Zelquistinel in the Treatment of Major Depressive Disorder

Inclusion Criteria

• Written informed consent from the participant has been obtained prior to any study -related procedures (as described in Appendix 3).
• Male or female participants must be 18 to 65 years of age, inclusive, at the time of signing the informed consent.
• Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for MDD (based on confirmation from the modified Structured Clinical Interview for DSM disorders [SCID]), with a current major depressive episode of at least 8 weeks and not exceeding 18 months in duration at Visit 1.
• Have a minimum score of 26 on the rater-administered Montgomery-Asberg depression rating scale (MADRS) and a minimum score of 24 on the computer-administered MADRS at both Visit 1 (Screening) and Visit 2 (Baseline).
• Have a difference of no greater than 7 points between the rater-administered MADRS and computer-administered MADRS at both Visit 1 (Screening) and Visit 2 (Baseline).
• Have a clinical global impression-severity (CGI-S) score ≥ 4 at both Visit 1 (Screening) and Visit 2 (Baseline).
• Have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test if a woman of childbearing potential (WOCBP).
• Female participants willing to minimize the risk of becoming pregnancy for the duration of the clinical study and follow-up period. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• not a WOCBP OR
• A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 of protocol during the treatment period and for at least 5 terminal half-lives after the last dose of study treatment.
• Male participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period. A male participant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 5 terminal half-lives after the last dose of study treatment and refrain from donating sperm during this period.
• Able, as assessed by the investigator, and willing to follow study instructions and likely to complete all required study visits.
• Normal physical-examination findings, clinical-laboratory test results, and electrocardiogram (ECG) results from Visit 1 (Screening) or abnormal results that are determined to be not clinically significant by the investigator.
• Body mass index (BMI) within the range 18 and 40 kg/m^2 (inclusive).
• Eligibility confirmed through a formal adjudication process (see Section 9 Diagnostic Assessments).

Exclusion Criteria

Psychiatric and Treatment-Related Criteria

• DSM-5-based diagnosis of any disorder other than MDD that was the primary focus of treatment within 6 months before Visit 1. Comorbid generalized anxiety disorder, social anxiety disorder, or specific phobias are acceptable provided they play a secondary role in the balance of symptoms and are not the primary driver of treatment decisions.
• Lifetime history of meeting DSM-5 criteria for:
• Schizophrenia spectrum or other psychotic disorder
• Bipolar or related disorder
• Major neurocognitive disorder
• Neurodevelopmental disorder of greater than mild severity or of a severity that impacts the participant's ability to consent, follow study directions, or otherwise safely participate in the study
• Dissociative disorder
• Posttraumatic stress disorder
• MDD with psychotic features
• History of meeting DSM-5 criteria for alcohol or substance use disorder (other than nicotine or caffeine) within the 6 months before Visit 1.
• DSM-5-based diagnosis of any personality disorder of sufficient severity to interfere with participation in this study in the opinion of the investigator.
• History (based on participant report and/or medical records, and investigator judgment) of:
• Inadequate response to electroconvulsive therapy (ECT), a monoamine oxidase inhibitor, ketamine, or adjunctive treatment with an an