Introduction
Major depressive disorder (MDD) is a leading cause of disability and a major contributor of disease burden worldwide.Reference Baldessarini, Forte and Selle1, 2 Estimates of global prevalence among adults is 5.0%, which appears to increase with age.2 In the United States, the 12-month prevalence among adults is more than double this number, at 10.4%, with many patients demonstrating moderate or severe symptoms.Reference Hasin, Sarvet and Meyers3 Much of the disability associated with MDD is a result of the substantial proportion of patients who do not respond adequately to treatment. Approximately one-third of patients with MDD have treatment-resistant depression (TRD),Reference Rush, Trivedi and Wisniewski4 commonly defined as inadequate response to two or more oral antidepressants (OADs) of adequate dose and duration in the current episode.Reference Gaynes, Asher and Gartlehner5
Patient-reported outcomes have increasingly demonstrated value in assessing therapeutic efficacy, effectiveness, and safety of MDD treatment strategies and have garnered interest from academic, industry, and regulatory stakeholders alike.Reference Zimmerman, Walsh, Friedman, Boerescu and Attiullah6–Reference Pandina, Revicki and Kleinman10 Contemporary guidance on trial design from the United States Food and Drug Administration and European Medicines Agency has focused on clinical outcome end points that assess how patients feel, function, and cope. A combination of patient-reported, observer-reported, clinician-reported, and performance outcome measures best assesses clinical benefits and risks of therapeutic strategies, patient experience, and disease progression. Patient experience data are valuable considerations when evaluating the efficacy and safety of new treatments. Patient self-rating scales are a valuable way to incorporate experience from the patient perspective when evaluating efficacy.
The Montgomery–Åsberg Depression Rating Scale (MADRS) is a 10-item clinician-reported questionnaireReference Montgomery and Asberg11 used to measure the severity of MDD symptoms. Although it is accepted by regulatory authorities as an appropriate primary efficacy measure among patients diagnosed with TRD, the MADRS scale is most likely to be used in a clinical research setting and is not regularly implemented in routine clinical practice. The 9-item Patient Health Questionnaire (PHQ-9) is a patient-reported outcome measure that can provide the patient perspective of MDD and has been validated for use in real-world settings.Reference Costantini, Pasquarella and Odone12
The PHQ-9 can assess depressive symptom severity, monitor treatment effect, and provide additional information with which to evaluate depressive symptoms.Reference Hudgens, Floden and Blackowicz13, Reference Mitchell14 Additionally, the PHQ-9 offers an effective cross-cultural measurement of invariance across genders, races, and ethnicitiesReference Patel, Oh and Rand15 and is easy to use, understand, implement, and analyze because data can also be gathered via electronic medical records. Both assessments provide valuable insight into the efficacy of therapeutic strategies; however, there is little research evaluating relationships between MADRS and PHQ-9 scores.Reference Floden, Hudgens and Jamieson7, Reference Hudgens, Floden and Blackowicz13 Understanding this relationship will allow clinicians to more precisely assess the severity of depression at each visit and the success of a treatment for reducing depressive symptoms.
Esketamine nasal spray (ESK) is a noncompetitive N-methyl-D-aspartate receptor antagonist approved by the United States Food and Drug Administration, in conjunction with an OAD, for the treatment of TRD in adults and for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior.Reference Hudgens, Floden and Blackowicz13
In the TRANSFORM-1 (NCT02417064)Reference Fedgchin, Trivedi and Daly16 and TRANSFORM-2 (NCT02418585)Reference Popova, Daly and Trivedi17 phase 3 trials of ESK plus a newly initiated OAD (ESK + OAD) in adults with TRD, clinically meaningful reductions in MADRS total score were observed with ESK + OAD versus OAD + placebo nasal spray (OAD + PBO) after 4 weeks of treatment (primary end point). Eligible patients from TRANSFORM-1 or TRANSFORM-2 could enroll in SUSTAIN-1 (NCT02493868),Reference Daly, Trivedi and Janik18 a longer-term relapse-prevention study that evaluated ESK + OAD versus OAD + PBO among adults in stable remission following at least 16 weeks of ESK optimization. Improvements in mean MADRS score persisted with continuous ESK treatment in SUSTAIN-1.
