Effects of esketamine nasal spray on depressive symptom severity in adults with treatment-resistant depression and associations between the Montgomery-Åsberg Depression Rating Scale and the 9-item Patient Health Questionnaire.

OBJECTIVE: To examine the effect of esketamine nasal spray (ESK) plus newly initiated oral antidepressant (OAD) versus OAD plus placebo nasal spray (PBO) on the association between Montgomery-Åsberg Depression Rating Scale (MADRS) and 9-item Patient Health Questionnaire (PHQ-9) scores in adults with treatment-resistant depression (TRD). METHODS: Data from TRANSFORM-1 and TRANSFORM-2 (two similarly designed, randomized, active-controlled TRD studies) and SUSTAIN-1 (relapse prevention study) were analyzed. Group differences for mean changes in PHQ-9 total score from baseline were compared using analysis of covariance. Associations between MADRS and PHQ-9 total scores from TRANSFORM-1/TRANSFORM-2 were assessed using simple parametric, nonparametric, and multiple regression models. RESULTS: In TRANSFORM-1/TRANSFORM-2 (ESK + OAD, n = 343; OAD + PBO, n = 222), baseline PHQ-9 mean scores were 20.4 for ESK + OAD and 20.6 for OAD + PBO (severe depression). At day 28, significant group differences were observed in least squares mean change (SE) in PHQ-9 scores from baseline (-12.8 [0.46] vs -10.3 [0.53], P < .001) and in clinically substantial change in PHQ-9 scores (≥6 points; 77.1% vs 64%, P < .001) in ESK + OAD and OAD + PBO groups, respectively. A nonlinear relationship between MADRS and PHQ-9 was observed; total scores demonstrated increased correlation over time. In SUSTAIN-1, 57.3% of patients receiving ESK + OAD (n = 89) versus 44.2% receiving OAD + PBO (n = 86) retained remission status (PHQ-9 score ≤4) at maintenance treatment end point (P = .044). CONCLUSIONS: In adults with TRD, ESK + OAD significantly improved severity of depressive symptoms, and more patients achieved clinically meaningful changes in depressive symptoms based on PHQ-9, versus OAD + PBO. PHQ-9 outcomes were consistent with those of clinician-rated MADRS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02417064, NCT02418585, NCT02493868.

Efficacy and Safety of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression Who Completed a Second Induction Period: Analysis of the Ongoing SUSTAIN-3 Study.

BACKGROUND: Treatment-resistant depression (TRD) is a chronic illness requiring long-term treatment. Esketamine nasal spray (ESK) has been studied in several long-term trials of patients with TRD, including SUSTAIN-1 (NCT02493868) and SUSTAIN-3 (NCT02782104). This subgroup analysis of SUSTAIN-3 evaluated patients with TRD who received a second induction (IND) and maintenance treatment with ESK plus oral antidepressant (AD) after a relapse in SUSTAIN-1. METHODS: Patients aged 18-64 years who achieved stable remission or response with ESK and subsequently relapsed after randomization to continue ESK or switch to placebo nasal spray (PBO) in SUSTAIN-1 and entered the IND phase of SUSTAIN-3 were included in this interim analysis. Response (≥50% improvement in total score from baseline for Montgomery-Åsberg Depression Rating Scale [MADRS] and Patient Health Questionnaire 9-item [PHQ-9]), remission (MADRS score ≤12; PHQ-9 total score <5), changes in depression rating scores (measured as mean change from baseline), and safety were evaluated (incidence of treatment-emergent and serious adverse events [AE]). RESULTS: Of the 96 eligible patients who entered IND in SUSTAIN-3, 32 (33.3%) were taking ESK+AD at the time of relapse in SUSTAIN-1 and 64 (66.7%) were taking AD+PBO. Substantial improvements in depressive symptoms were observed over the second IND phase in both groups and were maintained over the optimization/maintenance (OP/M) phase. MADRS response rates following a second IND were 71.9% and 73.4% for previously relapsed (PR) ESK+AD and PR-AD+PBO, respectively; remission rates were 62.5% and 60.9%, respectively. During the IND and OP/M phases, 58.3% and 83.3% of patients experienced a treatment-emergent AE, respectively. No patients discontinued due to an AE during the second IND. CONCLUSIONS: Patients with TRD benefitted from receiving a second IND and maintenance treatment with ESK and no new safety signals were identified.

Factors associated with COVID-19 Infection among a national population of individuals with schizophrenia or schizoaffective disorder in the United States.

BACKGROUND: Individuals with schizophrenia are a vulnerable and under-served population who are also at risk for severe morbidity and mortality following COVID-19 infection. Our research was designed to identify factors that put individuals with schizophrenia at increased risk of COVID-19 infection. METHODS: This study was a retrospective cohort analysis of medical and pharmacy claims among 493,796 individuals residing in the United States with schizophrenia or schizoaffective disorder, between January 1, 2019 and June 30, 2020. A confirmed diagnosis of COVID-19 infection by September 30, 2020 was regressed on demographics, social determinants, comorbidity, and pre-pandemic (December 2019 - February 2020) healthcare utilization characteristics. RESULTS: A total of 35,249 (7.1%) individuals were diagnosed with COVID-19. Elevated odds of COVID-19 infection were associated with age, increasing consistently from 40-49 years (OR: 1.16) to 80+ years (OR:5.92), male sex (OR: 1.08), Medicaid (OR: 2.17) or Medicare (OR: 1.23) insurance, African American race (OR: 1.42), Hispanic ethnicity (OR: 1.23), and higher Charlson Comorbidity Index. Select psychiatric comorbidities (depressive disorder, adjustment disorder, bipolar disorder, anxiety, and sleep-wake disorder) were associated with elevated odds of infection, while alcohol use disorder and PTSD were associated with lower odds. A pre-pandemic psychiatry (OR:0.56) or community mental health center (OR:0.55) visit were associated with lower odds as was antipsychotic treatment with long-acting injectable antipsychotic (OR: 0.72) and oral antipsychotic (OR: 0.62). CONCLUSIONS: Among individuals with schizophrenia, risk of COVID-19 infection was substantially higher among those with fewer economic resources, with greater medical and psychiatric comorbidity burden, and those who resided in African American or Hispanic communities. In contrast, individuals actively engaged in psychiatric treatment had substantially lower likelihood of infection. These results provide insights for healthcare providers that can translate into improved identification of at-risk individuals and interventions to reduce the risk and consequences of COVID-19 infection.