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

Inclusion Criteria:

• Be medically stable on the basis of physical examination, medical history, vitalsigns, and 12-lead electrocardiogram (ECG) performed at screening and baseline

• Have a Hamilton Depression Rating Scale 17 item (HDRS-17) total score of 20 orhigher at the first and second screening interviews and must not demonstrate aclinically significant improvement between the first and the second independentHDRS-17 assessments

• Meet Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5)diagnostic criteria for recurrent or single episode major depressive disorder (MDD),without psychotic features, based upon clinical assessment and confirmed by thestructured clinical interview for DSM-5 Axis I disorders-clinical trials version (SCID-CT). Participants 65 years of age or older must have had the first onset ofdepression prior to 55 years of age

• Have had an inadequate response to at least 1 oral antidepressant treatment,administered at an adequate dose (at or above the minimum therapeutic dose perMassachusetts General Hospital Antidepressant Treatment Response Questionnaire [MGHATRQ]) and duration (at least 6 weeks) in the current episode of depression. Aninadequate response is defined as less than(<) 50% reduction in depressive symptomseverity but with some improvement (>0%) (ie, there may be minimal to moderatesymptomatic improvement since the initiation of treatment, but some of the initialsymptoms are still present, troubling to the participant and affecting behavior andfunction), as assessed by the MGH ATRQ

• Is currently receiving and tolerating well any one of the following selectiveserotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for depressive symptoms at screening, in any approved formulation andavailable in the participating country/territory: citalopram, duloxetine,escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine,sertraline, venlafaxine, desvenlafaxine at a stable dose for at least 6 weeks. Thecurrent antidepressant cannot be the first antidepressant treatment for the firstlifetime episode of depression

• Participant's current major depressive episode, and antidepressant treatmentresponse in the current depressive episode, must all be confirmed by the siteindependent qualification assessment

Exclusion Criteria:

• Have had in the current depressive episode, no response (treatment failure) to 5 ormore antidepressant treatments including the current SSRI/SNRI (that is, the onepresumed to be continued in the treatment phase) assessed using the MassachusettsGeneral Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ)

• Has a history or evidence of clinically meaningful noncompliance with currentantidepressant therapy

• Has a history of moderate-to-severe substance use disorder including alcohol usedisorder according to DSM-5 criteria within 6 months before screening

• Has had in the current episode an inadequate response to adequate course ofintravenous or intranasal ketamine or esketamine, electroconvulsive therapy, vagalnerve stimulation, or deep brain stimulation device

• Has current, or a history (past 6 months), of seizures

• Has a current homicidal ideation/intent, per the investigator's clinical judgment,or has suicidal ideation with some intent to act within 3 months prior to the startof the Screening Phase, per the investigator's clinical judgment or based on theColumbia Suicide Severity Rating Scale (C-SSRS), corresponding to a response of "Yes" on Item 4 or Item 5, or a history of suicidal behavior within the past 6months prior to the start of the Screening Phase. Participants reporting suicidalideation with intent to act or suicidal behavior at baseline should be excluded

• Has one or more of the following diagnoses: a) A DSM-5 diagnosis (which has been theprimary focus of psychiatric treatment within the past 2 years) of any of thefollowing: panic disorder, generalized anxiety disorder, social anxiety disorder,specific phobia; b) A current (in the past year) DSM-5 diagnosis of:obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), anorexianervosa, bulimia nervosa; c) A current or prior (lifetime) DSM-5 diagnosis of: apsychotic disorder or MDD with psychotic features, bipolar or related disorders,intellectual disability, autism spectrum disorder, borderline personality disorder,antisocial personality disorder, histrionic personality disorder, narcissisticpersonality disorders, somatoform disorders