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Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02487485
Recruitment Status : Completed
First Posted : July 1, 2015
Results First Posted : July 7, 2020
Last Update Posted : July 16, 2020
Sponsor:
Information provided by (Responsible Party):
Yale University

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.

Condition or disease Intervention/treatment Phase
Depression Drug: Ketamine Drug: sirolimus Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Other
Official Title: Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects
Study Start Date : March 2016
Actual Primary Completion Date : January 2020
Actual Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants

Arm Intervention/treatment
Experimental: ketamine + sirolimus (placebo at time 2)
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.
Drug: Ketamine
. 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).

Drug: sirolimus
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.
Other Name: Rapamune

Drug: Placebo
Placebo oral dose

Placebo Comparator: ketamine + placebo (sirolimus at time 2)
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.
Drug: Ketamine
. 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).

Drug: sirolimus
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.
Other Name: Rapamune

Drug: Placebo
Placebo oral dose




Primary Outcome Measures :
  1. Montgomery-Asberg Depression Rating Scale [ Time Frame: Pretreatment and 2 week ]
    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 :
  1. Quick Inventory of Depressive Symptoms (QIDS) [ Time Frame: Pretreatment and 2 week ]
    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).

  2. Hamilton Anxiety Rating Scale (HAMA) [ Time Frame: Pretreatment and 2 week ]
    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).

  3. Clinician Administered Dissociative States Scale (CADSS) [ Time Frame: During infusion, approximately 40 mins ]
    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).

  4. Positive and Negative Symptom Scale (PANSS) - Positive [ Time Frame: During infusion, approximately 40 mins ]
    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).

  5. Rapamycin Level [ Time Frame: During infusion, approximately 0 mins ]
    Plasma level of rapamycin (a.k.a. sirolimus).

  6. Ketamine Level [ Time Frame: During infusion, approximately 40 mins ]
    Plasma level of ketamine



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02487485


Locations
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United States, Connecticut
Yale New Haven Hospital
New Haven, Connecticut, United States, 06511
West Haven Veterans Affairs
West Haven, Connecticut, United States, 06516
Sponsors and Collaborators
Yale University
Investigators
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Principal Investigator: Chadi Abdallah, MD Yale University
  Study Documents (Full-Text)

Documents provided by Yale University:
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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT02487485    
Other Study ID Numbers: 1504015604
First Posted: July 1, 2015    Key Record Dates
Results First Posted: July 7, 2020
Last Update Posted: July 16, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Depression
Behavioral Symptoms
Sirolimus
Ketamine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors