Trial Outcomes & Findings for A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy (NCT NCT05550532)

Last Updated: 2026-01-02

Results Overview

The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consists of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score is the sum of scores from individual question items, which ranges from 0 to 60; higher scores represent a more severe condition. Negative change in MADRS total score indicates improvement.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

444 participants

Primary outcome timeframe

Baseline (Day 1) to Day 43

Results posted on

2026-01-02

Participant Flow

Adult participants aged 18 to 64 years who had major depressive disorder (MDD) with or without moderate-to-severe anhedonia (ANH+ or ANH-) and elderly participants aged 65 to 74 years with MDD (ANH+ and ANH-) who had an inadequate response to an ongoing antidepressant therapy were randomized in the study.

Participant milestones

Participant milestones
Measure	Placebo During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg During DB treatment phase, participants received aticaprant 10 milligrams (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Overall Study STARTED	225	219
Overall Study Participants Who Entered Follow-up Phase	21	18
Overall Study COMPLETED	211	209
Overall Study NOT COMPLETED	14	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg During DB treatment phase, participants received aticaprant 10 milligrams (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Overall Study Withdrawal by Subject	8	3
Overall Study Adverse Event	2	3
Overall Study Lost to Follow-up	4	0
Overall Study Other	0	4

Baseline Characteristics

A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With MDD With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=223 Participants During DB treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=217 Participants During DB treatment phase, participants received aticaprant 10 mg tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Total n=440 Participants Total of all reporting groups
Age, Continuous	49.3 Years STANDARD_DEVIATION 13.11 • n=228 Participants	49.1 Years STANDARD_DEVIATION 13.14 • n=115 Participants	49.2 Years STANDARD_DEVIATION 13.11 • n=343 Participants
Age, Customized Adults (18-64 years)	200 Participants n=228 Participants	192 Participants n=115 Participants	392 Participants n=343 Participants
Age, Customized From 65 to 74 years	23 Participants n=228 Participants	25 Participants n=115 Participants	48 Participants n=343 Participants
Sex: Female, Male Female	168 Participants n=228 Participants	161 Participants n=115 Participants	329 Participants n=343 Participants
Sex: Female, Male Male	55 Participants n=228 Participants	56 Participants n=115 Participants	111 Participants n=343 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	74 Participants n=228 Participants	74 Participants n=115 Participants	148 Participants n=343 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	141 Participants n=228 Participants	137 Participants n=115 Participants	278 Participants n=343 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants n=228 Participants	6 Participants n=115 Participants	14 Participants n=343 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=228 Participants	1 Participants n=115 Participants	1 Participants n=343 Participants
Race (NIH/OMB) Asian	15 Participants n=228 Participants	16 Participants n=115 Participants	31 Participants n=343 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	2 Participants n=228 Participants	1 Participants n=115 Participants	3 Participants n=343 Participants
Race (NIH/OMB) Black or African American	9 Participants n=228 Participants	9 Participants n=115 Participants	18 Participants n=343 Participants
Race (NIH/OMB) White	182 Participants n=228 Participants	177 Participants n=115 Participants	359 Participants n=343 Participants
Race (NIH/OMB) More than one race	2 Participants n=228 Participants	2 Participants n=115 Participants	4 Participants n=343 Participants
Race (NIH/OMB) Unknown or Not Reported	13 Participants n=228 Participants	11 Participants n=115 Participants	24 Participants n=343 Participants
Region of Enrollment Argentina	35 Participants n=228 Participants	37 Participants n=115 Participants	72 Participants n=343 Participants
Region of Enrollment Brazil	8 Participants n=228 Participants	4 Participants n=115 Participants	12 Participants n=343 Participants
Region of Enrollment Bulgaria	9 Participants n=228 Participants	9 Participants n=115 Participants	18 Participants n=343 Participants
Region of Enrollment Czech Republic	11 Participants n=228 Participants	7 Participants n=115 Participants	18 Participants n=343 Participants
Region of Enrollment France	10 Participants n=228 Participants	10 Participants n=115 Participants	20 Participants n=343 Participants
Region of Enrollment Poland	13 Participants n=228 Participants	14 Participants n=115 Participants	27 Participants n=343 Participants
Region of Enrollment Slovakia	19 Participants n=228 Participants	17 Participants n=115 Participants	36 Participants n=343 Participants
Region of Enrollment South Africa	12 Participants n=228 Participants	14 Participants n=115 Participants	26 Participants n=343 Participants
Region of Enrollment Korea, Republic of	9 Participants n=228 Participants	10 Participants n=115 Participants	19 Participants n=343 Participants
Region of Enrollment Taiwan	3 Participants n=228 Participants	2 Participants n=115 Participants	5 Participants n=343 Participants
Region of Enrollment United Kingdom	4 Participants n=228 Participants	5 Participants n=115 Participants	9 Participants n=343 Participants
Region of Enrollment United States	90 Participants n=228 Participants	88 Participants n=115 Participants	178 Participants n=343 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1) to Day 43

