The BIO-K Study: A Single-Arm, Open-Label, Biomarker Development Clinical Trial of Ketamine for Non-Psychotic Unipolar Major Depression and Bipolar I or II Depression.

The investigators will enroll 100 adults with treatment-resistant unipolar or bipolar major
depression (TRD) across 7 clinical sites and provide three IV ketamine infusions (0.5 mg/kg,
infused over 100 minutes) and measure their depressive symptom responses. Biomarkers will be
developed using blood samples from study subjects, taken prior to (predictive biomarkers) and
following ketamine treatment (change biomarkers). The investigators will begin by studying
the predictive value of mechanistic target of rapamycin (mTOR) target engagement by ketamine
using a white blood cell (WBC) assay for antidepressive response to ketamine (Aim 1);
however, samples will be used to develop multiple blood-based biomarkers for ketamine
antidepressive effects (Aim 2). The investigators will also examine the effect of combining
multiple blood-based biomarkers for predicting antidepressive response to ketamine in adults
with TRD (Aim 3).

Baseline WBC markers of impaired cellular energy regulation will be associated with measures
of clinical response to ketamine (predictive biomarker). Changes in WBC markers of impaired
cellular energy regulation will be associated with clinical response to ketamine (change
biomarker).

Inclusion criteria:

- Ability to provide informed consent

- Current psychiatric inpatient (voluntary only) or outpatient treatment

- Meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic
criteria for major depressive disorder, bipolar I disorder, or bipolar II disorder

- Patient Health Questionnaire (PHQ-9) total score > 15 at screening and at baseline
(just prior to first acute phase ketamine infusion);

- Treatment-resistant depression, as defined by failure of at least two previous
antidepressant or mood stabilizing treatments within the current depressive episode

- Failed antidepressant or mood stabilizing treatments can include pharmacotherapy for
depression at an adequate dose for at least 8 weeks, or an acute series of at least 6
administrations of electroconvulsive therapy (ECT)

- Ability to pass a comprehension assessment test related to effects of ketamine and
trial objectives and criteria

Exclusion Criteria:

- Diagnosis of schizophrenia, schizoaffective disorder, or active psychotic symptoms

- Ongoing prescription of > 4 mg lorazepam equivalents (total) daily, or morning dosing
of any benzodiazepine at the time of assessment

- Currently undergoing ECT, transcranial magnetic stimulation, vagal nerve stimulation,
or deep brain stimulation as either an acute or maintenance treatment of depression

- Any active or unstable medical condition judged by the study psychiatrist as
conferring too great a level of medical risk to allow inclusion in the study

- Use or abuse of methamphetamine, cocaine, cannabis, or stimulants (prescribed and
illicit) within the past 12 months

- Any current abuse or dependence of alcohol or drugs (excluding nicotine and caffeine)
Note: Persons will be allowed to enroll in this study if their drug or alcohol
abuse/dependence is in complete (not partial) and sustained (> 1 year) remission

- History of traumatic brain injury that resulted in loss of consciousness

- Developmental delay, mental retardation, or intellectual disorder

- Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical
diagnosis within the prior 12 months

- Cognitive disorder (mild and major categories, per DSM-5)

- Prior participation in another study of ketamine for depression within the prior 6
months

- History of either poor antidepressive response to or poor tolerability of ketamine
(any route of administration) when previously administered for treating symptoms of
depression

- History of hypothyroidism unless taking a stable dose of thyroid medication and
asymptomatic for 6 months

- Significant unstable medical condition

- Hepatic insufficiency (2.5 X upper limit of normal (ULN) for aspartate
aminotransferase (AST) or ALT) within 1 year of consent, past liver transplant
recipient, and/or clinical diagnosis of cirrhosis of the liver

- Pregnancy, or nursing

- Prisoners

- Involuntary psychiatric hospitalization