SUMMARY

• SPRAVATO is not specifically indicated, nor was it studied, for the treatment of anhedonia. Anhedonia is a symptom of depression and was measured as part of the Montgomery‐Åsberg Depression Rating Scale (MADRS) and Patient Health Questionnaire-9 (PHQ-9). The primary trials for SPRAVATO assessed the total scores for these measures^1-4 
• In post hoc analyses of two phase 3 trials, SPRAVATO plus an oral antidepressant (OAD) was associated with improvements in anhedonia symptoms in both a short‑term, placebo‑controlled study (TRANSFORM‑2¹) and a long‑term, open‑label study (SUSTAIN‑2⁵).⁶ 
• In a secondary analysis of real‑world REAL‑ESK study, SPRAVATO+OAD was associated with significant improvements in anhedonia among patients with treatment-resistant depression (TRD) and bipolar TRD (B-TRD), with similar effectiveness and safety profiles between groups.^7,8 
• A post hoc analysis of a randomized, placebo-controlled trial assessed the MADRS anhedonia factor score in adult patients with TRD treated with SPRAVATO monotherapy compared to placebo for 28 days. The least squares (LS) mean change from baseline in the MADRS anhedonia factor score was significantly greater in SPRAVATO 56 mg and 84 mg groups compared with placebo at day 28 (P<0.001) and as early as day 2 (P<0.01; 24 hours post treatment).⁹ 
• Post hoc analyses of short-term, phase 3 trials in TRD (TRANSFORM-2¹) and major depressive disorder with active suicidal ideation and behavior (ASPIRE-1² and ASPIRE-2³) assessed individual items of the MADRS and PHQ-9 and found greater improvement in symptoms, including those associated with anhedonia, in patients treated with SPRAVATO+OAD compared to placebo+OAD/standard-of-care (SOC). These post hoc analyses were not adjusted for multiplicity; therefore, any statistical significance was nominal.^10-12 
• A real-world study reported significant improvements in depression symptoms following 3 months of treatment with SPRAVATO in patients with TRD. Additionally, positive correlations were reported between clinician-rated and patient-rated assessments of core symptoms, including anhedonia.¹³

Clinical Data

Post Hoc Analyses of Studies in Treatment-Resistant Depression

Fu et al (2026)⁶ conducted post hoc analyses of TRANSFORM‑2¹, a phase 3, 4‑week, double‑blind study, and SUSTAIN‑2⁵, a phase 3, 52‑week, open‑label study, to evaluate the short and long‑term effects of SPRAVATO on anhedonia. In TRANSFORM‑2, participants were randomized in a 1:1 ratio to receive either flexibly dosed SPRAVATO (56 or 84 mg) or placebo both used in combination with a newly initiated OAD, administered twice weekly for a 4‑week induction phase. SUSTAIN‑2 was a single‑arm study that enrolled participants either directly or via transfer from a phase 3 trial in older adults (≥65 years) with TRD (TRANSFORM‑3¹⁴; NCT02422186). MADRS anhedonia factor scores (range, 0-30) were used to assess anhedonia symptoms. This score was derived from a subset of five items from the 10‑item MADRS (reported sadness, apparent sadness, concentration difficulties, lassitude, and inability to feel). These endpoints were not adjusted for multiple comparisons. Therefore, the p-values displayed are nominal, and statistical significance has not been established.

Results

• At baseline, participants had moderate to severe depressive symptoms with anhedonia in both trials.
• In the TRANSFORM‑2 study population, LS mean (standard error [SE]) changes from baseline in MADRS anhedonia factor scores for the SPRAVATO+OAD group were -4.8 (0.59) at day 2 and -12.0 (0.77) at day 28, compared with -2.6 (0.62) and -9.0 (0.78), respectively, for the placebo+OAD group (see Figure: Change from baseline in MADRS anhedonia factor A) score over time).
• LS mean (SE) changes in individual MADRS anhedonia items were reported at day 2 and day 28 (see Figure: B) Items at Day 2 and Day 28).
• Among patients in the SPRAVATO+OAD group (n=114), 17.4% (19/109) and 69.3% (70/101) of patients achieved a ≥50% reduction in MADRS anhedonia factor scores at Days 2 and 28, respectively. In the placebo+OAD group (n=109), the rates were 10.8% (11/102) and 52.0% (52/100), respectively (see Figure: C) Percentage (left) and odds ratio (right) of participants achieving ≥50% reduction in MADRS anhedonia factor score at Day 2 and Day 28).
  • Participants treated with SPRAVATO+OAD were more likely to experience a ≥50% reduction in MADRS anhedonia factor scores at day 2 (OR,1.75) and at day 28 (OR=2.08) compared to placebo+OAD.
• The least squares mean (SE) change from baseline to Day 28 in PHQ‑9 item 1 was -1.5 (0.11) in the SPRAVATO+OAD group and -1.2 (0.11) in the placebo+OAD group (see Figure: D) Change from baseline in PHQ-9 item 1 at Day 28).

