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Effect of Lithium Versus Placebo in Adults With Treatment-Resistant Depression Who Are Receiving Ketamine

Primary Purpose

Treatment Resistant Depression

Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Lithium
Placebo
Ketamine
Sponsored by
William V. Bobo, M.D.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Treatment Resistant Depression focused on measuring depression, bipolar I disorder, bipolar II disorder

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Ability to provide informed consent;
  • Current psychiatric inpatient (voluntary only) or outpatient treatment;
  • Meets Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) diagnostic criteria for major depressive disorder, bipolar I disorder, or bipolar II disorder;
  • 9-item 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);
  • Adequate social support, defined as having at least one individual identified who is committed to function as support, including providing transportation to and from outpatient ketamine infusion visits;
  • 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;
  • On active lithium treatment;
  • Serious risk for suicide, as assessed by the evaluating study clinician; a serious suicide risk will be considered: (a) an inability to control suicide impulses or imminent or unacceptably high risk of suicide in the investigator's judgment; or (b) a recent history of suicidal behavior, which is defined as either one or more suicide attempts (or interrupted suicide attempts) in the 12 months before study entry; or (c) history of serious suicidal behavior, defined as one or more suicide attempts (or interrupted attempts) in the last 3 years with a potential lethality judged by the evaluating study clinician to have possibly resulted in serious injury or death;
  • 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 Alanine Aminotransferase (ALT)) within 1 year of consent, past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver;
  • 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 medical condition(s) which are not recommended to be taken concurrently with lithium; Current anti-depressive pharmacotherapies will not be allowed during the acute phase KET infusions.
  • Pregnancy, or nursing;
  • Prisoners;
  • Involuntary psychiatric hospitalization.

Sites / Locations

  • Mayo Clinic in Rochester

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Ketamine plus Lithium

Ketamine plus Placebo

Arm Description

Lithium will be used in conjunction to Ketamine infusions for the treatment of major depression disorder or bipolar disorder type I or II. Before the first ketamine infusion, subjects will be randomized to 2 weeks of lithium treatment. All subjects will receive three IV ketamine infusions (0.5 mg/kg, over 100 min.) over 7 days. Those who achieve positive response (>50% decrease in MADRS total score from baseline) will be given 4 additional once-weekly ketamine infusions (same dose and infusion rate) and lithium treatment .

Placebo tablets will be used in conjunction to Ketamine infusions for the treatment of major depression disorder or bipolar disorder type I or II. Before the first ketamine infusion, subjects will be randomized to 2 weeks of placebo treatment. All subjects will receive three IV ketamine infusions (0.5 mg/kg, over 100 min.) over 7 days. Those who achieve positive response (>50% decrease in MADRS total score from baseline) will be given 4 additional once-weekly ketamine infusions (same dose and infusion rate) and placebo treatment.

Outcomes

Primary Outcome Measures

Change in Montgomery-Asberg Depression Rating Scale (MADRS)
The Montgomery Asberg Depression Scale (MADRS) is a 10-item observer rating scale assessing symptoms of depression. The score ranges from 0 (no depression) to 60 (very depressed).
Change in Montgomery-Asberg Depression Rating Scale (MADRS)
The Montgomery Asberg Depression Scale (MADRS) is a 10-item observer rating scale assessing symptoms of depression. The score ranges from 0 (no depression) to 60 (very depressed).

Secondary Outcome Measures

Full Information

First Posted
September 20, 2017
Last Updated
August 14, 2018
Sponsor
William V. Bobo, M.D.
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1. Study Identification

Unique Protocol Identification Number
NCT03290963
Brief Title
Effect of Lithium Versus Placebo in Adults With Treatment-Resistant Depression Who Are Receiving Ketamine
Official Title
Targeting mTOR/GSK3 With Lithium Augmentation to Enhance and Sustain Rapid Antidepressant Actions of Ketamine in Adults With Treatment-Resistant Depression: A Precision Medicine Approach for Psychiatry
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Withdrawn
Why Stopped
Principal Investigator moved to Jacksonville, FL campus.
Study Start Date
November 30, 2017 (Actual)
Primary Completion Date
December 2018 (Anticipated)
Study Completion Date
December 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
William V. Bobo, M.D.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this research study is to compare the antidepressant effect of lithium versus placebo in adults receiving ketamine. Lithium is available commercially for depression; ketamine is available commercially and can help the symptoms of depression; however, it has not been approved by the U.S. Food and Drug Administration (FDA) for this use. The FDA has allowed the use of this drug in this research study.
Detailed Description
This is a randomized clinical trial in adults with Treatment-Resistant Depression. All participants will receive three intravenous (IV) Ketamine (KET) infusions over 7 days. Before receiving the first KET infusion, subjects will be randomized to 2 weeks of pre-KET treatment with either Lithium or matching placebo. Pre-treatment medications will then be continued in a double-blind manner during the acute phase administration of ketamine. Questionnaires will be administered at baseline, prior to each KET infusion, and at 40, 100, and 120 minutes after each infusion, and again at weekly intervals following the third (final) KET infusion for 4 weeks, using standardized rating scales. Those who achieve positive response (>50% decrease in questionnaire total score from baseline) will be given 4 additional once-weekly KET infusions (same dose and infusion rate).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Treatment Resistant Depression
Keywords
depression, bipolar I disorder, bipolar II disorder

