Suicide-specific mortality among patients with treatment-resistant major depressive disorder, major depressive disorder with prior suicidal ideation or suicide attempts, or major depressive disorder alone.

BACKGROUND: The impact of treatment-resistant depression (TRD) or prior suicidal ideation/suicide attempt (SI/SA) on mortality by suicide among patients with major depressive disorder (MDD) is not well known. This retrospective, observational, descriptive cohort study characterized real-world rates of suicide-specific mortality among patients with MDD with or without TRD or SI/SA. METHODS: Adult patients with MDD among commercially insured and Medicare enrollees in Optum Research Database were included and assigned to three cohorts: those with treatment-resistant MDD (TRD), those with MDD and SI/SA (MDD+SI/SA), and those with MDD without TRD or SI/SA (MDD alone). Suicide-specific mortality was obtained from the National Death Index. The effects of demographic characteristics and SI/SA in the year prior to the end of observation on suicide-specific mortality were assessed. RESULTS: For the 139,753 TRD, 85,602 MDD+SI/SA, and 572,098 MDD alone cohort patients, mean age ranged from 55 to 59 years and the majority were female. At baseline, anxiety disorders were present in 53.92%, 44.11%, and 21.72% of patients with TRD, MDD+SI/SA, and MDD alone, respectively. Suicide-mortality rates in the three cohorts were 0.14/100 person-years for TRD, 0.27/100 person-years for MDD+SI/SA, and 0.04/100 person-years for MDD alone. SI/SA during the year prior to the end of observation, younger age, and male sex were associated with increased suicide risk. CONCLUSIONS: Patients with TRD and MDD+SI/SA have a heightened risk of mortality by suicide compared with patients with MDD alone. Suicide rates were higher in patients with recent history versus older or no history of SI/SA, men versus women, and those of young age versus older age.

Assessment of health-related quality of life and health status in patients with treatment-resistant depression treated with esketamine nasal spray plus an oral antidepressant.

BACKGROUND: Patients with treatment-resistant depression (TRD) report significant deficits in physical and mental health, as well as severely impaired health-related quality of life (HRQoL) and functioning. Esketamine effectively enhances the daily functioning in these patients while also improving their depressive symptoms. This study assessed HRQoL and health status of patients with TRD, who were treated with esketamine nasal spray and an oral antidepressant (ESK + AD) vs. placebo nasal spray and an AD (AD + PBO). METHODS: Data from TRANSFORM-2, a phase 3, randomized, double-blind, short-term flexibly dosed study, were analyzed. Patients (aged 18-64 years) with TRD were included. The outcome assessments included the European Quality of Life Group, Five Dimension, Five Level (EQ-5D-5L), EQ-Visual Analogue Scale (EQ-VAS), and Sheehan Disability Scale (SDS). The health status index (HSI) was calculated using EQ-5D-5L scores. RESULTS: The full analysis set included 223 patients (ESK + AD: 114; AD + PBO: 109; mean [SD] age: 45.7 [11.89]). At Day 28, a lower percentage of patients reported impairment in the ESK + AD vs. AD + PBO group in all five EQ-5D-5L dimensions: mobility (10.6% vs. 25.0%), self-care (13.5% vs. 32.0%), usual activities (51.9% vs. 72.0%), pain/discomfort (35.6% vs. 54.0%), and anxiety/depression (69.2% vs. 78.0%). The mean (SD) change from baseline in HSI at Day 28 was 0.310 (0.219) for ESK + AD and 0.235 (0.252) for AD + PBO, with a higher score reflecting better levels of health. The mean (SD) change from baseline in EQ-VAS score at Day 28 was greater in ESK + AD (31.1 [25.67]) vs. AD + PBO (22.1 [26.43]). The mean (SD) change in the SDS total score from baseline to Day 28 also favored ESK + AD (-13.6 [8.31]) vs. AD + PBO (-9.4 [8.43]). CONCLUSIONS: Greater improvements in HRQoL and health status were observed among patients with TRD treated with ESK + AD vs. AD + PBO. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02418585.

Economic burden of treatment-resistant depression in privately insured US patients with co-occurring anxiety disorder and/or substance use disorder.