• In the SUSTAIN-2 study population, the LS mean (SE) change in MADRS anhedonia factor score was -11.81 (0.15) from baseline to day 28 and -13.11 (0.37) from baseline to week 48 (see Figure: Change from induction phase baseline in MADRS anhedonia factor A) score over time)
• Individual changes in anhedonia items were reported from baseline to the end of the induction phase (day 28) and the end of the O/M phase (week 48) (see Figure: B) items at Day 28 and Week 48).
• At day 28, 85.1% (493/579) of participants achieved a ≥50% reduction in MADRS anhedonia factor scores and 89.9% (125/139) at week 48 (see Figure: C) Percentage of participants achieving ≥50% reduction in MADRS anhedonia factor score at Day 28 and Week 4).
• Improvements in PHQ‑9 item 1 from induction phase baseline were observed, with mean (SE) changes of -1.38 (0.04) at day 28 and -1.75 (0.08) at week 47 (see Figure: D) Change from induction phase baseline in PHQ-9 item 1 over time)

d’Andrea et al (2025)⁷ conducted a secondary analysis of the REAL-ESK study⁸  (a multicenter, observational, real-world investigation conducted across Italian clinical settings) to evaluate the effects of repeated SPRAVATO administration on anhedonia in 253 patients with TRD, including 54 with B-TRD and 199 with unipolar TRD. All patients received SPRAVATO (28 mg, 56 mg, or 84 mg) plus an OAD. Anhedonia was assessed using a validated 5-item subscale of MADRS (visible sadness, expressed sadness, problems with concentration, fatigue, and inability to experience pleasure) at baseline (T0), 1 month (T1), and 3 months (T2). Response was defined as ≥50% reduction in the MADRS anhedonia subscale score from baseline.

Results

• At baseline, 68.5% of patients with B-TRD and 67.3% of patients with TRD had clinically significant anhedonia (MADRS subscale score ≥18).
• In the B-TRD group, the mean MADRS anhedonia score significantly decreased from baseline (20.1) to T1 (14.9; P<0.0001; Cohen’s d=0.928) and from baseline to T2 (10.0; P<0.0001; d=1.810). Similarly, in the TRD group, the mean MADRS anhedonia score decreased from baseline (20.2) to T1 (14.5; P<0.0001; d=1.039) and from baseline to T2 (11.3; P<0.0001; d=1.612).
• The response rate was 17.3% at T1 and 51.9% at T2 in the B-TRD group and 22.3% at T1 and 38.0% at T2 in the TRD group.
• AEs were reported in 64.8% of patients with B-TRD and 72.4% of patients with TRD. The most common events in both groups included dissociation (B-TRD, 33.3%; TRD, 41.7%), sedation (B-TRD, 22.2%; TRD, 23.1%), and manic symptoms (B-TRD, 5.6%; TRD, 2.0%), dizziness/headache (B-TRD, 5.6%; TRD, 4.5%), increased blood pressure (B-TRD, 1.9%; TRD, 8.6%), and anxiety (B-TRD, 1.9%; TRD, 3.5%). The incidence of overall AEs and manic symptoms did not differ significantly between the B-TRD and TRD groups.

Chepke et al (2025)⁹ conducted a post hoc analysis evaluating changes in the MADRS anhedonia factor score following 4 weeks of SPRAVATO monotherapy in patients with TRD.¹³  Patients were randomly assigned 1:1:2 to receive SPRAVATO at doses of 56 mg (n=86), 84 mg (n=95), or placebo (n=197) twice weekly for 4 weeks in the double-blind treatment phase. Anhedonia was assessed using the 5-item MADRS anhedonia factor score.

Results

• The majority of patients were female (61.1%) and White (86.8%) with mean (SD) age of 45.4 (14.1) years. At baseline, patients had a mean (SD) 10-item MADRS total score of 37.3 (4.88) and a similar 5-item MADRS anhedonia factor score across the 3 treatment groups (means ranged from 2.56 to 2.86).
• The LS mean change from baseline in the MADRS anhedonia factor score was significantly greater in SPRAVATO 56 mg and SPRAVATO 84 mg groups compared with placebo at day 28 (P<0.001) and as early as day 2 (P<0.01; 24 hours post treatment; see Figure: LS mean change from baseline in (A) 5-item MADRS anhedonia factor score over time).
  • At day 28, the LS mean difference (95% CI) from placebo for SPRAVATO 56 mg and SPRAVATO 84 mg were −3.4 (−5.4 to −1.4) and −4.8 (−6.7 to −2.9), respectively. All individual MADRS items scores (reported sadness, apparent sadness, concentration difficulties, lassitude, inability to feel) were significantly improved compared with placebo (P<0.05; see Figure: LS mean change from baseline in (B) individual MADRS item scores at day 28).