The efficacy and safety of ESK + OAD for the treatment of TRD have been demonstrated in both short-term and long-term studies.Reference Fedgchin, Trivedi and Daly16–Reference Daly, Trivedi and Janik18 Here, we report the findings of the impact of ESK + OAD versus OAD + PBO on TRD symptoms in the TRANSFORM-1 and TRANSFORM-2 short-term studies and the SUSTAIN-1 long-term study using clinician- (MADRS) and patient-reported (PHQ-9) assessment tools. We also evaluate the associations between clinician- and patient-reported outcomes using the MADRS and PHQ-9 among adult patients with TRD in TRANSFORM-1 and TRANSFORM-2.
Methods
Study design
Data from TRANSFORM-1, TRANSFORM-2, and SUSTAIN-1 were used in these analyses (Figure 1). TRANSFORM-1 and TRANSFORM-2 were two similarly designed, 4-week, randomized, controlled studies of ESK + OAD versus OAD + PBO in adults with TRD.Reference Fedgchin, Trivedi and Daly16, Reference Popova, Daly and Trivedi17 SUSTAIN-1 was a longer term, phase 3, double-blind, active-controlled, randomized withdrawal, relapse prevention study evaluating ESK + OAD versus OAD + PBO in adults in stable remission following ESK optimization.Reference Daly, Trivedi and Janik18 Eligible patients were enrolled into SUSTAIN-1, either directly or after completing the double-blind phase of the TRANSFORM-1 or TRANSFORM-2 studies.Reference Daly, Trivedi and Janik18 The studies included in this analysis were registered at ClinicalTrials.gov (NCT02417064, NCT02418585, and NCT02493868) and approved by the local ethics committees, and written informed consent was obtained from all participating patients.
Study designs of (A) TRANSFORM-1Reference Fedgchin, Trivedi and Daly16 and TRANSFORM-2,Reference Turkoz, Daly and Singh21 and (B) SUSTAIN-1.Reference Daly, Trivedi and Janik18 TRANSFORM-1 and TRANSFORM-2 had similar designs; however, flexible dosing was used in TRANSFORM-2 and fixed dosing was used in TRANSFORM-1.
aNonresponse to ongoing OAD at end of screening was defined as a ≤25% improvement in MADRS total score from week 1 to week 4 and MADRS total scores ≥28 at weeks 2 and 4.
bThe randomization ratio was 2:1 (ESK + OAD:OAD + PBO) for the TRANSFORM-1 study and 1:1 for the TRANSFORM-2 study.
cOnly responders proceeded to the optimization phase. Response in TRANSFORM-1 and TRANSFORM-2 was defined as ≥50% reduction from baseline in MADRS total score at day 28.
dAfter optimization, patients receiving ESK + OAD who achieved stable remission or stable response were randomized to either continue ESK + OAD or be switched to OAD + PBO until relapse or study completion.
eStable response was defined as ≥50% reduction from baseline in MADRS total score in each of the last 2 weeks of the optimization phase in patients who did not meet criteria for stable remission; stable remission was defined as MADRS total score ≤12 for at least 3 of the last 4 weeks of the optimization phase, with up to 1 excursion (MADRS score > 12) or 1 missing MADRS assessment permitted at week 13 or 14 only.
The MADRS
The MADRS is a 10-item clinician-rated instrument used to measure depression severity. The scale ranges from a score of 0 to 60, with higher scores indicating greater severity of depression.Reference Hudgens, Floden and Blackowicz13 Each item is rated on a 7-point continuum (0 = no abnormality, 6 = severe depression).Reference Montgomery and Asberg11 In the TRANSFORM-1 and TRANSFORM-2 studies, the MADRS was administered at baseline and at days 2, 8, 15, 22, and 28. During SUSTAIN-1, the MADRS was administered at baseline; at days 8, 15, 22, and 28 during the induction phase; and weekly throughout the optimization and maintenance phases. In these analyses, a clinically substantial improvement in MADRS score was defined as a ≥12-point change in the total score and a clinically meaningful improvement was defined as a ≥6-point change in the total score.Reference Hudgens, Floden and Blackowicz13, Reference Turkoz, Alphs and Singh19 Response, defined as ≥50% improvement in MADRS total score during double-blind induction phase, was also calculated.
