Zelquistinel in the Treatment of Adults With Major Depressive Disorder

Inclusion Criteria: * Written informed consent from the participant has been obtained prior to any study-related procedures * Meet DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria (American Psychiatric Association, 2013). for MDD (based on confirmation from the modified SCID), with a current major depressive episode of at least 8 weeks and not exceeding 18 months in duration at Visit 1. * Have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening (Visit 1) if a WOCBP (Women of Childbearing Potential). * 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 (Women of Childbearing Potential). OR * A WOCBP (Women of Childbearing Potential). who agrees to follow the contraceptive guidance in during the treatment period and for at least 4 to 5 weeks 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 during the treatment period and for at least 10 weeks 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. Exclusion Criteria: Psychiatric and Treatment-Related Criteria * DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) 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 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition)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 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria for alcohol or substance use disorder (other than nicotine or caffeine) within the 6 months before Screening (Visit 1). * History (based on participant report and/or medical records, and investigator judgment) of the following: * Inadequate response to ECT, a monoamine oxidase inhibitor, ketamine, or adjunctive treatment with an antipsychotic * Treatment with clozapine or any depot antipsychotic * ECT, vagus nerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system treatment during the current episode or in the 6 months before Screening (Visit 1) whichever is longer) * Tardive dyskinesia, serotonin syndrome, or neuroleptic malignant syndrome * Having received: * Anticonvulsant/mood stabilizer, within 1 year prior to Screening (Visit 1) * Antipsychotic in the current episode, with the exception of quetiapine given for insomnia ≤ 50 mg/day provided it can be safely discontinued prior to Visit 2 * Combination therapy of more than 2 ADTs in the current episode if given for depression at adequate dose and duration * ADT augmentation agent in the current episode * Lifetime history of nonresponse to ≥ 2 antidepressants after adequate trials (adequate treatment is defined as at least 6 weeks at an adequate dose(s) based on approved package insert recommendations). * Positive result at Screening (Visit 1) from the UDS (Urine Drug Screen) test for any prohibited medication. Exception: Participants with a positive UDS (Urine Drug Screen) at Screening for opiates, cannabinoids, or episodic use of benzodiazepines may be allowed in the study provided: * The drug was used for a legitimate medical purpose; * The drug can be safely discontinued prior to participation in the study (except for episodic use of benzodiazepines which may be continued); and * A repeat UDS is negative for these substances prior to enrollment (except for episodic use of benzodiazepines which may be continued) * Part B participants who have regularly been using benzodiazepines (even for legitimate medical purposes) for more than 2 months should not be included in the study if there is doubt that the medication can be safely discontinued during screening. * A suicide attempt within the past year * Prior participation in any investigational study of AGN-241751 * Initiation or termination of psychotherapy for depression within the 3 months preceding Screening (Visit 1), or plans to initiate, terminate, or change such therapy during the course of the study. (Support meetings or counseling \[eg, marital counseling\] are allowed provided they are no more frequent than weekly and do not have treatment of depression as their objective.) * Ongoing treatment with phototherapy, or termination of phototherapy within 1 month of Visit 1. * Known allergy or sensitivity to the study medication or its components. * Hypothyroidism or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no change in dosage for at least 1 month before Screening (Visit 1) * History of seizure disorder, stroke, significant head injury, tumor of the central nervous system, or any other condition that predisposes to seizure. * Known HIV infection * Part B: Previously diagnosed hearing loss; current hearing aid users (within the last 6 months), or history of gross hearing loss, such as conductive hearing loss, congenital hearing loss, sudden hearing loss, hearing loss due to recent noise or occupational exposure. * Current enrollment in an investigational drug or device study or participation in such a study within 6 months of entry into this study (or within 3 months of entry into this study (Part B). * Part B: Prior participation in any investigational study of AGN-241751, rapastinel, ketamine, or esketamine. Part B participants should not have participated in Part A at any time, and Part A participants should not have participated in Part B at any time (ie, Part A is not a contingent step to participate in Part B). * Employee, or immediate relative of an employee, of the sponsor, any of its affiliates or partners, or the study center * Inability to speak, read, and understand the English language sufficiently to understand the nature of the study, to provide written informed consent, or to allow the completion of all study assessments.