Inclusion Criteria:

• Outpatients with nonpsychotic MDD. Outpatient status assumes that the subject is not psychiatrically hospitalized or in an active suicidal crisis requiring hospitalization.
• A total score of > 10 on the QIDS-CR and on the QIDS-SR (equivalent to a HAMD17 score of 13 [ids-qids.org, accessed on April 12, 2019]) given that when medication exceeds the effect of  placebo in primary care, participants have a 17-item HAMD score > 12.  We added 2 HAMD points to take into account the possibility of measurement error. This is a very similar approach taken to the successful recruitment of subjects into the PGRN-AMPS trial.
• Antidepressant treatment is deemed appropriate by the study clinician.
• Adults who are between 18-64 years of age. 
• Ability to provide informed consent
• Ability to understand English.

Exclusion Criteria:

• A medical contraindication that precludes SSRI or SNRI treatment.
• Presence of a general medical condition that, in the opinion of this study clinician, is the cause of their depressive symptoms, will be exclusionary.
•  People with treatment-resistant depression will be excluded from participating. For this study, treatment resistance will be defined as failure to respond to two or more adequate therapeutic trials of SSRIs and at least on SNRI therapeutic trial (sufficient antidepressant dose, for 6 weeks or longer) during the current depressive episode.  Failure to tolerate a therapeutic trial of a given medication (resulting in discontinuation due to adverse effects) will not be counted as exclusionary. Persons who have failed to respond to two or more adequately designed and executed therapeutic trials of SSRIs but have no history of least one failure to respond to SNRI treatment during the current depressive episode will be eligible to receive treatment with an SNRI in this study.
• Diagnosis of schizophrenia, schizoaffective disorder, bipolar I or II disorder, or bipolar disorder NOS (including other specified or other unspecified bipolar disorders) or a primary psychiatric condition that requires a different initial treatment than an antidepressant. 
• Currently taking an antidepressant medication with subtherapeutic results in terms of antidepressive efficacy and unwilling to undergo a medication taper prior to initiation of a study drug from this protocol.  The subject will be closely monitored by the study clinician during the medication taper. The design of the medication taper will be at the discretion of the study clinician.    
• Use of antidepressant medication primarily for management of nicotine dependence, chronic pain, migraine prophylaxis or other diagnoses. 
• Active substance use disorder. Persons meeting DSM-5 diagnostic criteria for a substance use disorder in sustained full remission (> 12 months) and a negative urine drug of abuse screen at the screening visit will be considered eligible. Persons with a positive UDS may participate in the study as long as they do not meet DSM-5 diagnsotic criteria for a substance use disorder. Note: An additional urine drug screen will not be necessary for individuals with a negative urine drug screen documented in the medical record where the date of testing occurred within 12 weeks (84 days) of the screening/baseline study visit. However, study clinicians can still obtain a urine drug screen based on their clinical judgement even in participants with a negative drug screen within the 12 weeks preceding the screening/baseline study visit.
• Pregnant subjects and those who are currently breastfeeding and who plan to continue breastfeeding will be excluded.
• Persons currently undergoing ECT, TMS or DBS as acute series or for maintenance.
• Patients currently psychiatrically hospitalized or in an active suicidal crisis requiring hospitalization in the opinion of the study clinician. 

• As an additional stipulation, individuals whose total QIDS-CR score is is 10 or higher at the screening visit but decrease (improve) to a total score less than 10 on the QIDS-CR at the baseline visit will be excluded. Ultimately, the evaluating study clinician(s) confirm study entry and continued participation based on their clinical judgement and assessment of safety (concerning the individual’s participation).

Eligibility last updated 12/1/22. Questions regarding updates should be directed to the study team contact.