Freeman MP
      • Markowitz JC
      • et al.
      The American Psychiatric Association Practice Guideline for the Treatment of Patients With Major Depressive Disorder.
      ,
      • Husain MM
      • Rush AJ
      • Fink M
      • et al.
      Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report.
      Although ECT is widely regarded as a rapid and effective treatment for MDD, it is generally recommended for patients with more severe symptoms or more refractory illness,
      • Gelenberg AJ
      • Freeman MP
      • Markowitz JC
      • et al.
      The American Psychiatric Association Practice Guideline for the Treatment of Patients With Major Depressive Disorder.
      likely related to its invasive nature (ie, requirement for general anesthesia)
      • Lihua P
      • Su M
      • Ke W
      • Ziemann-Gimmel P.
      Different regimens of intravenous sedatives or hypnotics for electroconvulsive therapy (ECT) in adult patients with depression.
      and cognitive adverse event (ie, memory impairment).
      • Squire LR
      • Slater PC.
      Electroconvulsive therapy and complaints of memory dysfunction: a prospective three-year follow-up study.
      Therefore, novel treatment that is less invasive and does not cause cognitive dysfunction may be embraced earlier in the TRD disease course. Importantly, patients with TRD should be informed of the risk–benefit profiles of different treatment options (eg, through discussion with their clinician with the support of evidence-based patient decision aid) to facilitate shared treatment decision-making, a patient-centered approach that is increasingly advocated for patients with psychiatric conditions.
      • Shillington AC
      • Langenecker SA
      • Shelton RC
      • et al.
      Development of a patient decision aid for treatment resistant depression.
      Apart from the ECT cohort, another cohort with baseline health care costs higher than that in the esketamine cohort was the adjunctive gabapentin cohort. Relative to other cohorts, mental health–related costs explained a lower proportion of all-cause health care costs in the adjunctive gabapentin cohort. Patients in the adjunctive gabapentin cohort were older and seemed to have a higher burden of physical comorbidities at baseline, which likely contributed to the high all-cause health care costs before initiation of gabapentin.
      Given that TRD is a challenging-to-treat and often debilitating disease which is frequently associated with considerable comorbidities
      • Otte C
      • Gold SM
      • Penninx BW
      • et al.
      Major depressive disorder.
      ,
      • Greden JF.
      The burden of disease for treatment-resistant depression.
      and that it contributes to risk of suicidal ideation or behavior,
      • Kessler RC
      • Berglund P
      • Borges G
      • Nock M
      • Wang PS.
      Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990-1992 to 2001-2003.
      ,
      • Mrazek DA
      • Hornberger JC
      • Altar CA
      • Degtiar I.
      A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013.
      it is crucial to address the current needs of patients with TRD when making clinical and health care policy-related decisions. Clinicians prescribing treatments for TRD are encouraged to consider individual patient characteristics as well as preferences, which may be influenced by comorbidities, the time to onset of treatment effects, treatment duration, and dosing routes and schedules, to improve the quality of care for patients with TRD.
      • Gelenberg AJ
      • Freeman MP
      • Markowitz JC
      • et al.
      The American Psychiatric Association Practice Guideline for the Treatment of Patients With Major Depressive Disorder.
      ,
      • Kasper S
      • Cubala WJ
      • Fagiolini A
      • et al.
      Practical recommendations for the management of treatment-resistant depression with esketamine nasal spray therapy: basic science, evidence-based knowledge and expert guidance.
      The findings from the present study also emphasize that any future real-world comparison of outcomes in patients with TRD initiated on esketamine or other conventional MDD therapies must be interpreted with caution because, depending on the therapy, the baseline disease severity of the different patient groups can vary markedly even if all patients show evidence of TRD. As additional real-world data on esketamine use become available, similar analyses may be conducted in the future to observe changes in the profiles of patients receiving esketamine and other MDD therapies. This information will enhance our understanding of the patient factors affecting therapy choices for the treatment of TRD in the real-world setting. It may also improve clinicians’ knowledge of how pretreatment patient characteristics could influence therapy choices, which may assist in tailoring treatment plans to patients’ individual clinical profiles.
      The present study evaluated characteristics among commercially insured patients with TRD, given that the majority of individuals living in the United States have private insurance rather than Medicaid or Medicare,
      • Keisler-Starkey K
      • Bunch LN.
      Health Insurance Coverage in the United States: 2020—Current Population Reports.
      and that esketamine is expected to be used predominantly among patients with commercial insurance. In addition, commercial insurance claims data are more current compared with Medicaid or Medicare data. Altogether, these were important considerations for the size of the esketamine cohort. Because TRD largely affects working-age adults, Medicare data are generally of lesser interest for the analysis of real-world esketamine use; however, future studies evaluating characteristics, treatment patterns, and outcomes among esketamine users with Medicaid insurance would be of interest.
      The present study is subject to several limitations. As with all claims database studies, the results may not be representative of patients without health insurance or with insurance plans (eg, Medicaid) other than the ones analyzed. The clinical information to identify TRD was not available in claims data, and the algorithm relied exclusively on pharmacy prescription fills, which do not guarantee that the medication dispensed was taken as prescribed and do not capture out-of-pocket expenses on some medications. Furthermore, the reasons for treatment change are also unknown. In addition, although the present study used the most common definition of TRD, this definition may differ from prior authorization criteria imposed for esketamine by different payers. Meanwhile, medications identified as adjunctive to antidepressants for the management of MDD may have been prescribed to treat other conditions or symptoms. Lastly, specialized mental health service use may be underreported because services such as psychotherapy are often paid out-of-pocket and thus are not reflected in the study results.

      Conclusions

      In this analysis, commercially insured adults with TRD initiated on esketamine exhibited a high prevalence of severe MDD along with substantial utilization of specialized mental health care resources relative to those initiating conventional therapies. Based on the selected characteristics before therapy initiation, adults with TRD initiated on esketamine seemed largely comparable to those initiated on TMS, more severe than those initiated on benchmark oral pharmacologic therapies, and less severe than those initiated on ECT. These findings highlight that despite the clinical value of esketamine, it is being reserved for patients at a much later line of therapy.

      Declaration of Interest

      Ms Zhdanava, Mr Pilon, Ms Morrison, Ms Shah, and Mr Lefebvre are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC, which funded the development and conduct of this study and manuscript. Ms Karkare and Ms Joshi are employees of Janssen Scientific Affairs, LLC, and stockholders of Johnson & Johnson. Dr Nash was an employee of Janssen Scientific Affairs, LLC, at the time of study conduct.
      The sponsor was involved in the study design, data collection, data analysis, manuscript preparation, and publication decisions.

      Acknowledgments

      This study was supported by Janssen Scientific Affairs, LLC. Medical writing assistance was provided by Flora Chik, PhD, an employee of Analysis Group, Inc.
      Ms Zhdanava, Mr Pilon, Ms Morrison, Ms Shah, and Mr Lefebvre contributed to study conception and design, data analysis and interpretation, and drafting of the manuscript. Ms Karkare, Dr Nash, and Ms Joshi contributed to study conception and design, data analysis, and interpretation. All authors revised the manuscript critically for intellectual content and contributed to the decision to submit the final manuscript for publication. All authors agree to be accountable for all aspects of the work.

      Appendix. Supplementary materials

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