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.

Study Overview
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Brief Summary
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The purpose of this research study is to find out if the medication known as ketamine can help the symptoms of depression. This drug is approved by the Food and Drug Administration (FDA) but the investigators will use it for a non-FDA approved reason (depression).

Detailed Description
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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).

Official Title
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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.

Conditions
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Major Depression, Bipolar I Disorder, Bipolar II Disorder, Unipolar Depression

Intervention / Treatment
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* Drug: Ketamine Hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>Subjects will receive three IV Ketamine Hydrochloride 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). | Drug: Ketamine Hydrochloride<br>* Subjects will receive three IV ketamine infusions at 0.5 mg/kg, infused over 100 minutes.<br>* Other names: Ketalar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Remission of Depression | Total number of subjects with ≤ 9 MADRS score 24 hours post Ketamine infusion #3. The Montgomery Åsberg Depression Scale (MÅDRS) is a 10-item observer rating scale assessing symptoms of depression. The score ranges from 0 (no depression) to 60 (very depressed). For this study a score of less than or equal to 9 was considered clinical remission of depression. | 24 hours post infusion #3 | 
| Suicidal Ideation | Total number of subjects to have a reduction of suicidality, as defined by a 50% reduction on the Beck Scale for Suicidal Ideation (BSS) 24 hours post Ketamine infusion #3. The Beck Scale for Suicidal Ideation consists of 19 items which can be used to evaluate a patient's suicidal intentions. Each of the 19 items is rated on a 0-3 point scale (range 0-38, with higher scores indicating greater suicidal ideations or risk), and includes specific items that assess wish to live, wish to die, desire to make an active suicide attempt, passive suicidal desire, duration of suicidal ideations, frequency of suicidal ideations, and subjective level of control over suicidal actions. | 24 hours post infusion #3 |