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Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects

Primary Purpose

Depression

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ketamine
sirolimus
Placebo
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Depression

Eligibility Criteria

21 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Veterans and non-Veterans between the ages of 21-65.
  2. Diagnosis of Major Depressive Episode (unipolar or bipolar) as determined by the Mini International Neuropsychiatric Interview (MINI).
  3. Antidepressant-resistant depressive symptoms, defined by a history of failure of one or more adequate antidepressant trials.
  4. Stable doses of antidepressants (if prescribed) for a period of four weeks or longer at the time of randomization, except for MAOIs which are prohibited.
  5. Stable course of psychotherapy (if engaged in) for a period of four weeks or longer at the time of randomization.
  6. Females will be included if they are not pregnant or breastfeeding and agree to utilize a medically accepted birth control method (to include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile. For those women who are taking an oral contraceptive, we will also ask that they use (or ask their partners to use) a barrier method contraceptive.
  7. Able to provide written informed consent according to VA HSS guidelines.
  8. Ability to read and write in English.
  9. A score greater than or equal to 18 on the Montgomery Åsberg Depression Rating Scale (MADRS).

Exclusion Criteria:

  1. Subjects with a diagnostic history of schizophrenia or schizoaffective disorder, or currently exhibiting manic or mixed episodes or psychotic features as confirmed by the Mini International Neuropsychiatric Inventory.
  2. Current, ongoing serious suicidal risk as assessed by evaluating investigator or by scoring 5 or more on the item-10 of the MADRS.
  3. Patients with unstable or inadequately controlled medical conditions.
  4. Patient requiring prohibited medication.
  5. Patient with history of organ transplant.
  6. Meet criteria for a diagnosis of substance dependence (amphetamines, cocaine, hallucinogens, inhalants, opioids, sedatives/hypnotics/anxiolytics) within the three months prior to screening date.
  7. Positive urine drug screen for cannabis, cocaine, PCP, or barbiturates.
  8. Positive pregnancy test at screening at any screen given during the study.
  9. Known sensitivity to sirolimus or ketamine.
  10. History of sensitivity to heparin or heparin-induced thrombocytopenia.
  11. Resting blood pressure lower than 85/55 or higher than 150/95, or resting heart rate lower than 45/min or higher than 100/min.

Sites / Locations

  • Yale New Haven Hospital
  • West Haven Veterans Affairs

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

ketamine + sirolimus (placebo at time 2)

ketamine + placebo (sirolimus at time 2)

Arm Description

Participants will be treated twice with ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of sirolimus 6 mg orally. After two weeks, they will recieve another infusion of ketamine, and a single dose of placebo.

Participants will be treated twice with ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of sirolimus 6 mg placebo. After two weeks, they will recieve another infusion of ketamine, and a single dose of sirolimus 6 mg.

Outcomes

Primary Outcome Measures

Montgomery-Asberg Depression Rating Scale
Montgomery-Asberg Depression Rating Scale (MADRS): The MADRS is a standardized instrument to ascertain depressed mood and neurovegetative signs and symptoms of depression. Ranges from 0-60 (higher is worse).

Secondary Outcome Measures

Quick Inventory of Depressive Symptoms (QIDS)
Quick Inventory of Depressive Symptoms - Self-Report (QIDS-SR): The QIDS-SR is a patient-rated depression instrument. Ranges from 0-27 (higher is worse).
Hamilton Anxiety Rating Scale (HAMA)
Hamilton Anxiety Rating Scale (HAM-A): The HAM-A is a standardized clinician-rated instrument to evaluate the severity of anxiety symptoms. Ranges from 0-56 (higher is worse).
Clinician Administered Dissociative States Scale (CADSS)
Clinician Administered Dissociative States Scale (CADSS): The CADSS has self and interviewer-administered items including 5 subscales, generated a priori, evaluating dissociation including altered environmental perception, time perception, spatial/body perception, derealization and memory impairment. Ranges from 0-108 (higher is worse).
Positive and Negative Symptom Scale (PANSS) - Positive
Positive and Negative Symptom Scale (PANSS): The PANSS is commonly used to measure the severity of symptoms in psychotic disorders. It is a clinician- administered scale and includes three categories of symptoms: (1) positive symptoms, such as hallucination and delusion; (2) negative symptoms, such as flat affect and difficulty in abstract thinking; (3) general psychopathology, such as mannerisms and posturing. Ranges from 0-49 for positive scale (higher is worse).
Rapamycin Level
Plasma level of rapamycin (a.k.a. sirolimus).
Ketamine Level
Plasma level of ketamine

Full Information

First Posted
June 29, 2015
Last Updated
July 2, 2020
Sponsor
Yale University
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1. Study Identification

Unique Protocol Identification Number
NCT02487485
Brief Title
Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects
Official Title
Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
March 2016 (undefined)
Primary Completion Date
January 2020 (Actual)
Study Completion Date
January 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The aim of the study is to provide insight into the impact of the immunosuppressant drug sirolimus, on the antidepressant effects of the prototypal rapid-acting antidepressant medication, ketamine.
Detailed Description
This is a double blind, placebo-controlled, crossover, randomized controlled trial investigating the impact of sirolimus on ketamine's antidepressant effects in participants with antidepressant-resistant depressive symptoms. Prior to this, there was a phase 1 which included monitoring 3 subjects over the course of 7 days after a single dose of sirolimus and ketamine in order to inquire about side effects or interaction effects.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Depression

