Evaluation of Individual Items of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) in Adults with Treatment-Resistant Depression Treated with Esketamine Nasal Spray Combined with a New Oral Antidepressant

This posthoc analysis of the TRANSFORM-2 trial assessed the effects of esketamine plus an oral antidepressant (AD) using the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS). The odds of improving in those treated with esketamine plus AD were at least two times greater than with placebo plus AD.

Abstract

“Objective: The objective of this study was to determine which symptoms measured by the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) improve in those treated with esketamine nasal spray in combination with oral antidepressant (AD) compared with those treated with placebo plus AD for adult patients with treatment-resistant depression (TRD). These results complement the interpretation of PHQ-9 and MADRS total scores.

Methods: The TRANSFORM 2 study evaluated the efficacy and safety of esketamine nasal spray in combination with AD. This posthoc analysis used PHQ-9 and MADRS data to evaluate symptom changes. The total scores change and proportions of individual item change scores on the PHQ-9 and MADRS were evaluated at days 15 and 28; analysis of variance was used to test differences in total scores. Generalized estimation equations of logistic regression models were used to estimate the likelihood of improvement on instrument items.

Results: The mean total score reduction of the PHQ-9, indicating improvement, was greater in the esketamine plus AD arm compared with placebo plus AD at day 15 (- 1.8; p = 0.045) and day 28 (- 2.8; p = 0.006). Proportions of those who improved (≥ 1 point on a 4-point scale and ≥ 2 points on a 7-point scale for the PHQ-9 and MADRS, respectively) was greater in the esketamine plus AD group compared with the placebo plus AD group across all items. The odds of improving for those in the esketamine plus AD group compared with the placebo plus AD group were over two times greater on the PHQ-9 items: “Little interest/pleasure in things” (OR 2.252, 95% CI 1.165-4.355); “Feeling down, depressed, or hopeless” (OR 2.767, 95% CI 1.400-5.470); and “Feeling tired or having little energy” (OR 2.171, 95% CI 1.153-4.087). The mean reduction in total scores on the MADRS, indicating improvement, was numerically greater at day 15 (- 2.0; p = 0.189) and statistically significantly greater at day 28 (- 4.4; p = 0.017) in the esketamine plus AD arm compared with placebo plus AD. The odds of improving for those in the esketamine plus AD group compared with the placebo plus AD group were over two times greater on the MADRS items measuring “Apparent sadness” (OR 2.007, 95% CI 1.096-3.674); and “Inability to feel” (OR 2.099, 95% CI 1.180-3.735).

Conclusion: Improvement in mean total scores in those treated with esketamine plus AD compared with placebo plus AD are important results to confirm efficacy. The odds of improving in those treated with esketamine plus AD was at least two times greater than with placebo plus AD on three patient- and two clinician-reported individual symptoms of TRD. These findings provide patient-relevant quantification of the esketamine plus AD treatment benefit, adding understanding as to which symptoms are most improved with treatment.”

Authors: Lysbeth Floden, Stacie Hudgens, Carol Jamieson, Vanina Popova, Wayne C. Drevets, Kimberly Cooper & Jaskaran Singh

Summary

Abstract

In the TRANSFORM 2 study, patients treated with esketamine nasal spray in combination with oral antidepressant showed improved symptoms on the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) compared with those treated with placebo plus AD.

The mean total score reduction of the PHQ-9 was greater in the esketamine plus AD arm compared with placebo plus AD at day 15 and day 28, and the odds of improving were over two times greater in the esketamine plus AD group compared with the placebo plus AD group across all items.

Esketamine plus AD improved mean total scores in those treated with esketamine plus AD compared with placebo plus AD on three patient- and two clinician-reported individual symptoms of TRD.

Adult patients treated with esketamine plus AD compared with placebo plus AD improved on the PHQ-9 and MADRS and were over two times more likely to improve on symptoms such as apparent sadness and inability to feel.

1 Introduction

Major depressive disorder (MDD) or depression is a leading cause of global long-term disability. Treatment-resistant depression (TRD) contributes to the disease burden by increasing mortality and morbidity, and increasing treatment costs.

Prior to 2019 there were limited treatment options for individuals diagnosed with TRD, with fluoxetine/ olanzapine being the only treatment approved in the US.

Esketamine, the S-enantiomer of ketamine racemate, was approved as a nasal spray for the treatment of TRD in early 2019 and was subsequently approved in other countries.