Population: Full analysis set (ANH+) included all adult randomized participants in rest of the world (ROW; countries/territories other than China) with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo n=159 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=154 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Change From Baseline to Day 43 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score	-9.4 Units on a scale Standard Error 0.96	-10.0 Units on a scale Standard Error 0.96

SECONDARY outcome

Timeframe: Baseline (Day 1) to Day 43

Population: Full analysis set (ANH+) included all adult randomized participants in ROW (countries/territories other than China) with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure.

The DARS is a 17-item self-report questionnaire that is designed to assess anhedonia in MDD across the 4 domains: hobbies, social activities, food/drink, and sensory experience. The DARS scale measures desire, motivation, effort, and consummatory pleasure. The DARS is rated on a 5-point Likert scale (0=not at all, 1=slightly, 2=moderately, 3=mostly, 4=very much) and responses are summed to generate the total score (range of 0 to 68). A lower total score is indicative of greater anhedonia. Positive changes in DARS total score indicate improvement.

Outcome measures

Outcome measures
Measure	Placebo n=150 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=147 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Change From Baseline to Day 43 in Dimensional Anhedonia Rating Scale (DARS) Total Score	8.2 Units on a scale Standard Error 1.39	8.8 Units on a scale Standard Error 1.39

SECONDARY outcome

Timeframe: Baseline (Day 1), Day 15, Day 29, and Day 43

Population: Full analysis set (ANH+) included all adult randomized participants in ROW (countries/territories other than China) with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants analyzed at specified timepoints.

Change from baseline over time in MADRS total score is reported. The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consists of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score is the sum of scores from individual question items, which ranges from 0 to 60; higher scores represent a more severe condition. Negative change in MADRS total score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo n=161 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=160 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Change From Baseline Over Time in MADRS Total Score Day 15	-4.4 Units on a scale Standard Error 0.75	-5.4 Units on a scale Standard Error 0.74
Change From Baseline Over Time in MADRS Total Score Day 29	-7.5 Units on a scale Standard Error 0.89	-8.0 Units on a scale Standard Error 0.89
Change From Baseline Over Time in MADRS Total Score Day 43	-9.4 Units on a scale Standard Error 0.96	-10.0 Units on a scale Standard Error 0.96

SECONDARY outcome

Timeframe: At Day 43

Population: Full analysis set (ANH+) included all adult randomized participants in ROW (countries/territories other than China) with MDD ANH+ who received at least 1 dose of study intervention.

Percentage of participants who achieved response on depressive symptoms scale based on MADRS total score at Day 43 are reported. Responders are defined as participants with a \>=50 percent (%) improvement in the MADRS total score from baseline to a given timepoint. The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consists of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score is the sum of scores from individual question items, which ranges from 0 to 60; higher scores represent a more severe condition. Negative change in MADRS total score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo n=166 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=165 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Percentage of Participants Who Achieved Response on Depressive Symptoms Scale Based on MADRS Total Score at Day 43	28.3 Percentage of participants	27.9 Percentage of participants

SECONDARY outcome

Timeframe: At Day 43

Population: Full analysis set (ANH+) included all adult randomized participants in ROW (countries/territories other than China) with MDD ANH+ who received at least 1 dose of study intervention.

Percentage of participants with remission of depressive symptoms based on MADRS total score at Day 43 is reported. Participant is defined as a remitter at a given time point if the MADRS total score is less than or equal to (\<=)10 at that time point. The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consists of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score is the sum of scores from individual question items, which ranges from 0 to 60; higher scores represent a more severe condition. Negative change in MADRS total score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo n=166 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=165 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Percentage of Participants With Remission of Depressive Symptoms Based on MADRS Total Score at Day 43	16.3 Percentage of participants	15.8 Percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1) to Day 43

Change from baseline to Day 43 in PHQ-9 total score is reported. The PHQ-9 is a 9-item, participant reported outcome measure to assess depressive symptoms. The scale scores each of the 9 symptom domains of the Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) MDD criteria. Each item is rated on a 4 point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19) and severe (20-27). Negative changes in PHQ-9 total score indicate improvement.

