The goal of this clinical trial is to learn if ACP-211 can help treat adults with major depressive disorder (MDD) who have not improved with antidepressant therapy (ADT), including those with treatment resistant depression (TRD).

The main questions the study aims to answer are:

• Does ACP-211 work better than a placebo (a look-alike capsule with no medicine) to reduce symptoms of depression?
• What adverse events do participants have when taking ACP-211?

Inclusion Criteria:

• Adults ≥18 and ≤65 years of age
• Provides written informed consent
• Clinical diagnosis of MDD
• History of inadequate response to at least two antidepressants, with at least one inadequate response documented during the current episode
• Currently treated with an approved antidepressant at a stable dose prior to Screening
• MADRS total score ≥28, CGI-S score ≥4 , and QIDS-SR16 score ≥16 at Screening and Baseline
• Females of childbearing potential must have a negative pregnancy test and agree to use acceptable contraception; males must agree to use barrier protection and refrain from sperm donation

Exclusion Criteria:

• Current diagnosis of certain personality disorders or persistent depressive disorder
• Recent substance use disorders, excluding caffeine or nicotine
• Active suicidal risk or recent suicidal attempt
• History of schizophrenia, psychotic disorders, bipolar disorder, or MDD with psychotic features
• Current treatment requirement for PTSD, acute stress disorder, panic disorder, or OCD
• History of neuroleptic malignant syndrome, serotonin syndrome, or epilepsy (except single febrile seizure in infancy)
• Documented non-response to ADT, including ketamine or esketamine
• Allergy or sensitivity to ketamine or esketamine
• Significant cardiovascular disease
• Positive history of hepatitis B, hepatitis C, or HIV infection
• Unstable diabetes or uncontrolled medical conditions
• Positive urine drug test for an illicit drug or cannabis
• Received neuromodulation therapies (ECT,TMS, VNS, DBS) in the current depressive episode
• Recent initiation or change in psychotherapy Additional inclusion/exclusion criteria apply. Participants will be evaluated at Screening to ensure that all criteria for study participation are met.