• Compared with placebo, significantly more SPRAVATO-treated patients had clinically meaningful improvement (≥3-point reduction) in the MADRS anhedonia factor score at day 28 (P<0.001) and day 2 (P<0.01) and clinically substantial improvement (≥6-point reduction) at day 28 (P<0.01) and day 2 (P<0.01; see Figure: Proportion of patients with (A) ≥3-point or (B) ≥6-point improvement in 5-item MADRS anhedonia factor score).

• Significantly more SPRAVATO-treated patients achieved ≥50% improvement from baseline in the MADRS anhedonia factor score at day 28 (SPRAVATO 56 mg, 31.7%; SPRAVATO 84 mg, 33.7%, placebo, 16.2%; P<0.01), and as early as day 2 (P<0.05).
• The most commonly reported treatment-emergent adverse events were nausea (24.8%), dissociation (24.3%), dizziness (21.7%), and headache (19.0%). Most treatment-emergent adverse events occurred on dosing days, were mild or moderate in severity, and resolved on the same day.
• Note that while the 5-item MADRS anhedonia actor score has been previously used to measure changes in anhedonia symptoms after treatment, it was not specifically designed to measure anhedonia.

Borentain et al (2022)⁴ conducted a post hoc analysis of data from the TRANSFORM-1 and -2 studies,^1,15 which were short-term, phase 3 trials that evaluated the efficacy and safety of SPRAVATO+OAD vs placebo+OAD in adult patients with TRD. The study used exploratory (TRANSFORM-2) and confirmatory factor (TRANSFORM-1) analyses to identify statistically and clinically significant clusters of depressive symptoms in the MADRS items and to evaluate the impact of SPRAVATO+OAD vs placebo+OAD on the trajectories of the clusters identified. MADRS assessments were conducted at baseline and on days 2, 8, 15, 22, and 28. Analyses were not corrected for multiple comparisons.

Results

• The analysis included 223 patients from TRANSFORM-2 and 342 from TRANSFORM-1. The demographic and baseline characteristics were similar between treatment groups in each study and between the studies.
• The exploratory factor analysis for TRANSFORM-2 identified the following clusters (Factors) from the 10-item MADRS scale:
  • Factor 1 (affective and anhedonic symptoms) represented 22.4% of the scale variance and included “apparent sadness”, “reported sadness”, “lassitude”, and “inability to feel”.
  • Factor 2 (anxiety and vegetative symptoms) represented 18% of the scale variance and included “inner tension”, “reduced sleep”, “reduced appetite”, and “concentration difficulties”.
  • Factor 3 (hopelessness) included “pessimistic thoughts” and “suicidal thoughts”.
  • The inter-factor correlation between Factors 1 and 2 was 0.37; Factors 1 and 3, 0.24; and Factors 2 and 3, 0.07.
• Confirmatory factor analysis using TRANSFORM-1 suggested that the 3-factor structure identified above was an acceptable model fit.
• In TRANSFORM-2, improvements in MADRS scores were observed for all 3 factors at all timepoints in both treatment groups, with greater improvements in the SPRAVATO+OAD group compared to that of the placebo+OAD group.
  • Significant treatment effects were observed in the SPRAVATO+OAD group for:
    • Factor 1, on days 2, 22, and 28
    • Factor 2, at all timepoints (nominal P<0.05)
    • Factor 3, on day 2
  • At day 28, the effect sizes for the SPRAVATO+OAD group compared to the placebo+OAD group were 0.29 for Factor 1, 0.35 for Factor 2, and 0.25 for Factor 3.

Floden et al (2022)¹⁰ conducted a post hoc analysis of the TRANSFORM-2¹ study to compare the changes from baseline in total and individual item scores of the PHQ-9 and MADRS scales between the SPRAVATO+OAD group and the placebo+OAD group. Although the study did not measure anhedonia as a distinct subscale, it was reported on the individual items within the PHQ-9 and MADRS scales. PHQ-9 and MADRS assessments were conducted at baseline and on days 15 and 28. Analyses were not adjusted for multiple comparisons.