OBJECTIVE: To assess the burden of treatment-resistant depression (TRD) among privately insured patients with anxiety disorder and/or substance use disorders (SUD). METHODS: Adults <65 years old were identified in the Optum Health Care Solutions Inc. database (July 2009-March 2017). Among those with major depressive disorder (MDD) and antidepressant use, patients who initiated a third antidepressant (index date) after two regimens at adequate dose and duration were classified in the TRD cohort and patients without evidence of TRD were classified in the non-TRD MDD control cohort. The non-MDD control cohort comprised patients without MDD. In the non-TRD MDD and non-MDD cohorts, the index date was imputed to mimic the distribution of time in the TRD cohort from the first antidepressant to the index date or from the start of eligibility to the index date, respectively. Patients with <6 months of continuous insurance eligibility pre-/post-index, psychosis, schizophrenia, bipolar disorder and related conditions, dementia, and development disorders, and/or no baseline anxiety disorder and/or SUD were excluded. Patients with TRD were matched 1:1 to patients with non-TRD MDD and patients without MDD, based on exact matching factors (i.e. availability of work loss data) and propensity scores computed based on characteristics measured pre-index. Outcomes, including healthcare resource use (HRU) and costs, work productivity loss and related costs measured per patient per year ≤24 months post-index were compared between matched TRD, non-TRD MDD and non-MDD cohorts. RESULTS: A total of 3166 patients were identified in the TRD cohort and matched to non-TRD MDD and non-MDD cohorts. Among patients with TRD (mean age 39 years, 60.5% female), 87.3% had an anxiety disorder, 24.1% had SUD. The TRD cohort had higher HRU vs non-TRD MDD and non-MDD cohorts: 0.32 vs 0.20 and 0.14 inpatient admissions, 0.91 vs 0.73 and 0.58 emergency department visits, and 23.8 vs 16.8 and 11.6 outpatient visits, respectively (all p < .01). The TRD cohort had higher healthcare costs ($16,674) vs non-TRD MDD ($10,945) and non-MDD ($6493) cohorts (all p < .01). Among patients with work loss data (N = 310/cohort), patients with TRD had more work loss days (54) and higher work loss-related costs ($13,674) vs patients with non-TRD MDD (32 days; $7131) and without MDD (17 days; $4798; all p < .01). CONCLUSIONS: In patients with an anxiety disorder and/or SUD, TRD was associated with higher HRU, healthcare costs, work loss days and work loss-related costs.

Economic Burden of Treatment-Resistant Depression in Privately Insured U.S. Patients with Physical Conditions.

BACKGROUND: Little is known about the economic burden of treatment-resistant depression (TRD) in patients with physical conditions. OBJECTIVE: To assess health care resource utilization (HRU) and costs, work loss days, and related costs in patients with TRD and physical conditions versus patients with the same conditions and non-TRD major depressive disorder (MDD) or without MDD. METHODS: Adults aged < 65 years with MDD treated with antidepressants were identified in the OptumHealth Care Solutions database (July 2009-March 2017). Patients who received a diagnosis of MDD and initiated a third antidepressant regimen (index date) after 2 regimens of adequate dose and duration were defined as having TRD. Patients with non-TRD MDD and without MDD were assigned a random index date. Patients with < 6 months of continuous health plan eligibility pre- or post-index; a diagnosis of psychosis, schizophrenia, bipolar disorder/mania, dementia, and developmental disorders; and/or no baseline physical conditions (cardiovascular, metabolic, and respiratory disease or cancer) were excluded. Patients with TRD were matched 1:1 to each of the non-TRD MDD and non-MDD cohorts based on propensity scores. Per patient per year HRU, costs, and work loss outcomes were compared up to 24 months post-index date using negative binominal and ordinary least square regressions. RESULTS: A total of 2,317 patients with TRD (mean age, 47.6 years; 63.1%, female; mean follow-up, 19.7 months) had ≥ 1 co-occurring key physical condition (cardiovascular, 52.5%; metabolic, 48.2%; respiratory, 16.4%; and cancer, 9.5%). Relative to non-TRD MDD and non-MDD cohorts, respectively, patients with TRD had 46% and 235% more inpatient admissions, 28% and 128% more emergency department visits, and 53% and 155% more outpatient visits (all P < 0.05). Health care costs were $22,541 in the TRD cohort, $17,450 in the non-TRD MDD cohort, and $10,047 in the non-MDD cohort, yielding cost differences of $5,091 (vs. non-TRD MDD) and $12,494 (vs. non-MDD; all P < 0.01). In patients with work loss data available (n = 278/cohort), those with TRD had 2.0 and 2.9 times more work loss as well as $8,676 and $10,323 higher work loss costs relative to those with non-TRD MDD and without MDD, respectively (all P < 0.001). CONCLUSIONS: In patients with physical conditions, those with TRD had higher HRU and health care costs, work loss days, and associated costs compared with non-TRD MDD and non-MDD cohorts. DISCLOSURES: This study was sponsored by Janssen Scientific Affairs (JSA), which was involved in all aspects of the research, including the design of the study; the collection, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. Joshi and Daly are employed by JSA. Zhdanava, Pilon, Rossi, Morrison, and Lefebvre are employees of Analysis Group, which received funding from JSA for conducting this study and has received consulting fees from Novartis Pharmaceuticals and GSK, unrelated to this study. Kuvadia is employed by Integrated Resources, which has provided research services to JSA unrelated to this study; Joshi reports past employment by and stock ownership in Johnson & Johnson; Nelson reports advisory board, data and safety monitoring board, and consulting fees from Assurex, Eisai, FSV-7, JSA, Lundbeck, Otsuka, and Sunovion and royalties from UpToDate, unrelated to this study. This work was presented at AMCP Nexus 2019, held in National Harbor, MD, from October 29 to November 1, 2019.

Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

The relationship between adverse events during selective serotonin reuptake inhibitor treatment for major depressive disorder and nonremission in the suicide assessment methodology study.

Little is known about the association between antidepressant treatment-emergent adverse events and symptom nonremission in major depressive disorder. The objective of the current analysis was to determine whether particular baseline symptoms or treatment-emergent symptoms (adverse events) during the first 2 weeks are associated with nonremission after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI).Outpatients clinically diagnosed with nonpsychotic major depressive disorder were recruited from 6 primary and 9 psychiatric care sites. Participants (n = 206) were treated with an SSRI antidepressant (citalopram [20-40 mg/d], escitalopram [10-20 mg/d], fluoxetine [20-40 mg/d], paroxetine [20-40 mg/d], paroxetine CR [25-37.5 mg/d], or sertraline [50-150 mg/d]) for 8 weeks. Remission was defined as having a score of 5 or less on the 16-item Quick Inventory of Depressive Symptomatology-Clinician-Rated at week 8, or using last observation carried forward. Adverse events were identified using the 55-item Systematic Assessment for Treatment Emergent Events-Systematic Inquiry completed by participants at baseline and week 2.Findings indicated that the emergence of adverse events of weakness/fatigue, strange feeling, and trouble catching breath/hyperventilation at week 2 were independently associated with lack of remission even after controlling for the potential confounders of baseline depressive severity, anxious symptoms, antidepressant medication, chronic depression, race, burden of general medical comorbidity, and time in study. Hearing/seeing things appeared to have a protective effect. In conclusion, during SSRI treatment, the adverse events of weakness/fatigue, feeling strange, and trouble catching breath/hyperventilation are associated with nonremission, possibly due to lower adherence, early attrition, difficulty increasing the dose, and reduced efficacy.

Health-related quality of life in depression: a STAR*D report.

BACKGROUND: Although major depressive disorder (MDD) is associated with significant impairments in health-related quality of life (HRQOL), few studies have evaluated HRQOL dysfunction in multiple domains. This report examined the psychological, physical, and social domains in a large sample of outpatients who entered the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHODS: The relationship of HRQOL and baseline sociodemographic and clinical features, including depressive severity, was evaluated. We assessed HRQOL with the 12-item Short Form Health Survey, the 5-item Work and Social Adjustment Scale, and the 16-item Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: Among 2307 participants, greater depressive symptom severity was associated with poorer HRQOL. After controlling for age and depression severity, lower HRQOL was related independently to being African American or Hispanic, less educated, unemployed, divorced or separated, having public medical insurance, and to having more general medical disorders. We found impairments across all 3 domains, with low correlations between the 3 measures of HRQOL chosen, suggesting that they evaluate different and nonoverlapping aspects of function. CONCLUSION: Sociodemographically disadvantaged patients with greater general medical and depressive illness burden are at greatest risk for poorer quality of life. Distinct impairments are seen in the 3 domains of HRQOL.

Assessing physicians' use of treatment algorithms: Project IMPACTS study design and rationale.

Effective treatments for major depressive disorder have been available for 35 years, yet inadequate pharmacotherapy continues to be widespread leading to suboptimal outcomes. Evidence-based medication algorithms have the potential to bring much-needed improvement in effectiveness of antidepressant treatment in "real-world" clinical settings. Project IMPACTS (Implementation of Algorithms using Computerized Treatment Systems) addresses the critical question of how best to facilitate integration of depression treatment algorithms into routine care. It tests an algorithm implemented through a computerized decision support system using a measurement-based care approach for depression against a paper-and-pencil version of the same algorithm and non-algorithm-based, specialist-delivered usual care. This paper reviews issues related to the Project IMPACTS study rationale, design, and procedures. Patient outcomes include symptom severity, social and work function, and quality of life. The economic impact of treatment is assessed in terms of health care utilization and cost. Data collected on physician behavior include degree of adherence to guidelines and physician attitudes about the perceived utility, ease of use, and self-reported effect of the use of algorithms on workload. Novel features of the design include a two-tiered study enrollment procedure, which initially enroll physicians as subjects, and then following recruitment of physicians, enrollment of subjects takes place based initially on an independent assessment by study staff to determine study eligibility. The study utilizes brief, easy-to-use symptom severity measures that facilitate physician decision making, and it employs a validated, phone-based, follow-up assessment protocol in order to minimize missing data, a problem common in public sector and longitudinal mental health studies. IMPACTS will assess the success of algorithm implementation and subsequent physician adherence using study-developed criteria and related statistical approaches. These new procedures and data points will also allow a more refined assessment of algorithm-driven treatment in the future.