The PHQ-9
The PHQ-9 is a self-rated assessment tool used to detect and evaluate the severity of depression. The score ranges from 0 to 27, with higher scores indicating greater severity of depression.Reference Kroenke, Spitzer and Williams20 In the TRANSFORM-1 and TRANSFORM-2 studies, the PHQ-9 was administered at baseline, day 15, and day 28. During SUSTAIN-1, the PHQ-9 was administered at baseline, day 15, and day 28 during the induction phase and every other week throughout the optimization/maintenance phases. In this analysis, a clinically substantial improvement in PHQ-9 score was defined as a ≥6-point change, with a clinically meaningful improvement defined as a ≥3-point change.Reference Hudgens, Floden and Blackowicz13, Reference Turkoz, Daly and Singh21 A PHQ-9 score ≤4 indicates “no depressive symptom status”Reference Zimmerman22; the patient was therefore considered to be in remission. Response, defined as ≥50% improvement in PHQ-9 total score during double-blind induction phase, was also calculated.
Statistical analyses
Patients were pooled from the full analysis set of the TRANSFORM-1 and TRANSFORM-2 studies that includes all randomly assigned patients who received at least one dose of intranasal study medication and one dose of OAD medication. Changes in MADRS and PHQ-9 total scores from baseline at days 15 and 28 between treatment groups were compared using analysis of covariance models with fixed effects for treatment, study ID, region, and class of OAD (serotonin and norepinephrine reuptake inhibitor [SNRI] or selective serotonin reuptake inhibitor [SSRI]), and baseline values as a covariate. Data for least squares mean change from baseline are shown only for days 15 and 28 to align with the timing of PHQ-9 assessments. Differences in proportions of patients attaining clinically substantial improvement, achieving response, and having no depressive symptom status were examined using the Cochran–Mantel–Haenszel test controlling for region and class of OAD (SNRI or SSRI). Chi-square tests were used to compare the proportion of patients with a MADRS score ≤12 and who retained remission statusReference Daly, Turkoz and Salvadore23 on the PHQ-9. Parametric and nonparametric simple and multiple regression models were used to explore the relationship between MADRS and PHQ-9 scores from baseline to day 15, day 28, and study end point as dependent variables for TRANSFORM-1 and TRANSFORM-2 studies. Assuming potential deviations from linearity for sensitivity analysis purposes, proportional odds models were used to examine the relationship between MADRS and PHQ-9 scores at TRANSFORM-1 and TRANSFORM-2 study end point.
Adult patients who participated in the SUSTAIN-1 study were also included as part of the analysis. Differences between treatment groups in the proportion of patients achieving remission status at the end of the maintenance phase of SUSTAIN-1 were examined using a chi-square test.
Results
Baseline demographics and disease characteristics
A total of 565 patients from TRANSFORM-1 and TRANSFORM-2 (ESK + OAD, n = 343; OAD + PBO, n = 222) and 176 patients from SUSTAIN-1 (ESK + OAD, N = 90; OAD + PBO, N = 86) were included in the analysis. Patient baseline demographic and clinical characteristics were similar across all studies and treatment groups (Table 1). The mean age was 45.4–46.6 years, and most patients were female (64.4%–68.6%) and White (86.2%–88.9%) with a mean duration of current episode of 110.5–175.7 weeks. The mean baseline MADRS (37.4–37.6) and PHQ-9 (19.2–20.6) scores were indicative of severe depression for both treatment groups in both studies, respectively.