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ketamine + sirolimus (placebo at time 2)
Arm Type
Experimental
Arm Description
Participants will be treated twice with ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of sirolimus 6 mg orally. After two weeks, they will recieve another infusion of ketamine, and a single dose of placebo.
Arm Title
ketamine + placebo (sirolimus at time 2)
Arm Type
Placebo Comparator
Arm Description
Participants will be treated twice with ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of sirolimus 6 mg placebo. After two weeks, they will recieve another infusion of ketamine, and a single dose of sirolimus 6 mg.
Intervention Type
Drug
Intervention Name(s)
Ketamine
Intervention Description
. Subjects will receive an infusion of ketamine (0.5 mg/kg infusion over approximately 40 minutes). All subjects will receive two ketamine infusions-once with a placebo and once with a single dose of sirolimus (6 mg, oral administration).
Intervention Type
Drug
Intervention Name(s)
sirolimus
Other Intervention Name(s)
Rapamune
Intervention Description
Subjects will receive a single 6 mg oral dose via oral solution of sirolimus or a dose of placebo approximately two hours prior to the infusions. As above, the order of placebo and sirolimus is randomized. The sirolimus dose as well as the placebo solution will be given in 6 ounces of orange juice.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo oral dose
Primary Outcome Measure Information:
Title
Montgomery-Asberg Depression Rating Scale
Description
Montgomery-Asberg Depression Rating Scale (MADRS): The MADRS is a standardized instrument to ascertain depressed mood and neurovegetative signs and symptoms of depression. Ranges from 0-60 (higher is worse).
Time Frame
Pretreatment and 2 week
Secondary Outcome Measure Information:
Title
Quick Inventory of Depressive Symptoms (QIDS)
Description
Quick Inventory of Depressive Symptoms - Self-Report (QIDS-SR): The QIDS-SR is a patient-rated depression instrument. Ranges from 0-27 (higher is worse).
Time Frame
Pretreatment and 2 week
Title
Hamilton Anxiety Rating Scale (HAMA)
Description
Hamilton Anxiety Rating Scale (HAM-A): The HAM-A is a standardized clinician-rated instrument to evaluate the severity of anxiety symptoms. Ranges from 0-56 (higher is worse).
Time Frame
Pretreatment and 2 week
Title
Clinician Administered Dissociative States Scale (CADSS)
Description
Clinician Administered Dissociative States Scale (CADSS): The CADSS has self and interviewer-administered items including 5 subscales, generated a priori, evaluating dissociation including altered environmental perception, time perception, spatial/body perception, derealization and memory impairment. Ranges from 0-108 (higher is worse).
Time Frame
During infusion, approximately 40 mins
Title
Positive and Negative Symptom Scale (PANSS) - Positive
Description
Positive and Negative Symptom Scale (PANSS): The PANSS is commonly used to measure the severity of symptoms in psychotic disorders. It is a clinician- administered scale and includes three categories of symptoms: (1) positive symptoms, such as hallucination and delusion; (2) negative symptoms, such as flat affect and difficulty in abstract thinking; (3) general psychopathology, such as mannerisms and posturing. Ranges from 0-49 for positive scale (higher is worse).
Time Frame
During infusion, approximately 40 mins
Title
Rapamycin Level
Description
Plasma level of rapamycin (a.k.a. sirolimus).
Time Frame
During infusion, approximately 0 mins
Title
Ketamine Level
Description
Plasma level of ketamine
Time Frame
During infusion, approximately 40 mins

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Veterans and non-Veterans between the ages of 21-65. Diagnosis of Major Depressive Episode (unipolar or bipolar) as determined by the Mini International Neuropsychiatric Interview (MINI). Antidepressant-resistant depressive symptoms, defined by a history of failure of one or more adequate antidepressant trials. Stable doses of antidepressants (if prescribed) for a period of four weeks or longer at the time of randomization, except for MAOIs which are prohibited. Stable course of psychotherapy (if engaged in) for a period of four weeks or longer at the time of randomization. Females will be included if they are not pregnant or breastfeeding and agree to utilize a medically accepted birth control method (to include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile. For those women who are taking an oral contraceptive, we will also ask that they use (or ask their partners to use) a barrier method contraceptive. Able to provide written informed consent according to VA HSS guidelines. Ability to read and write in English. A score greater than or equal to 18 on the Montgomery Åsberg Depression Rating Scale (MADRS). Exclusion Criteria: Subjects with a diagnostic history of schizophrenia or schizoaffective disorder, or currently exhibiting manic or mixed episodes or psychotic features as confirmed by the Mini International Neuropsychiatric Inventory. Current, ongoing serious suicidal risk as assessed by evaluating investigator or by scoring 5 or more on the item-10 of the MADRS. Patients with unstable or inadequately controlled medical conditions. Patient requiring prohibited medication. Patient with history of organ transplant. Meet criteria for a diagnosis of substance dependence (amphetamines, cocaine, hallucinogens, inhalants, opioids, sedatives/hypnotics/anxiolytics) within the three months prior to screening date. Positive urine drug screen for cannabis, cocaine, PCP, or barbiturates. Positive pregnancy test at screening at any screen given during the study. Known sensitivity to sirolimus or ketamine. History of sensitivity to heparin or heparin-induced thrombocytopenia. Resting blood pressure lower than 85/55 or higher than 150/95, or resting heart rate lower than 45/min or higher than 100/min.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chadi Abdallah, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale New Haven Hospital
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06511
Country
United States
Facility Name
West Haven Veterans Affairs
City
West Haven
State/Province
Connecticut
ZIP/Postal Code
06516
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects

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