terminated during COVID due to inability to see participants in person.

PRECISE-D is a single site, randomized, open label 8-week clinical trial that will enroll 70 participants to evaluate if the level of inflammation in our body can predict how we will respond to antidepressants. C-reactive protein (CRP) is a substance in the body that is associated with inflammation. Previous research has suggested that people with high CRP (i.e., high inflammation levels) tend to have greater improvement of depressive symptoms with an antidepressant called bupropion, while individuals with low CRP (i.e., low inflammation levels) appear to have more benefit from selective serotonin reuptake inhibitors antidepressants (SSRI), such as escitalopram. However, it is not completely clear if CRP can predict your response to these two antidepressants.

Participants will undergo a screening visit that includes a physical exam, overall health evaluation, assessment of mental health history, and a toxicology and pregnancy test. Once screening is complete, participants will be randomized to one of two groups that will determine whether their CRP levels will be used to select which antidepressant they will receive. Participants will then complete 4 follow up visits at weeks 2, 4, 6, and 8. A follow-up phone call from the study team will occur at week 12.

PRECISE-D is a single site, randomized, open label 8-week clinical trial that will enroll 70 participants. Participants will be asked to attend approximately 5 visits with the researchers or study staff.

The screening process will take approximately 2 hours, and will include a physical examination, toxicology and pregnancy test, as well as the completion of assessments. We will ask participants a series of questions regarding their general health, mental health history, and any medications they are currently taking. Additionally, some self-report questionnaires will be used as part of this process. The results of the screening exams, tests, and/or procedures will be reviewed to determine whether a participant will be allowed to continue in the study. In the event that there are questions about a participant's eligibility or screening procedures are remaining, the screening visit may be conducted over 2 visits.

Once eligibility is determined, the baseline visit (Week 0) will be completed. This visit will last approximately 1 hour and 15 minutes and will include the following:

• Bloodwork: We will obtain levels of CRP and other inflammatory substances. We will also examine electrolytes, kidney function, thyroid function, lipid panel, blood cell count, and other tests of general health.
• Self-Report Questionnaires: Participants will complete 8 questionnaires. These include questions about mental health and mood. The questionnaires range from 5 to 20+ items.
• Cognitive tests: We will examine the participant's attention, memory, and cognition using a series of computerized assessments.

Participants will be assigned to a study group based on their CRP level: CRP less than 1 (low CRP), or CRP greater than or equal to 1 (high CRP). Within this group assignment, participants will then be randomized, or assigned by chance (like flipping a coin), to one of 2 study groups:

• CRP consistent antidepressant selection (medication will be prescribed based on participant's CRP level).

If CRP less than 1, participant will be prescribed escitalopram. If CRP greater than or equal to 1, participant will be prescribed bupropion XL.

• CRP inconsistent antidepressant selection (medication will be prescribed in contradiction to participant's CRP level) If CRP less than 1, participant will be prescribed bupropion XL. If CRP greater than or equal to 1, participant will be prescribed escitalopram.

In each group participants will receive either escitalopram or bupropion XL.

• 1 tablet of 150 mg of bupropion-XL per day (initial dose). The dose will be increased to 300mg per day after the first week, and may be increased up to 450 mg/per day if deemed necessary by the clinician.
• 1 tablet of 5 mg of escitalopram per day (initial dose). The dose will be increased to 10 mg per day after the first week, followed by an additional increase to 20 mg/day if deemed necessary by clinician.

Participants and study doctors will know which medication is being used, but not which group the participant is in; that is, participants and study doctors will not know the participant's CRP levels nor whether the medication assignment is consistent with CRP levels. The dose of the medication may be adjusted up or down during the study to improve effects of the medication or reduce possible side effects. Dose changes will be made based on how the participant is feeling and any side effects.

Participants will then complete a clinical visit at Week 2, 4, and 6. These visits will last approximately 1 hour and 15 minutes, and will include the following:

• Clinical Evaluation: a psychiatrist will check the participant's vital signs and assess their overall wellbeing. Symptom changes, side effects, and adherence to treatment will be evaluated. Medication dosage adjustments will be made as necessary.
• Self-Report Questionnaires

The final clinical visit will occur at week 8. This visit will be the last in person visit and will last approximately 1 hour and 45 minutes. The following will be completed

• Clinical Evaluation
• Self-Report Questionnaires
• Cognitive tests
• Bloodwork
• Pregnancy test (if you are a female able to become pregnant)

After study completion, participants who wish to remain on treatment will be given a four week supply of study drug while they transition care.

Additionally, a remote follow up assessment will be done at Week 12. Participants will be contacted via phone to complete a series of questionnaires. Additionally, they will receive a series of self reports via email. Paper forms will be also available at the Center for Depression Research and Clinical Care if the participant prefers to answer them on paper or don't have access to an email.

The self-report questionnaires, study evaluations, and assessment of CRP levels and additional inflammatory substances in this study are designed for research, not for medical purposes. Even though the researchers are not specifically looking at blood to find a medical problem, participants will be notified if any abnormal results are identified.

Participants will also have the option to participate in a Finger Prick Blood CRP substudy that will compare CRP results based on the blood source: venous blood obtained via venipuncture and capillary blood obtained via finger prick. A few drops of capillary blood will be collected via finger prick once during the study at week 0 (screening/baseline). We will compare the finger prick results to the results obtained from venipuncture at the same visit.

Inclusion Criteria:

• Women and men ages 18-65
• Current diagnosis of Major Depressive Disorder
• Able to read, speak, and understand English

Exclusion Criteria:

• Antidepressant use within the last 8 weeks
• Active infection or uncontrolled autoimmune disease
• Currently on oral corticosteroids or active immune suppressive therapy (methotrexate, cyclosporine, anti-cytokines medications, etc).
• Current diagnosis of uncontrolled HIV, hepatitis C or significant immunodeficiency
• Alcohol or substance use disorder
• Positive urine drug test for illicit substances or substances used out of the context of prescription
• Cognitively unable to give informed consent
• Pregnant or breastfeeding women, women of childbearing potential who are not using an accepted means of birth control, or women with a positive urine pregnancy test
• History of seizure disorder
• Previous significant adverse reaction to escitalopram or bupropion
• History of non-response to adequate doses of escitalopram or bupropion XL
• Current use of concomitant psychotropic agents (anticonvulsants, benzodiazepines, hypnotics, opiates, triiodothyronine (T3), modafinil, psychostimulants, buspirone, melatonin, folate, l-methylfolate, s-adenosyl methionine, lithium) not on the same dose for at least four weeks prior to study entry or who do not agree to continue at the same dose during the acute phase of the study.
• Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder or other psychotic disorder
• Current anorexia nervosa or bulimia nervosa
• Suicidal ideation of the degree that, in the opinion of the evaluating clinician, participation in the study would place them at significantly increased risk of suicide
• Unstable medical issues of such degree that, in the opinion of the evaluating clinician, participation in the study would place them at significant risk of a serious adverse event

12 weeks

Participant, care provider, investigator, and outcomes assessor will only be blinded to the participant's CRP levels and group assignment. However, the study is open label, meaning the participant, care provider, investigator, and outcomes assessor will know what medication the participant is taking.