Baseline demographics and disease characteristics in the TRANSFORM-1, TRANSFORM-2, and SUSTAIN-1 studies
Abbreviations: ESK, esketamine nasal spray; MADRS, Montgomery–Åsberg Depression Rating Scale; OAD, oral antidepressant; PBO, placebo nasal spray; PHQ-9, 9-item Patient Health Questionnaire; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
Data for SUSTAIN-1 reflect characteristics at the start of the induction phase for patients with stable remittance. In SUSTAIN-1, stable remission was defined as MADRS total score ≤12 for at least 3 of the last 4 weeks of the optimization phase, with up to 1 excursion (MADRS score >12) or one missing MADRS assessment permitted at week 13 or 14 only.
a Other includes patients who identified as American Indian or Alaskan native, more than 1 race, and those with race not reported.
b TRANSFORM-1 and TRANSFORM-2 ESK + OAD n = 341, OAD + PBO n = 222, and SUSTAIN-1 ESK + OAD n = 90 and OAD + PBO n = 84.
Clinician-rated depressive symptoms MADRS outcome findings in TRANSFORM-1 and TRANSFORM-2
Least squares mean MADRS total scores for the pooled TRANSFORM-1 and TRANSFORM-2 patients were significantly lower in the ESK + OAD group compared with the OAD + PBO group starting from day 2 and persisting through day 28 (Figure 2A). MADRS total scores improved from baseline to each post-baseline time point in both treatment arms. However, the least squares mean change from baseline in MADRS total score was significantly greater in the ESK + OAD group compared with the OAD + PBO group on days 15 (−13.2 vs −10.1, P = .002) and 28 (−21.6 vs −17.2, P < .001 [Figure 2B]). A significantly greater proportion of patients who received ESK + OAD attained a clinically substantial improvement in MADRS (ie, ≥12-point change from baseline) compared with patients who received OAD + PBO (46.5% vs 33.7%, P = .002, on day 15 and 69.0% vs 55.3%, P < .001, on day 28 [Figure 3A], respectively). A clinically meaningful improvement in MADRS (ie, ≥6-point change from baseline) was attained by a significantly greater proportion of patients who received ESK + OAD compared with patients who received OAD + PBO on day 15 (69.3% vs 58.2%, P = .008) and day 28 (79.7% vs 68.8%, P = .001). A similar pattern was observed in the proportion of patients who attained response per MADRS total score on day 15 (26.3% vs 18.3%, P = .023) and day 28 (58.7% vs 45.2%, P < .001) (Figure 3C).
Total scores in TRANSFORM-1 and TRANSFORM-2. (A) MADRS least squares mean actual score (±SE) throughout the study. (B) MADRS least squares mean (±SE) change from baseline at days 15 and 28. (C) PHQ-9 least squares mean actual score (±SE) throughout the study.a (D) PHQ-9 least squares mean (±SE) change from baseline at days 15 and 28. *P ≤ .01. Between-group comparisons were based on an analysis of covariance model with fixed effects for treatment, study identification, region, and class of OAD, and baseline value as covariate. **P ≤ .001. Between-group comparisons were based on an analysis of covariance model with fixed effects for treatment, region, and class of OAD, and baseline value as covariate.
aDepression severity based on PHQ-9 score was defined as normal (score of 0–4), mild (score of 5–9), moderate (score of 10–14), moderately severe (score of 15–19), or severe (score of 20–27).Reference Kroenke, Spitzer and Williams20
Proportions of patients with a clinically substantial improvement. (A) ≥12-point improvement in MADRS total score. (B) ≥6-point improvement from baseline in PHQ-9 total score in TRANSFORM-1 and TRANSFORM-2 and proportions of patients with response. (C) ≥50% improvement in MADRS total score. (D) ≥50% improvement in PHQ-9 total score in TRANSFORM-1 and TRANSFORM-2.
