Baseline Demographics and Clinical Characteristics Associated With Relapse

Summary

• The SUSTAIN-1 study was a phase 3, randomized, double-blind, multicenter study conducted in adults with treatment-resistant depression (TRD). It comprised an initial
  4-week open-label induction and a 12-week optimization phase followed by a randomized withdrawal maintenance phase of variable duration and a 2-week posttreatment follow-up phase to evaluate the efficacy of continuing treatment with SPRAVATO + oral antidepressant (OAD) vs switching to placebo nasal spray + OAD in delaying relapse of depressive symptoms.¹
  • Induction/optimization phase: patients received intranasal SPRAVATO (56 mg or
    84 mg, flexibly dosed) twice weekly + a new OAD taken daily.
  • Maintenance phase: patients who attained stable response or stable response remission were randomized in a 1:1 ratio to either continue SPRAVATO + OAD or discontinue SPRAVATO and receive placebo + OAD during the maintenance phase.
• Shelton et al (2026)² conducted a post hoc analysis of SUSTAIN-1 to evaluate potential predictors of relapse (focused on baseline demographics and disease-related characteristics) in patients randomized to the placebo + OAD group after 16 weeks of treatment with SPRAVATO + OAD.
  • At maintenance baseline, relapse occurred more frequently in the placebo + OAD group (45.3%) compared with the SPRAVATO + OAD group (26.7%).
  • Potential predictors of relapse for patients who discontinued SPRAVATO treatment included ≥3 prior antidepressant treatments, a lifetime history of suicidal behavior, or being categorized as “markedly ill” per Clinical Global Impression-Severity (CGI-S) category.

CLINICAL STUDIES

Post Hoc Analysis of the SUSTAIN-1 Study

Shelton et al (2026)² conducted a post hoc analysis of the SUSTAIN-1 study to evaluate potential predictors of relapse in patients randomized to the placebo + OAD group (after 16 weeks of treatment with SPRAVATO + OAD). This analysis focused on the baseline demographics and disease-related characteristics that may be associated with an increased risk of relapse in these patients.

Study Design/Methods

• In SUSTAIN-1, patients received intranasal SPRAVATO (56 mg or 84 mg) + OAD during the 16-week induction and optimization phases.
• Patients who attained stable remission were randomized in a 1:1 ratio to either continue SPRAVATO + OAD or discontinue SPRAVATO and receive placebo + OAD during the maintenance phase.
• Montgomery-Åsberg Depression Rating Scale (MADRS) assessments were conducted weekly during the maintenance phase.
• Stable remission was defined as MADRS total score ≤12 for at least 3 of the last 4 weeks of the optimization phase.
• Relapse was defined as MADRS total score ≥22 for 2 consecutive assessments and/or hospitalization for suicidality or worsening depression or any other clinically relevant event (assessed by the investigator).
• Initial screening of candidate predictors used univariate Cox proportional hazards models; variables with nominal significance (P<0.3) were advanced with no multiplicity adjustment.
• Candidate predictors were then entered into a stepwise multivariate Cox proportional hazards model, with candidates entered sequentially and removed if they became nonsignificant; the final model retained predictors with nominal P<0.05.

Results

Baseline Demographics and Clinical Characteristics

• A total of 176 patients attained stable remission after 16 weeks of SPRAVATO + OAD and were subsequently randomized to continue SPRAVATO + OAD (n=90) or switch to placebo + OAD (n=86).
  • At maintenance baseline, relapses occurred more frequently in the placebo + OAD group (45.3%) compared with the SPRAVATO + OAD group (26.7%).
• In patients who discontinued SPRAVATO (randomized to the placebo + OAD group in the maintenance phase, n=86), statistically significant differences were found between relapsed and nonrelapsed patients for age (P=0.040), number of previous antidepressants (P=0.046), class of OAD (P=0.047), and baseline CGI-S (P<0.001).

Predictors of Relapse

• Initial screening candidates identified as potential predictors of relapse (nominal P<0.3) were current age, presence of hypertension, employment status of “other” vs employed, age at MDD diagnosis, duration of current MDD episode, 2 vs ≥3 prior antidepressants, class of OAD (selective serotonin reuptake inhibitors [SNRI] vs (serotonin-norepinephrine reuptake inhibitors [SSRI]), specific OADs (escitalopram vs duloxetine, sertraline vs duloxetine, and venlafaxine ER vs duloxetine), screening Columbia Suicide Severity Rating Scale (lifetime suicidal ideation vs. no event), and baseline CGI-S category (markedly vs mildly and moderately ill).
• Potential independent predictors of relapse were identified using a stepwise multivariate Cox model. See Table: Variables Associated With Increased Risk of Relapse Identified Using a Stepwise Multivariate Cox Proportional Hazards Model.

• Initial screening variables not meeting statistical significance (P>0.03) were baseline age, race, ethnicity, BMI, status of unemployed vs employed, C-SSRS (lifetime suicidal behavior vs no event), screening C-SSRS in past 6 or 12 months (suicidal ideation and behavior vs no event), screening 30-item Inventory of Depressive Symptomatology, baseline MADRS/Patient health questionnaire-9 (PHQ-9) total score, baseline CGI-S, including CGI-S category of severely and most extremely vs mildly and moderately ill.

Limitations of the Study

• Generalizability may be limited due to exclusion of patients with significant comorbidities or substance dependence.
• As a non-prespecified analysis with a small sample size, findings may have limited statistical power and interpretation of the results.
• The modeling approach (univariate screening followed by multivariate analysis without multiplicity adjustment) may introduce overfitting and selection bias.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 15 September 2026.