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
Triple blinded study. The staff accessible to the blind includes pharmacy staff and one assigned investigator.
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ketamine plus Lithium
Arm Type
Active Comparator
Arm Description
Lithium will be used in conjunction to Ketamine infusions for the treatment of major depression disorder or bipolar disorder type I or II. Before the first ketamine infusion, subjects will be randomized to 2 weeks of lithium treatment. All subjects will receive three IV ketamine infusions (0.5 mg/kg, over 100 min.) over 7 days. Those who achieve positive response (>50% decrease in MADRS total score from baseline) will be given 4 additional once-weekly ketamine infusions (same dose and infusion rate) and lithium treatment .
Arm Title
Ketamine plus Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo tablets will be used in conjunction to Ketamine infusions for the treatment of major depression disorder or bipolar disorder type I or II. Before the first ketamine infusion, subjects will be randomized to 2 weeks of placebo treatment. All subjects will receive three IV ketamine infusions (0.5 mg/kg, over 100 min.) over 7 days. Those who achieve positive response (>50% decrease in MADRS total score from baseline) will be given 4 additional once-weekly ketamine infusions (same dose and infusion rate) and placebo treatment.
Intervention Type
Drug
Intervention Name(s)
Lithium
Other Intervention Name(s)
Lithane, Lithobid
Intervention Description
Lithium will be dosed in units (LI level > or = 0.4 milliequivalents (mEq)/L)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo tablets, dosed in units
Intervention Type
Drug
Intervention Name(s)
Ketamine
Other Intervention Name(s)
Ketalar
Intervention Description
All subjects will receive 3 IV ketamine infusions of 0.5mg/kg, over 100 min. over 7 days.
Primary Outcome Measure Information:
Title
Change in Montgomery-Asberg Depression Rating Scale (MADRS)
Description
The Montgomery Asberg Depression Scale (MADRS) is a 10-item observer rating scale assessing symptoms of depression. The score ranges from 0 (no depression) to 60 (very depressed).
Time Frame
baseline, at the end of the first infusion (approximately 1 day)
Title
Change in Montgomery-Asberg Depression Rating Scale (MADRS)
Description
The Montgomery Asberg Depression Scale (MADRS) is a 10-item observer rating scale assessing symptoms of depression. The score ranges from 0 (no depression) to 60 (very depressed).
Time Frame
baseline, at the end of third infusion (approximately 7 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Ability to provide informed consent; Current psychiatric inpatient (voluntary only) or outpatient treatment; Meets Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) diagnostic criteria for major depressive disorder, bipolar I disorder, or bipolar II disorder; 9-item 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); Adequate social support, defined as having at least one individual identified who is committed to function as support, including providing transportation to and from outpatient ketamine infusion visits; 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; On active lithium treatment; Serious risk for suicide, as assessed by the evaluating study clinician; a serious suicide risk will be considered: (a) an inability to control suicide impulses or imminent or unacceptably high risk of suicide in the investigator's judgment; or (b) a recent history of suicidal behavior, which is defined as either one or more suicide attempts (or interrupted suicide attempts) in the 12 months before study entry; or (c) history of serious suicidal behavior, defined as one or more suicide attempts (or interrupted attempts) in the last 3 years with a potential lethality judged by the evaluating study clinician to have possibly resulted in serious injury or death; 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 Alanine Aminotransferase (ALT)) within 1 year of consent, past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver; 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 medical condition(s) which are not recommended to be taken concurrently with lithium; Current anti-depressive pharmacotherapies will not be allowed during the acute phase KET infusions. Pregnancy, or nursing; Prisoners; Involuntary psychiatric hospitalization.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William V Bobo
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Effect of Lithium Versus Placebo in Adults With Treatment-Resistant Depression Who Are Receiving Ketamine

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