PHQ-9 patient-rated outcome findings in TRANSFORM-1 and TRANSFORM-2
The least squares mean PHQ-9 total scores were lower in the ESK + OAD versus OAD + PBO group at days 15 and 28 and were indicative of mild-to-moderate MDD (Figure 2C). Changes in PHQ-9 total score with ESK treatment shared directional changes with those observed for MADRS total score. The least squares mean change from baseline in PHQ-9 total score was significantly greater in the ESK + OAD group compared with the OAD + PBO group at days 15 and 28, −9.0 versus −7.2, P = .001 and −12.8 versus −10.3, P < .001, respectively (Figure 2D), representing a clinically meaningful improvement from baseline. A higher proportion of patients who received ESK + OAD attained a clinically substantial improvement in PHQ-9 total score (ie, ≥6-point change from baseline) compared with patients who received OAD + PBO on both day 15 (64.4% vs 52.8%, respectively, P = .005) and day 28 (77.1% vs 64.7%, respectively, P < .001) (Figure 3B). A clinically meaningful improvement in PHQ-9 (ie, ≥3-point change from baseline) was attained by a significantly greater proportion of patients who received ESK + OAD compared with patients who received OAD + PBO on both day 15 (75.8% vs 68.5%, P = .043) and day 28 (85.8% vs 71.5%, P < .001). A similar pattern was observed in the proportion of patients who attained response per PHQ-9 total score on day 15 (43.8% vs 34.3%, P = .027) and day 28 (65.8% vs 52.9%, P < .001) (Figure 3D).
MADRS/PHQ-9 alignment results in TRANSFORM-1 and TRANSFORM-2
With a simple linear regression model, a 1-point increase in PHQ-9 total score at day 28 corresponded to a 1.5-point (standard error, 0.04) shift in the MADRS total score in TRANSFORM-1 and TRANSFORM-2 (Table 2). In this setting, the PHQ-9 total score can account for 73% of the MADRS total score variation. The alignment between the MADRS and the PHQ-9 total scores at day 28 is shown in Figure 4. The relationship between the MADRS and the PHQ-9 total scores tended to follow a nonlinear trend. This relationship was not constant over time, with the least alignment between MADRS and PHQ-9 total scores observed at baseline, with an increased correlation over time (Table 3). The relationship between MADRS and PHQ-9 scores at TRANSFORM-1 and TRANSFORM-2 study end point was examined, with predicted probabilities listed for widely used scoring categories for the PHQ-9 scores (Table 4). Different levels of severity in MADRS total score and PHQ-9 levels were not perfectly aligned.
MADRS total score over time associated with a 1-point shift in PHQ-9 total score during TRANSFORM-1/TRANSFORM-2
Abbreviations: MADRS, Montgomery–Åsberg Depression Rating Scale; PHQ-9, 9-item Patient Health Questionnaire.
PHQ-9 total score was set as a predictor.
Relationship between MADRS total scores and PHQ-9 total scores at day 28. Dotted line denotes the locally weighted smoothing regression line (LOESS).
Correlation coefficients of PHQ-9 and MADRS total score by visit during TRANSFORM-1 and TRANSFORM-2
Abbreviations: MADRS, Montgomery–Åsberg Depression Rating Scale; PHQ-9, 9-item Patient Health Questionnaire.
Distribution of MADRS total scores by PHQ-9 total score at TRANSFORM-1 and TRANSFORM-2 study end point
Abbreviations: MADRS, Montgomery–Åsberg Depression Rating Scale; PHQ-9, 9-item Patient Health Questionnaire.
Predicted probabilities are listed as percentages from proportional odds models. Probabilities greater than ≥20% are bolded and indicate the relationship between the PHQ-9 and MADRS total scores at end point.
Clinician-rated depressive symptoms MADRS outcome findings in SUSTAIN-1
In SUSTAIN-1, the median (range) duration of exposure in the maintenance phase was 17.7 (0–83) weeks in the ESK + OAD group and 10.2 (0–76) weeks in the OAD + PBO group. The mean MADRS total scores decreased substantially in patients treated with ESK + OAD during the optimization phase and this decrease in total score was sustained throughout the maintenance phase (Figure 5A). A significantly higher percentage of patients treated with ESK + OAD than OAD + PBO retained a MADRS score of ≤12 (mild to no depressive symptoms) at maintenance treatment end point (57.6% vs 35.2%, P < .001) (Figure 5B).