Outcome measures

Outcome measures
Measure	Placebo n=150 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=150 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Change From Baseline to Day 43 in Patient Health Questionnaire, 9-Item (PHQ-9) Total Score	-5.5 Units on a scale Standard Error 0.58	-5.2 Units on a scale Standard Error 0.58

SECONDARY outcome

Timeframe: Baseline (Day 1), Days 15, 29, and 43

Population: Full analysis set (ANH+) included all adult randomized participants in ROW (countries/territories other than China) with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants who were analyzed at specified timepoints.

Change from baseline over time in DARS total score is reported. The DARS is a 17-item self-report questionnaire that is designed to assess anhedonia in MDD across the 4 domains: hobbies, social activities, food/drink, and sensory experience. The DARS scale measures desire, motivation, effort, and consummatory pleasure. The DARS is rated on a 5-point Likert scale (0=not at all, 1=slightly, 2=moderately, 3=mostly, 4=very much) and responses are summed to generate the total score (range of 0 to 68). A lower total score is indicative of greater anhedonia. Positive changes in DARS total score indicate improvement.

Outcome measures

Outcome measures
Measure	Placebo n=152 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=149 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Change From Baseline Over Time in DARS Total Score Day 29	6.9 Units on a scale Standard Error 1.27	7.1 Units on a scale Standard Error 1.27
Change From Baseline Over Time in DARS Total Score Day 43	8.2 Units on a scale Standard Error 1.39	8.8 Units on a scale Standard Error 1.39
Change From Baseline Over Time in DARS Total Score Day 15	3.5 Units on a scale Standard Error 1.17	4.2 Units on a scale Standard Error 1.17

SECONDARY outcome

Timeframe: Baseline (Day 1), Day 15, Day 29, and Day 43

Population: Full analysis set (ANH+) included all adult randomized participants in ROW (countries/territories other than China) with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants who were analyzed at specified timepoints.

Change from baseline over time in the PHQ-9 anhedonia-specific item (PHQ-9, item 1 is little interest or pleasure in doing things) is reported. The PHQ-9 is a 9-item, participant reported outcome measure to assess depressive symptoms. The scale scores each of the 9 symptom domains of the Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) MDD criteria. Each item is rated on a 4 point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19) and severe (20-27). PHQ-9, item 1 score ranged from 0-3. Higher score indicates more severe disease. Negative change in PHQ-9, item 1 score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=152 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) Day 15	-0.4 Units on a scale Standard Deviation 0.93	-0.6 Units on a scale Standard Deviation 1.08
Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) Day 29	-0.7 Units on a scale Standard Deviation 1.00	-0.8 Units on a scale Standard Deviation 1.05
Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) Day 43	-0.9 Units on a scale Standard Deviation 1.12	-0.9 Units on a scale Standard Deviation 1.08

SECONDARY outcome

Timeframe: At Day 43

Percentage of participants with a score \<2 in the PHQ-9 anhedonia-specific item (PHQ-9, item 1 is little interest or pleasure in doing things) at Day 43 is reported. The PHQ-9 is a 9-item, participant reported outcome measure to assess depressive symptoms. The scale scores each of the 9 symptom domains of the Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) MDD criteria. Each item is rated on a 4 point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19) and severe (20-27).

Outcome measures

Outcome measures
Measure	Placebo n=132 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=136 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Percentage of Participants With a Score Less Than (<) 2 in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) at Day 43	50.8 Percentage of participants	46.3 Percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1), Days 15, 29, and 43

Population: Full analysis set (ANH+) included all adult randomized participants in ROW (countries/territories other than China) with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants analyzed at specified timepoints.

