SUMMARY  

• A clinically meaningful within-group change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) has been reported to range between a 6- to 9-point reduction in total score.^1,2
  • A 6-point change from baseline on the MADRS has been shown to correspond to a clinically meaningful change (defined as a 1-point change) on the clinician’s rating of overall depression severity (Clinical Global Impression-Severity [CGI-S]).³
• When treatment groups are compared to each other, a 2-point difference in MADRS between groups has been found to be clinically meaningful.^4,5
  • When comparing groups of depressed patients whose MADRS scores differed by approximately 2 points across three clinical trials, the literature reports significantly greater rates of remission than seen in a matched sample (71.6% vs. 57.1%).⁶
• A brief summary of MADRS results in the SPRAVATO clinical trials is provided below.

BACKGROUND ON SCALES

MADRS

The MADRS is a 10-item, clinician-administered scale designed to measure overall severity of depressive symptoms in subjects with major depressive disorder (MDD). The scale is validated, reliable, and acceptable to regulatory health authorities as a primary efficacy endpoint in a patient population with MDD. Each item is scored between 0-6, leading to a total score of 0-60. The 10 items include the following symptoms: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts.⁷ Score ranges for severity have been proposed as: 0-6, normal; 7-19, mild depression; 20-34, moderate depression; and >34, severe depression.⁸ Measurement-based care is emerging, but not widespread in clinical practice.⁹ The MADRS is more likely to be used in a clinical research setting.

CGI-S

The CGI-S is a clinician-reported measure that assesses the global severity of illness based on factors such as the patient’s history, symptoms, behavior, and functioning. The instrument is scored on a scale ranging from 0 to 7, with 7 indicating the most extremely ill patients.⁷

CLINICALLY MEANINGFUL CHANGE AND DIFFERENCE IN madrs

Clinically MeaningfulChange in MADRS from Baseline for Individual Patients

• A clinically meaningful within-group change from baseline on the MADRS has been reported to range between a 6- to 9-point reduction in total score.^1,2 As depression is more severe at baseline, the change needed to be considered meaningful moves towards the higher end of the range.
• A 6-point change from baseline on the MADRS has been shown to correspond to a clinically meaningful change (defined as a 1-point change) on the CGI-S.³
  • CGI-S was used to estimate a clinically meaningful change in MADRS because it offers a clinical global measure of disease severity and helps to establish the meaning of a unit change on the global severity measure relative to other scales such as the MADRS. CGI-S provides a rapid and intuitive assessment of both functioning and symptoms, readily measures overall depression severity, and better reflects real-world clinical practice.³

Clinically Meaningful Difference in MADRS Between Treatment Groups

• When groups are compared to each other, a 2-point difference between groups has been found to be clinically meaningful.^4,5 When comparing groups of depressed patients whose MADRS scores differed by approximately 2 points across three clinical trials, a study by Duru et al (2008) reported significantly greater rates of remission than seen in a matched sample (71.6% vs. 57.1%).⁶
• Similarly, Thase et al (2011) demonstrated that what may appear to be a modest group difference can mask large, important differences for those that respond to treatment. Specifically, a modest mean difference of 2-4 points on the MADRS between groups favoring the treatment arm is explained by a large and clinically relevant effect (14- to 18-point change from baseline on the MADRS) among the subgroup of depressed patients who benefited from treatment.¹⁰

MADRS RESULTS in the SPRAVATO CLINICAL TRIALS

Short-Term Trials in TRD

In two Phase 3 double-blind, active-controlled trials assessing the efficacy and safety of SPRAVATO in patients with treatment-resistant depression (TRD), the primary efficacy endpoint was change in mean MADRS total score from baseline to day 28.^11,12

The SPRAVATO TRD trials had an active-control group and purposefully recruited MDD patients with a history of non-response to oral antidepressants (ADs); note this is in contrast to many major depressive disorder (MDD) studies that may enrich study populations by excluding patients with a history of oral AD non-response. When considering the mean difference observed between treatments groups in these trials, the SPRAVATO + oral AD group saw beneficial effects relative to those patients taking an oral AD + a placebo nasal spray, rather than compared solely to placebo.

• In TRANSFORM-2, the change in mean MADRS total score from baseline to day 28 was significantly greater with SPRAVATO + AD vs AD + placebo.¹¹
  • Least squares (LS) mean change from baseline at day 28
    • SPRAVATO (56 or 84 mg) + AD: -19.8; AD + placebo: -15.8
  • Least squares mean difference (LSMD) between treatment arms: -4.0 (95% CI: -7.31, -0.64); P=0.020
  • Remission rates at day 28:
    • SPRAVATO + AD: 52.5%; AD + placebo: 31%
    • Remission was defined as MADRS score ≤12
• In TRANSFORM -1, change in mean MADRS total score from baseline to day 28 was not statistically significant; however, both SPRAVATO + AD arms showed a clinically meaningful and numerically greater change vs AD + placebo.¹²
  • Mean change from baseline at day 28:
    • SPRAVATO 84 mg + AD: -18.8; SPRAVATO 56 mg + AD: -19.0
    • AD + placebo: -14.8
  • LSMD from placebo: SPRAVATO 84 mg + AD: -3.2; SPRAVATO 56 mg + AD: -4.1
  • Remission rates at day 28
    • SPRAVATO 56 mg + AD: 36.0%; SPRAVATO 84 mg + AD: 38.8%
    • AD + placebo: 30.6%

ASPIRE-I and ASPIRE-II Pooled Analysis

Two double-blind, randomized, placebo (PBO)-controlled studies evaluated the efficacy and safety of SPRAVATO in addition to comprehensive standard of care (SOC) for the rapid reduction of depressive symptoms in those who had moderate to severe MDD and active suicidal ideation with intent. Additional treatment effect was observed with SPRAVATO + SOC vs placebo + SOC, which was noteworthy given the substantial benefit of SOC which consisted of initial inpatient psychiatric hospitalization and newly initiated or optimized oral AD.¹³

• LS mean change in MADRS total score from baseline to 24 hours post first dose (Day 2) (primary efficacy endpoint)
  • SPRAVATO 84 mg + SOC: -16.0; PBO + SOC: -12.1
• LSMD in MADRS total score from baseline to 24 hours post first dose (Day 2)
  • -3.8 (95% CI: -5.75, -1.89)
• More patients achieved remission in the SPRAVATO + SOC group vs PBO + SOC at all time points during the double-blind phase; at Day 25 (4 hours post dose), remission rates were 50% and 37%, respectively.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 21 October 2024.