The purpose of this study is to validate a set of signatures, based on a panel of proteomic markers, that discriminate BDI, BDII, and MDD in people seeking treatment for a depressive episode.

This is a hypothesis-driven confirmatory study to validate the diagnostic signature (model) for distinguishing BDI from MDD that also aims to optimize the models to discriminate BDII from MDD and BDI. A binary classification model, using linear discriminant analysis and based on 13 a priori-defined proteomic markers will aim to distinguish BDI from MDD. An alternative binary classification model based on multiple logistic regression and using 10 a priori -defined proteomic markers will aim for the same result. To improve the predictive performance of the signatures, items from self-report mood rating scales and treatment-emergent changes in proteomic markers will be analyzed. In addition, the study will examine if baseline or early treatment-emergent changes in proteomic markers predict treatment response.

Inclusion Criteria:

• Diagnosed with BDI, BDII, or MDD, confirmed with the Structured Clinical Interview for DSM-5 (SCID).
• Currently depressed for ≥4 weeks and ≤104 weeks, without psychotic features,
• MADRS score ≥ 20 (consistent with at least moderately-severe depression)
• YMRS score ≤ 8 (consistent with the absence of hypomanic symptoms)

Exclusion Criteria:

• At high risk for suicide, defined as a score ≥4 on item 10 of the MADRS
• Current depression has psychotic features, diagnosed with the SCID
• Meeting criteria for severe alcohol, cannabis, or THC use disorders, as defined by DSM-5 and confirmed by the SCID, in the past 3 months, or meeting criteria for other substance use disorders of any severity (eg. cocaine use disorder). For substances other than alcohol, cannabis, and opioids, a positive drug screen at both the screening and baseline visits is also exclusionary. Caffeine and nicotine use disorders of any severity will not be exclusionary.
• Diagnosis of borderline personality disorder, diagnosed with the Zanarini Rating Scale for Borderline Personality Disorder.
• Medical conditions with neurological sequelae (eg. stroke, brain cancer, multiple sclerosis, loss of consciousness > 30 min, HIV)
• Severe chronic pain, at the discretion of the investigator
• Receiving treatment with high-potency immune-modulating medications, such as corticosteroids, chemotherapy, monoclonal antibodies, or disease-modifying agents for arthritis, multiple sclerosis
• Any acute unstable medical illness (at the discretion of the site investigator)
• In MDD patients: strong risk factors for bipolarity, including 1) short (1-3 day) mood elevations not meeting DSM-5 time criteria for hypomania; 2) a family history of BDI or BDII in a first-degree relative; and 3) a history of antidepressant-induced symptoms suggestive of bipolarity, particularly antidepressant-induced hypo/mania.

Patients seeking treatment for new on-set depression from academic programs and affiliated community mental health facilities (inpatient and outpatient