MADRS and PHQ-9 total scores in SUSTAIN-1. (A) MADRS total score (±SE) throughout the study. (B) Proportion of patients who retained a MADRS score of ≤12 at end point of the maintenance phase. (C) PHQ-9 mean (±SE) actual score throughout the study.a (D) proportion of patients who retained remission status on the PHQ-9 (≤4) at the end point of the maintenance phase.b
aDepression severity based on PHQ-9 score was defined as normal (score of 0–4), mild (score of 5–9), moderate (score of 10–14), moderately severe (score of 15–19), or severe (score of 20–27).Reference Kroenke, Spitzer and Williams20
bPatients who retained remission status had a PHQ-9 score of ≤4 at end point.27
PHQ-9 total scores in SUSTAIN-1
Mean PHQ-9 total scores decreased substantially in patients treated with ESK + OAD during the optimization phase, with lower PHQ-9 scores observed in the ESK + OAD group than in the OAD + PBO group throughout the maintenance phase (Figure 5C). More patients with stable remission who entered the double-blind maintenance phase and received ESK + OAD (N = 89) versus OAD + PBO (N = 86) retained remission status (PHQ-9 score ≤4) at maintenance treatment end point (57.3% vs 44.2%, P = .044) (Figure 5D). Significantly more patients in the OAD + PBO group versus than in the ESK + OAD group had a clinically substantial worsening in PHQ-9 total score (ie, an increase of ≥6 points) at week 2 (16.7% vs 3.5%, P = .004) and end point (38.4% vs 21.4%, P = .014) of the double-blind, randomized maintenance phase. Clinically meaningful worsening (ie, an increase of ≥3 points) was significantly greater in OAD + PBO patients compared with ESK + OAD patients at week 2 (33.3% vs 12.8%, P = .001) and numerically greater at the maintenance phase end point (53.5% vs 39.3%, P = .060).
Discussion
This post hoc analysis of three phase 3 studies of ESK + OAD versus OAD + PBO afforded an opportunity to highlight the associations between the MADRS and PHQ-9 and compare therapeutic interventions among patients who are severely ill with TRD. Regardless of the study length, ESK + OAD demonstrated greater efficacy than OAD + PBO for the treatment and management of TRD symptoms among adults. Furthermore, the short-term TRANSFORM-1 and TRANSFORM-2 studies demonstrated associations between clinician- (MADRS) and patient-reported (PHQ-9) outcomes, favoring treatment with ESK + OAD versus OAD + PBO, while the SUSTAIN-1 study provided an opportunity to demonstrate the long-term, sustained efficacy of ESK + OAD treatment compared to OAD + PBO. This analysis demonstrates the value of including patient-reported outcome assessments when evaluating the effectiveness of TRD treatment strategies.
Several studies of MDD and/or TRD have sought to assess the relationship between clinician-rated and patient-rated scales to characterize the trajectory of the course of disease and treatment effects.Reference Floden, Hudgens and Jamieson7, Reference Huang, Ma, Wang, Zhong, Sheng and Xu8, Reference Hudgens, Floden and Blackowicz13, Reference Turkoz, Alphs and Singh19, Reference Hawley, Gale and Smith24 Establishing quantitative relationships and clinically meaningful score changes provide clinicians with tools to facilitate the translation of clinical trial outcomes into meaningful approaches in clinical practice. Efforts to estimate clinically meaningful changes in the Clinical Global Impression-Severity scale with changes in the MADRS, Sheehan Disability Scale, and PHQ-9 have laid the foundation for linking score changes between clinician- and patient-rated assessment strategies.Reference Turkoz, Alphs and Singh19 One study conducted regression analyses to generate a predictive equation between depression scale pairs (PHQ-9 and MADRS, PHQ-9 and Beck Depression Inventory II, Zung Self-Rated Scale [SRS] and MADRS, and SRS and PHQ-9) to aid in translating scores between scales.Reference Hawley, Gale and Smith24 Results of the analyses showed conversion equations for depression scores were precise when applied to averages but were less useful at the idiographic level.Reference Hawley, Gale and Smith24 Others have equated the Hospital Anxiety and Depression Scale (HADS) depression (HADS-D) and anxiety (HADS-A) subscales to the PHQ-9 and Generalized Anxiety Disorder Scale, providing tables for converting raw scores between instruments.Reference Huang, Ma, Wang, Zhong, Sheng and Xu8 Recent emphasis has considered identification of meaningful assessment of complementary symptom changes assessed by the MADRS and PHQ-9.Reference Floden, Hudgens and Jamieson7, Reference Hudgens, Floden and Blackowicz13 The current analysis builds upon these studies, demonstrating the increased agreement between the MADRS and PHQ-9 outcomes throughout the pooled TRANSFORM-1 and TRANSFORM-2 patient populations.
