Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects

Phase 2

Completed

• Conditions: Depression
• Interventions: Drug: Ketamine; Drug: sirolimus; Drug: Placebo

• Registration Number: NCT02487485
• Lead Sponsor: 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.

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.

Study Timeline

• Study First Submitted: 2015-06-29
• Study First Submitted QC: 2015-06-29
• Study First Posted: 2015-07-01
• Study Start: 2016-03
• Primary Completion: 2020-01
• Study Completion: 2020-01
• Results First Submitted: 2020-04-22
• Status Verified: 2020-07
• Results First Submitted QC: 2020-07-01
• Last Update Submitted: 2020-07-02
• Results First Posted: 2020-07-07
• Last Update Posted: 2020-07-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
ketamine + placebo (sirolimus at time 2)	sirolimus	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.
ketamine + sirolimus (placebo at time 2)	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 orally. After two weeks, they will recieve another infusion of ketamine, and a single dose of placebo.
ketamine + placebo (sirolimus at time 2)	Ketamine	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.
ketamine + placebo (sirolimus at time 2)	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.
ketamine + sirolimus (placebo at time 2)	Ketamine	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.
ketamine + sirolimus (placebo at time 2)	sirolimus	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.

Primary Outcome Measures

Name	Time	Method
Montgomery-Asberg Depression Rating Scale	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

Name	Time	Method
Quick Inventory of Depressive Symptoms (QIDS)	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).
Hamilton Anxiety Rating Scale (HAMA)	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).
Clinician Administered Dissociative States Scale (CADSS)	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).
Positive and Negative Symptom Scale (PANSS) - Positive	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).
Rapamycin Level	During infusion, approximately 0 mins	Plasma level of rapamycin (a.k.a. sirolimus).
Ketamine Level	During infusion, approximately 40 mins	Plasma level of ketamine

Trial Locations

Locations (2)

Yale New Haven Hospital; 🇺🇸 New Haven, Connecticut, United States

West Haven Veterans Affairs; 🇺🇸 West Haven, Connecticut, United States