Change from baseline over time in the PROMIS-APS 8a is reported. This 8-item measure assesses participants' ability to participate in social roles and activities. The items measures the degree of involvement in social roles, activities, and responsibilities, including work, family, friends, and leisure. Each item is rated on a 5-point ordinal scale including 1=always, 2=usually, 3=sometimes, 4=rarely and 5=never, with higher scores indicating better social functioning. The total scores of PROMIS-APS 8a are scaled on a T-score metric with a mean of 50 and a standard deviation of 10. PROMIS-APS 8a total score ranges from 8 to 40 and T-score ranges from 25.9 to 65.4, a higher score indicates better social functioning. Positive change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo n=142 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=134 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Change From Baseline Over Time in Patient Reported Outcomes Measurement Information System Short Form - Ability to Participate in Social Roles and Activities - 8a (PROMIS-APS 8a) Day 15	1.4 T-score Standard Error 0.54	1.5 T-score Standard Error 0.55
Change From Baseline Over Time in Patient Reported Outcomes Measurement Information System Short Form - Ability to Participate in Social Roles and Activities - 8a (PROMIS-APS 8a) Day 29	3.2 T-score Standard Error 0.57	3.1 T-score Standard Error 0.59
Change From Baseline Over Time in Patient Reported Outcomes Measurement Information System Short Form - Ability to Participate in Social Roles and Activities - 8a (PROMIS-APS 8a) Day 43	3.9 T-score Standard Error 0.63	4.3 T-score Standard Error 0.64

SECONDARY outcome

Timeframe: From start of treatment (Day 1) up to Day 43

Population: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study intervention.

Percentage of participants with TEAEs during DB treatment phase are reported. An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAE is defined as any AE occurring at or after the initial administration of study intervention through the end of DB phase.

Outcome measures

Outcome measures
Measure	Placebo n=223 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=217 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
DB Treatment Phase: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)	38.1 Percentage of participants	44.2 Percentage of participants

SECONDARY outcome

Timeframe: From Day 44 up to Day 57

Population: Follow-up analysis set included all randomized participants in ROW (countries/territories other than China) who entered the follow-up phase after the double-blind treatment phase.

Percentage of participants with AEs during FU phase are reported. An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention.

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants During double blind (DB) treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor \[SSRI/SNRI\]). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).	Aticaprant 10 mg n=18 Participants During DB treatment phase, participants received aticaprant 10 milligram (mg) tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149).
Follow-up (FU) Phase: Percentage of Participants With AEs	0 Percentage of participants	5.6 Percentage of participants

Adverse Events

DB: Placebo

Serious events: 1 serious events

Other events: 18 other events

Deaths: 0 deaths

DB: Aticaprant 10 mg

Serious events: 0 serious events

Other events: 39 other events

Deaths: 0 deaths

FU: Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

FU: Aticaprant 10 mg

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	DB: Placebo n=223 participants at risk During DB treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI).	DB: Aticaprant 10 mg n=217 participants at risk During the DB treatment phase, participants received aticaprant 10 mg tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI).	FU: Placebo n=21 participants at risk Participants who received placebo and completed DB phase entered follow-up phase and were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57).	FU: Aticaprant 10 mg n=18 participants at risk Participants who received aticaprant 10 mg and completed DB phase entered follow-up phase and were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57).
Psychiatric disorders Anxiety	0.45% 1/223 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	0.00% 0/217 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	0.00% 0/21 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	0.00% 0/18 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.

Other adverse events

Other adverse events
Measure	DB: Placebo n=223 participants at risk During DB treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI).	DB: Aticaprant 10 mg n=217 participants at risk During the DB treatment phase, participants received aticaprant 10 mg tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI).	FU: Placebo n=21 participants at risk Participants who received placebo and completed DB phase entered follow-up phase and were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57).	FU: Aticaprant 10 mg n=18 participants at risk Participants who received aticaprant 10 mg and completed DB phase entered follow-up phase and were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57).
Gastrointestinal disorders Diarrhoea	4.0% 9/223 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	7.8% 17/217 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	0.00% 0/21 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	0.00% 0/18 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.
Psychiatric disorders Suicidal Ideation	0.45% 1/223 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	0.46% 1/217 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	0.00% 0/21 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	5.6% 1/18 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.
Skin and subcutaneous tissue disorders Pruritus	4.0% 9/223 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	11.5% 25/217 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	0.00% 0/21 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.	0.00% 0/18 • All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From Day 1 up to Day 43; FU phase: From Day 44 up to Day 57 All cause mortality: All participants randomized into the study. Serious and Other AEs: DB phase: Safety analysis set included all randomized participants (adults and elderly) in ROW (countries/territories other than China) who received at least 1 dose of study treatment. FU phase population included all randomized participants in ROW (countries/territories other than China) who entered the FU phase after the double-blind treatment phase.

Additional Information

Executive Medical Director

Janssen Research and Development, LLC

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.
Publication restrictions are in place

Restriction type: OTHER