XEN1101 for Major Depressive Disorder

Inclusion Criteria 1. Written informed consent (and assent when applicable) obtained from subject 2. Ability for subject to comply with the requirements of the study as determined by the PI; 3. Men and women, age 18-65 years; 4. Participants must meet DSM-5 criteria for current depressive disorder (major depressive disorder \[MDD\]) in a major depressive episode (MDE) as determined by a study psychiatrist and confirmed using the Structured Clinical Interview for DSM-5 Research Version (SCID-5-RV); 5. Clinically significant anhedonia as determined by a SHAPS score ≥ 20 at screening; 6. Current illness severity is at least moderate, defined as a score of ≥4 on the CGI-S Scale; 7. If female of childbearing potential, must agree to use of a medically accepted form of contraception, or else agree to abstinence until 6 months after the last dose of study drug. Exclusion Criteria 1. A primary psychiatric diagnosis other than MDD as defined by DSM-5; 2. Has a history of schizophrenia or other psychotic disorder, major depressive disorder with psychotic features, or bipolar I or II disorder. 3. History of non-response to \>4 adequate antidepressant trials in the current episode as determined by the Antidepressant Treatment Response Questionnaire (ATRQ); 4. History of non-response to electroconvulsive therapy in the current depressive episode; 5. A current diagnosis of depression with peripartum onset; 6. Diagnosis of a major neurocognitive disorder; 7. Meets criteria for a substance use disorder within the past 6 months, with the exception of nicotine use disorder; 8. Patient shows signs of retinal macular disease, or retinal pigment epithelium abnormality prior to randomization. 9. Male patients, if heterosexually active with partner who is female of childbearing potential, pregnant, or breastfeeding, who are unwilling to agree to barrier contraception for the treatment period and for at least 6 months after the last dose of study drug. Female partners of male participants who are unwilling to use at least one form of highly effective contraception starting at least one cycle prior to male patient study drug initiation until 6 months after the last dose of study drug. 10. Female participants who are pregnant, breastfeeding, or may become pregnant, or unwilling to practice birth control during participation in the study or the 6 months following; 11. Inability to swallow capsules; 12. Any contraindication to MRI including claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, and inability to lie still for 1 hour or more; 13. Positive urine toxicology screen for drugs of abuse at the time of screening\*; 14. Use of any dis-allowed medication according to the study protocol\*\*; 15. Serious and imminent risk of self-harm or violence as determined by the PI; 16. Extreme illness severity as defined by a CGI-S score \>=6; 17. Any current active suicidal ideation as measured by a Columbia Suicide Severity Rating Scale \[C-SSRS\] score of greater than 2 during the past month at the time of screening 18. History of suicide attempt in past 2 years; 19. Any unstable medical condition, including as follows; 19.1. History of skin or retinal pigment epithelium abnormalities caused by ezogabine; 19.2. Family history of sudden death of unknown cause; 19.3. Clinically significant abnormalities of laboratory tests, physical examination, or ECG; 19.4. History or presence of long QT syndrome; 19.5. QT corrected by Fridericia's formula (QTcF) \> 450 msec; 19.6. Alanine transferase (ALT; SGPT) or aspartate transferase (AST; SGOT) levels \>3 times the upper limit of normal (ULN) at screening; 20. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.