Dupilumab in Major Depressive Disorder

1. Written informed consent (and assent when applicable) obtained from subject;
2. Ability for the 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 Major Depressive Disorder [MDD]) in a current 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. If patient is taking antidepressant medication, they must be on a stable dose for at least 4 weeks prior to baseline (6 weeks for fluoxetine);
6. Quick Inventory of Depressive Symptoms - Clinician Administered (QIDS-C) score ≥ 14;
7. If female of childbearing potential, must agree to use of a medically accepted form of contraception (including barrier contraception such as condoms, oral contraceptive pills, or intrauterine devices) starting at least one cycle prior to study drug initiation, or else agree to abstinence until 6 months after the last dose of study drug.
8. Male patients, if heterosexually active with a partner who is female of childbearing potential, pregnant, or breastfeeding, must 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 must use at least one form of medically accepted contraception starting at least one cycle prior to male patient study drug initiation until 6 months after the last dose of study drug.

Exclusion Criteria for MDD Participants:

1. A primary psychiatric diagnosis other than MDD as defined by DSM-5; [comorbid anxiety disorders (including agoraphobia, generalized anxiety disorder, social anxiety disorder and panic disorder) and posttraumatic stress disorder (PTSD) are allowed];
2. Has a history of schizophrenia or other psychotic disorder, major depressive disorder with psychotic features, or bipolar I or II disorder;
3. Diagnosis of a major neurocognitive disorder;
4. Meets criteria for a moderate or severe substance use disorder within the past 6 months, with the exception of nicotine use disorder;
5. Any contraindication to MRI including claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, or inability to lie still for 1 hour or more;
6. Positive urine toxicology screen for illicit drugs (other than cannabis) at the time of screening;
7. Serious and imminent risk of self-harm or violence as determined by the PI;
8. History of suicide attempt in the past 2 years or screening CSSRS Ideation Score >2 in the past month;
9. Clinically significant abnormalities of laboratory tests or physical examination;
10. Unstable medical illnesses including hepatic, renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease); endocrinologic, neurologic (including history of severe head injury), immunologic/inflammatory, hematologic disease, or other medical conditions or abnormality (including relevant laboratory abnormalities at screening) that, in the opinion of the investigator, may suggest a new and/or insufficiently understood disease, may present an unreasonable risk to the study patient as a result of his/her participation in the study, may make patient's participation unreliable, may interfere with study assessments, or may compromise the safety of the patient or the quality of the data;
11. Concomitant treatments with other biologics or other immune-suppressant agents; PRN use of NSAIDs is permissible;
12. 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. Male participants or the female partners who are unwilling to adhere to the birth control requirements specified in Section 5.1 (points 8 and 9);
13. Presence of a known hypersensitivity to dupilumab or any excipients in dupilumab, or planned upcoming receipt of a live vaccination, or receipt of a live attenuated vaccination within 30 days prior to the receipt of the first dupilumab injection;
14. Presence of an active tuberculosis infection, untreated latent TB, or a positive result on TB test (Quantiferon Gold) at screening, as well as known history of human immunodeficiency virus (HIV) infection, Hepatitis B, and/or Hepatitis C.
15. History of malignancy within 5 years of baseline assessment (excluding non-melanoma skin cancers).

Inclusion Criteria for healthy control participants:

1. Written informed consent obtained from subject;
2. Ability for the subject to comply with the requirements of the study as determined by the PI;
3. Ages 18-65, any gender;
4. No current or past DSM-5 psychiatric disorder as determined by SCID-5-RV or MINI;
5. Meet all MRI safety criteria.

Exclusion Criteria for healthy control participants:

1. Any unstable medical illnesses including hepatic, renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease;
2. Concomitant treatments with other biologics or other immune-suppressant agents (PRN use of NSAIDs is permissible);
3. Female participants who are pregnant at the time of baseline assessments (e.g., MRI);
4. Positive urine toxicology screen for illicit drugs at the time of screening.