We are conducting an eight week longitudinal study to learn if blood levels of certain naturally occurring compounds and genetic markers differ between patients with depression and healthy adults who are not depressed, and if any such differences relate to memory performance, mood, and neurobiology. We are also interested in how the gut microbiome is affected by antidepressant treatment.

We will do this by comparing the unmedicated depressed patients with matched healthy controls at baseline and then following the depressed patients over the course of eight weeks of standardized antidepressant treatment to gauge which baseline abnormalities normalize over the course of treatment.

Following an initial telephone screen to assess inclusion and exclusion criteria, the evaluation will continue with an in-person screening evaluation to assess the presence or absence of active medical history and history of major psychiatric illness, as well as review of the consent document. If found to be eligible, participants would then be admitted to the study.

The next step for eligible, consenting depressed subjects and is a baseline visit. The baseline visit will last up to 3.5 hours. We will begin the baseline visit by collecting a urine sample for a drug (and, for women, pregnancy) test. As long as that is negative, we will then collect a blood sample of about 180 cc. After the blood draw, participants will complete cognitive tests and meet again with the study psychiatrist. Eligible consenting healthy controls will come in for a one time study visit and complete the same tests performed during the depressed subject baseline visit. Both depressed participants and healthy controls will return a stool sample collected at home with a kit given during the screening visit.

After the baseline visit, depressed subjects (but not healthy controls) will begin taking an FDA approved antidepressant, as prescribed by the study psychiatrist, for the next 8 weeks while they are enrolled in the study. The specific drug will be decided upon between the participant and the study psychiatrist at the in-person screening visit.

After 4 weeks, depressed participants will return to UCSF to meet again with the psychiatrist to discuss symptoms and how to continue treatment. They will be given an at home collection kit to return a stool sample at the last study visit.

4 weeks later (after 8 weeks in total), depressed participants will come back for an additional visit that will include the same blood draw and testing as the baseline visit. They also will return their stool sample. A physician-investigator will meet with the depressed subjects to review their clinical responses to treatment and to make further treatment suggestions, which the subjects may use in discussions of their future treatment options with their personal physicians. If a decision is made to discontinue antidepressant treatment, the subjects will be given instructions on how to withdraw from the medication, and will be given up to a 4 week supply of the drug to facilitate this withdrawal.

All participants must meet the following criteria:

• Age 21-60 and able to give informed consent.
• Not "needle phobic," by self-report.
• English-speaking (to allow accurate use of behavioral rating scales and verbal cognitive tests).
• Females of child-bearing capacity must be non-pregnant (confirmed by urine pregnancy test) and using effective non-hormonal birth control (e.g. abstinence, condoms, IUD).
• Good general medical health; no significant uncontrolled illnesses that will invalidate the designated outcome measures.
• Clinical labs (electrolytes, liver function test, CBC) with no clinically significant abnormalities that result in medical treatment that will invalidate the designated outcome measures.
• Negative urine toxicology (drugs of abuse) screen.
• Taking no medication or drugs likely to interfere with the study objectives (including statins or medications that affect hormones [e.g. birth control pills or steroids]).
• Free of all psychotropic medications (including antidepressants) for at least 6 weeks (with the exception of prn short-acting benzodiazepines or sedative-hypnotics, < 3 doses per week, and none for 5 drug half-lives before the study).
• No vaccines for at least 4 weeks prior to baseline blood draw (including the flu shot).
• Not currently anemic (Hct of 36-48 for females and 38-54 for males, or Hgb of 12.5-20) and has not donated blood for at least 8 weeks prior to baseline blood draw.
• No neurological disorders and no history of concussion with a black-out that lasted > 10 minutes.
• Willing to provide stool sample

Additional criteria for Depressed Participants:

• Current DSM-5 diagnosis of Major Depressive Disorder, unipolar, with non-psychotic features.
• Baseline 17-item Hamilton Depression Rating Scale (HDRS) rating of >= 17, or Baseline 25-item HDRS rating of >= 20.
• Current depressive episode duration of > 6 weeks.
• No current, active suicidal intent; HDRS "suicidality" item rating <= 2 OR by clinician determination.
• No recent (< 6 month) history of substance or alcohol use disorder(s), with the exception of tobacco use (DSM-5 criteria).
• No current (in the last month) diagnosis of Post-Traumatic Stress Disorder (DSM-5 criteria).
• No anticipated changes in psychotherapeutic interventions during the course of the study.

Additional criteria for Normal Controls:

• No history of DSM-5 Axis I diagnoses