Although the clinician-rated assessment of response is an important strategy for evaluating efficacy, the patient perspective provides a quantitative measure of treatment response and disease burden. Unlike other common long-term disorders, there are no laboratory or physical diagnostic tests to quantify how patients respond to TRD treatments. Often, clinician-rated and patient-rated assessments of symptom status differ,Reference Pandina, Revicki and Kleinman10 with patient-rated assessments conferring the real-world value of a therapeutic intervention and capturing the presence and burden of symptoms from the patient perspective. However, MADRS and PHQ-9 are similar in that the PHQ-9 measures the frequency of the same DSM-5 depressive symptoms that MADRS rates for severity. This analysis suggests that there is consistency between the MADRS and PHQ-9 in identifying symptom improvement. Further investigation is warranted to understand the role of perspective in the recognition and timing of minor symptom changes. The patient perspective may serve as a more timely and sensitive measure than the clinician perspective in recognizing early subtle symptom changes. The relationship established between the MADRS and PHQ-9 in this analysis facilitates the translation of a frequently used clinical trial measure of depressive symptoms with a patient-reported tool commonly used in clinical practice. Providing clinicians with greater confidence of the validity of the PHQ-9 in assessing MDD symptoms confers access to a reliable tool that is succinct and simple to administer in any healthcare setting.
Limitations
Data from TRANSFORM-1 and TRANSFORM-2 were pooled in this analysis; however, these studies were not identically designed in that TRANSFORM-1 involved fixed dosing and TRANSFORM-2 involved flexible dosing.Reference Fedgchin, Trivedi and Daly16, Reference Popova, Daly and Trivedi17 Regardless of the dosing strategy, a significant improvement from baseline was observed among patients treated with ESK + OAD compared with those treated with OAD + PBO (TRANSFORM-1 and TRANSFORM-2). The studies included in this post hoc analysis were not specifically designed to investigate the associations between the MADRS and PHQ-9 assessments. However, the nonlinear associations identified between the scales may contribute to more comprehensive evaluations in clinical decision-making. It is also important to note that data from clinical trial participants may not be generalizable to real-world populations of patients with TRD. In addition, the PHQ-9 is a patient-reported outcome that is dependent upon patient recall over time. Furthermore, because clinician- and patient-reported assessments were performed every 2 weeks (ie, baseline, day 15, and day 28), fluctuations in response to treatment may not have been captured. Approaches such as ecological momentary assessment, which involves collecting patient data on repeated occasions in real time and in the context of daily life (eg, via a smartphone), is a potential tool for more frequent assessments from a patient perspective.Reference Bell, Lim, Rossell and Thomas25 Although it is recognized that measurement-based care may enhance the quality of care and improve clinical outcomes, informed clinician judgment is also necessary to guide treatment decisions in real-world practice.
