AGN-241751 in the Treatment of 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 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:

1. Not a WOCBP (Women of Childbearing Potential).

OR

2. 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:

1. Schizophrenia spectrum or other psychotic disorder

2. Bipolar or related disorder

3. Major neurocognitive disorder

4. 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

5. Dissociative disorder

6. Posttraumatic stress disorder

7. 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:

1. Inadequate response to ECT, a monoamine oxidase inhibitor, ketamine, or
adjunctive treatment with an antipsychotic

2. Treatment with clozapine or any depot antipsychotic

3. 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)

4. Tardive dyskinesia, serotonin syndrome, or neuroleptic malignant syndrome

- Having received:

1. Anticonvulsant/mood stabilizer, within 1 year prior to Screening (Visit 1)

2. 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

3. Combination therapy of 2 or more ADTs in the current episode if given for
depression at adequate dose and duration

4. 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:

1. The drug was used for a legitimate medical purpose;

2. The drug can be discontinued prior to participation in the study (except for episodic
use of benzodiazepines which may be continued); and

3. A repeat UDS is negative for these substances prior to enrollment (except for episodic
use of benzodiazepines which may be continued)

- 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

- Current enrollment in an investigational drug or device study or participation in
such a study within 6 months of entry into this study

- 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.