Bipolar Proteomic Assay Validation Study

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.