To assess the Patient Health Questionnaire (PHQ-9) as a predictor of relapse of depressive symptoms in treatment-resistant depression (TRD).

Analysis included maintenance phase data from SUSTAIN-1 (NCT02493868), a randomized, double-blind, active-controlled study in TRD patients that evaluated efficacy of intranasal esketamine (ESK) + oral antidepressant (AD) vs AD + intranasal placebo in delaying relapse of depressive symptoms. A ≥50% reduction in initial symptom score and total score of ≤12 were considered as response and remission, respectively, using the Montgomery-Asberg Depression Rating Scale. PHQ-9 total score (range, 0–27), PHQ-2 total score (0–6), and individual items of the PHQ-9 (0–3) were examined as predictors of relapse. Data were collected every 2 weeks. Association between time-varying PHQ-9 and event of depression relapse was evaluated in Andersen-Gill Cox model.

Of 176 stable remitters, 63 had a relapse event (ESK+AD [n=24]; AD+placebo [n=39]). Of 121 stable responders, 50 had a relapse event (ESK+AD [n=16]; AD+placebo [n=34]). Among stable remitters, PHQ-9 total score (HR; 95% CI [1.12; 1.04–1.21]) and PHQ-2 total score (1.58; 1.25–1.99) were associated with relapse risk. PHQ-9 items #1 (loss of pleasure, 2.07; 1.38–3.09), #2 (feeling down, 2.18; 1.51–3.15), #4 (feeling tired, 1.54; 1.13–2.11), and #6 (negative self-view, 2.27; 1.41–3.66) were associated with relapse risk. PHQ-2 total scale yielded the smallest Akaike’s Information Criterion among stable remitters and responders.

PHQ-9, PHQ-2 total scores or individual items may be useful for predicting relapse of depressive symptoms among stable TRD patients.

This study was sponsored by Janssen Research and Development, LLC.

Major depressive disorder (MDD) has been ranked among the top causes worldwide of years lived with disability. In this study we assessed meaningful change for the PHQ-9 and the SDS and determined the meaningful change threshold (MCT) using anchor-based methods, which could be used to compare meaningful differences in patients within different treatment arms.

TRANSFORM-1 (NCT02417064) and -2 (NCT0241858) were Phase 3 trials that evaluated the efficacy and safety of fixed and flexible doses of esketamine nasal spray (56 mg or 84 mg) in combination with newly initiated oral antidepressant (ESK+AD) vs oral antidepressant + placebo nasal spray (AD+PBO) in TRD patients. Patient Reported Outcomes (PROs) were integrated into these trials to evaluate the patient perspective of treatment using instruments capturing concepts of importance to patients. The 9-item Patient Health Questionnaire (PHQ-9) is a PRO instrument used to assess self-reported depression symptoms and the Sheehan Disability Scale (SDS) is a PRO for self-reported function and disability. Blinded trial data (combined treatment groups) from TRANSFORM-1 was used for the anchor-based analysis. The Clinical Global Impression - Severity (CGI-S) was used as an anchor and patients were classified into response groups depending on their level of change over the course of the study. Patients were classified among all possible change categories (15 levels, ranging from -7 to 7 where negative change scores indicate improvement). Cumulative Distribution Function (CDF) curves of change from baseline to day 28 were generated using unblinded data from TRANSFORM-2 to visualize the range of responses demonstrated in the respective treatment groups for the PHQ-9 and SDS. MCT values were used to as thresholds to evaluate percentage of responders in each treatment group.

In anchor-based analyses using TRANSFORM-1 combined treatment groups, the correlation between change on the CGI-S and change on the PHQ-9 at Day 28 was high (> 0.60) with anchor-based MCTs ranging from 5 to 8 points. The magnitude of change (standardized effect size estimate within-subject change) for patients improving was exceptionally high (> 0.80). Similar results were observed on the SDS: high correlation of CGI-S and SDS at Day 28 (0.75), moderate SES (0.66), with suggested MCT ranging from 3 to 7 with an MCT value of 5 pts. CDF curves from TRANSFORM-2 showed clear separation between the ESK+AD vs AD+PBO across a number of responder definitions inclusive of those identified with the anchor-based analyses.

The current study is the first to derive an MCT on the PHQ-9 and SDS in TRD to measure meaningful change from the perspective of the patient using regulatory-preferred psychometric anchor-based methodology. These analyses assist with interpretation of meaningfulness of esketamine phase 3 clinical trial results from the patient perspective.

Study was funded by Janssen Global Services, LLC.

Recognizing the importance not only of the clinician’s opinion but also of the patient’s experience and perspective, Sequenced Treatment Alternatives to Relieve Depression (STAR*D) utilized both clinician-reported and patient-reported outcomes in a large-scale multi-step study on antidepressant effectiveness in real-world settings. Both approaches indicate that <17% of Major Depressive Disorder (MDD) patients respond to novel oral treatments after two prior antidepressant failures. To address this low response rate and continue to investigate the use of patient-rated outcomes in clinical trials, an antidepressant with a new mechanism of action is being investigated for efficacy and safety utilizing both clinician-rated and patient-reported scales.

This is a post-hoc analysis of a Janssen R&D Phase 2a clinical trial (ESKETINTRD2003). Subjects aged 20-64 withMDD without psychotic features (DSM IV) and a history of inadequate response to ≥2 antidepressants were randomized [3:1:1:1] to 1 week of twice-weekly treatment with intranasal placebo (n=33), esketamine 28 mg (n=11), 56 mg (n=11), or 84 mg (n=12). Participants taking oral antidepressants at study entry continued treatment during the study. Changes in depression severitywere measured using the Clinical Global Impression Severity (CGI-S) and the Patient Global Impression Severity (PGI-S) scales.

At all esketamine doses (28 mg, 56 mg, 84 mg), subjects reported a one-point mean change in PGI-S from baseline to week one compared to no change on placebo (p-values 0.005, 0.001, 0.032 respectively). Similarly, mean CGI-S scores improved for subjects receiving esketamine at all doses (p-values 0.028, 0.004, 0.049 respectively) compared to no change inplacebo subjects. These data are consistent with previously reported data based on the Montgomery Åsberg Depression Rating Scale (MADRS) and support positive correlation between patient-reported and clinician-reported outcomes.

Initial results from this Phase 2a study suggest clinically relevant improvement in depression symptoms in as early as one week when treated with twice-weekly intranasal esketamine as reported by both clinicians and patients. This work will help guide future investigations of esketamine in larger populations to provide better therapeutic options for treatment resistantMDD patients.

Janssen