The 9-item Patient Health Questionnaire (PHQ-9) and the 10-item Montgomery-Asberg Depression Rating Scale (MADRS) are used to measure depression symptoms and measure efficacy over time in a clinical setting.

The total score on the PHQ-9 and MADRS measures depression severity and is calculated by summing the item scores of multiple items that assess depression. However, individual items may contribute differently to overall depression severity, making evaluation of single items relevant to interpretation of the total score.

Results from the phase III TRANSFORM 2 randomized clinical trial assessing the efficacy of esketamine nasal spray for TRD are presented. The analyses evaluate patient-reported and clinician-reported improvements in depressive symptoms among adult patients with TRD receiving esketamine nasal spray plus a newly initiated oral AD.

2.1 Study Characteristics

TRANSFORM-2 was a phase III, double-blind, multicenter, active-controlled study that was approved by the local ethics committee and the Institutional Review Board.

Patients with MDD without psychotic features met the DSM 5 diagnostic criteria and were treatment-resistant to at least two different antidepressant treatments within the current depressive episode.

Patients received a double-blind flexible dose of esketamine nasal spray plus oral AD or oral AD plus intranasal placebo for 4 weeks.

2.2 Study Instruments

The PHQ-9 is a PRO instrument used to assess depression symptoms with nine items: little interest/pleasure in things, feeling down, depressed, or hopeless, trouble falling or staying asleep, sleeping too much, feeling tired, poor appetite, feeling bad about yourself, trouble concentrating, and moving slowly. This study used electronic data collection devices to collect PHQ-9 and other PRO data during onsite assessments. The PROs were translated and administered in the language that was most appropriate for the patient’s everyday language.

The MADRS is a clinician-reported outcome (ClinRO) scale designed to measure depression severity. It consists of ten items and scores from 0 to 60, with higher scores representing a more severe condition.

2.3 Statistical Analysis

The statistical analysis system (SAS) Version 9.4 was used to perform exploratory post-hoc analyses on adult patients with COA assessments at any time point within the intent-to-treat population.

Within-patient item-level improvement was defined as a decrease of at least 1 point on the PHQ-9 or 2 points on the MADRS, respectively, on the total score meaningful change thresholds.

The threshold for within-person meaningful change differs from the threshold for clinical relevance both conceptually and often numerically. The MID is used to judge clinical significance of mean difference in change between groups.

3.1 PHQ‑9 Patient‑Reported Outcome Findings

Most patients in both treatment groups experienced improvement on all items except Item 9 (thoughts you would be better off dead). The difference in scores was larger in the esketamine plus AD arm compared with the placebo plus AD arm at both day 15 and day 28.

The proportion of patients who experienced a 1-point improvement was greater in the esketamine plus AD group compared with placebo plus AD for all nine PHQ-9 items.

Feeling down, depressed, hopeless, tired, having little energy, bad about yourself are all associated with depression.

3.2 MADRS Clinical‑Reported Outcome Findings

Most patients in both treatment groups improved on all items on the MADRS from baseline to Day 15, but the proportion of patients who improved was greater in the esketamine/oral AD group compared with the placebo plus AD group across all items.

Patients in the esketamine plus AD group had greater improvement in all items on the MADRS compared with placebo plus AD at both day 15 and day 28.

4 Discussion

This study demonstrates that treatment with esketamine nasal spray plus oral AD improves all items on the PHQ-9 and MADRS, and that the odds of not feeling down, depressed, or hopeless after 1 month of treatment are twice that for those treated with esketamine plus AD compared with AD plus placebo.

The results suggest that esketamine/oral AD improves symptoms of depression in TRD adult patients, especially in items 1, 2, 4, and 6. These results can be used to identify the items driving overall score response for those on esketamine plus AD compared to those on placebo plus AD.

The likelihood of improving was greatest for items measuring little interest/pleasure in things, feeling down, depressed, or hopeless, and feeling tired or little energy on the PHQ-9 and MADRS.

The study had a short follow-up time and used a 4-week duration for the induction phase. It also did not evaluate the oral AD used, and further studies are needed to replicate these findings.

5 Conclusions

Single item analysis of the PHQ-9 and MADRS shows that treatment with esketamine plus AD can improve symptoms in TRD patients, with the greatest improvement being seen on items representing cardinal symptoms of depression.