With respect to SUSTAIN-1 outcomes, it should be noted that the same PHQ-9 thresholds (≥6-point change and ≥3-point change) were used to measure both clinical improvement and clinical worsening in depression severity. Additional studies are needed to determine if these PHQ-9 thresholds are appropriate to assess both improvement and worsening of depression severity in patients with TRD. Correlations evaluated in this study grew stronger at post-baseline visits, indicating a potential learning curve that brings both patients and clinicians into increasingly analogous frames of reference over time. It also suggests progression in integrating the perspective of the clinician and patient when focus is directed to similar aspects of the disease. This phenomenon has also been observed in other disease states with different clinician- and patient-reported outcomes.Reference Askanase, Tang, Zuraw, Gordon, Brotherton and Merrill26
An additional limitation is the small number of patients historically underrepresented in clinical trials, for example, patients of color who participated in the studies. Responses from a more diverse patient population could have provided additional interracial insights on the use of the PHQ-9 and how the assessment relates to MADRS total scores across different races and ethnicities. Further research in this area is warranted.
Conclusions
This post hoc analysis of treatment with ESK + OAD versus OAD + PBO resulted in significant benefit among patients severely ill with TRD as measured by both clinician- and patient-rated evaluation of depression symptoms. The PHQ-9, a measure of depression severity that is relevant and easily administered in routine clinical practice, produced results that are consistent with those observed for the clinician-rated MADRS assessment in adults with TRD. Compared to the MADRS, more clinically meaningful improvements in depressive symptoms were observed as measured by the patient-rated PHQ-9 assessment with ESK + OAD versus OAD + PBO treatment.
Acknowledgments
The authors thank Audrey Shor, PhD (ApotheCom, Yardley, PA, USA), for editorial and writing assistance, which was funded by Janssen Scientific Affairs, LLC.
Author contribution
J.K.S. and M.T.: Conceptualization, writing, reviewing, and editing. R.R.N. Jr, M.P.P., and P.C.: Writing, reviewing, and editing. I.T.: Conceptualization, methodology, software, validation, formal analysis, data curation, writing, reviewing, editing, and visualization.
Financial support
This study was funded by Janssen Scientific Affairs, LLC, Titusville, NJ, USA. The study sponsor was involved in the design and conduct of the study and in the collection, management, analysis, and interpretation of data. As detailed in the authorship statement, all authors made significant contributions to the development of the manuscript in accordance with ICMJE authorship criteria. All authors provided direction and comments on the manuscript, reviewed and approved the final version prior to submission, made the final decision about where to publish these data, and approved submission to this journal. All authors had full access to the study data and take responsibility for data integrity and the accuracy of the analyses.
Competing interest
J.K.S., R.R.N. Jr, M.P.P., and P.C. are employees of Janssen Scientific Affairs, LLC, and hold stock in Johnson & Johnson, Inc. I.T. is an employee of Janssen Research & Development, LLC, and holds stock in Johnson & Johnson, Inc. M.T. has provided consulting services to Alkermes Inc., Axsome Therapeutics, Biogen MA Inc., Cerebral Inc., Circular Genomics Inc., Compass Pathfinder Limited, GH Research Limited, Heading Health Inc., Janssen, Legion Health Inc., Merck Sharp & Dohme Corp., Mind Medicine (MindMed) Inc., Naki Health, Ltd., Neurocrine Biosciences Inc., Noema Pharma AG, Orexo US Inc., Otsuka American Pharmaceutical Inc., Otsuka Canada Pharmaceutical Inc., Otsuka Pharmaceutical Development & Commercialization Inc., Praxis Precision Medicines Inc., SAGE Therapeutics, Sparian Biosciences Inc., Takeda Pharmaceutical Company Ltd., and WebMD; is a member of the scientific advisory board of Alto Neuroscience Inc., Cerebral Inc., COMPASS Pathfinder Ltd., Heading Health, GreenLight VitalSign6 Inc., Legion Health Inc., Merck Sharp & Dohme Corp., Orexo US Inc., and Signant Health; has received editorial compensation from the American Psychiatric Association and Oxford University Press; and holds stock in Alto Neuroscience Inc., Cerebral Inc., Circular Genomics Inc., GreenLight VitalSign6 Inc., and Legion Health Inc.
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