Results

• The analysis included 223 patients (SPRAVATO group, n=114; placebo group, n=109). The demographic and baseline characteristics were similar between treatment groups.
• In both treatment groups, the total PHQ-9 and MADRS scores improved from baseline to days 15 and 28, with the SPRAVATO group showing greater improvement than the placebo group at day 15 and day 28 for PHQ-9, and at day 28 for MADRS.
  • The change in total MADRS scores on day 28 in the SPRAVATO+OAD group was significantly larger than that of the placebo+OAD group (P=0.017).
• The proportion of patients who experienced ≥1-point improvement for each of the 9 items of the PHQ-9 scale was greater in the SPRAVATO group than in the placebo group. Improvements on items 1 (little interest/pleasure in things) and 4 (feeling tired or having little energy) were significantly higher in the SPRAVATO+OAD.  
• See Table: Proportion of Patients With ≥1-point Improvement in PHQ-9 Items.

• The proportion of patients who improved by ≥2 points was higher in the SPRAVATO+OAD group vs the placebo+OAD group for all 10 items of the MADRS scale on days 15 and 28. Improvement on item 8 (inability to feel) was significantly higher in the SPRAVATO+OAD group. See Table: Proportion of Patients With ≥2-point Improvement in MADRS Items.

Post Hoc Analysis of Studies in Major Depressive Disorder and Active Suicidal Ideation with Intent

Canuso et al (2021)¹¹ conducted a post hoc analysis of data pooled from the ASPIRE-1 and-2 studies,^2,3 which were phase 3, short-term studies that evaluated the efficacy and safety of 84 mg SPRAVATO+SOC vs placebo+SOC in adult patients with major depressive disorder with active suicidal ideation with intent. Although the study did not measure anhedonia as a separate subscale, individual items from the MADRS subscale related to anhedonia were reported. MADRS subscale items were reported at 4 hours, 24 hours, and day 25 (predose). No adjustments were made for multiplicity.

Results

• The analysis included 451 patients (SPRAVATO+SOC, n=226; Placebo+SOC, n=225).
• In an analysis of individual MADRS items during the double-blind phase, patients in the SPRAVATO+SOC group vs the placebo+SOC group showed a greater likelihood of achieving clinically meaningful improvement (defined as ≥2-point improvement) on all symptoms of depression, including lassitude and inability to feel.
• A complete list of improvements in individual MADRS item scores were reported at 4 hours, 24 hours, and day 25 following the first SPRAVATO+SOC dose (see Table: Improvements in Individual Montgomery‐Åsberg Depression Rating Scale Item Scores)

Real-world Study in Treatment-Resistant Depression

Pepe et al (2023)¹² reported the effect of 3 months of treatment with SPRAVATO in patients with TRD using both clinician-rated and patient-rated scales. The study evaluated anhedonia (using the subitem 8 of MADRS [inability to feel] and the total score of Snaith-Hamilton Pleasure Scale [SHAPS]), sleep alterations (using the subitem 4 of MADRS and subitem 16 of Beck Depression Inventory [BDI]), cognitive symptoms (using the subitem 6 of MADRS, Digit Symbol Substitution Test [DSST], and Perceived Deficits Questionnaire for Depression - 5 items [PDQ-D5]), suicidality (using the subitem 10 of MADRS and subitem 9 of BDI), and anxiety (using the total scores of the Hamilton Anxiety Rating Scale [HARS] and the Self-Rating Anxiety Scale [SAS]).

Results

• The study included 25 patients in Italy (female, 44%; mean age, 55.1 years).
• A significant, positive correlation was found between the clinician-rated and patient-rated measures:
  • MADRS-BDI total scores: Pearson’s r, 0.65; P<0.001
  • MADRS item 8-SHAPS total score: Pearson’s r, 0.47; P< 0.001
  • MADRS item 4-BDI item 16: Pearson’s r, 0.34; P=0.01)
  • MADRS item 6-PDQ-D5 total score: Pearson’s r, 0.59; P<0.001
  • MADRS item 10-BDI item 9: Pearson’s r, 0.57; P<0.001
  • HARS-SAS total scores: Pearson’s r, 0.86; P<0.001
• A significant reduction in MADRS item 8 [inability to feel] scores were found at months 1, 2, and 3 from baseline: mean (standard error [SE]) change at 1 month, -0.83 (0.28); P=0.005; mean (SE) change at 2 months, -1.09 (0.29); P<0.001; and mean (SE) change at 3 months, -1.42 (0.30), P<0.001.
• Patient-rated evaluation for anhedonia using SHAPS showed significant improvements at months 2 and 3 from baseline: mean (SE) change at 1 month, -1.04 (0.77); P=0.181; mean (SE) change at 2 months, -1.38 (0.68); P=0.04; and mean (SE) change at 3 months, -2.38 (0.82), P=0.006.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 21 January 2026.

This response excludes case reports, case series, and phase 2 clinical trials.^16-19