Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects

Study Overview
=================
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.

Official Title
-----------------
Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects

Conditions
-----------------
Depression

Intervention / Treatment
-----------------
* Drug: Ketamine
* Drug: sirolimus
* Drug: Placebo


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ketamine + sirolimus (placebo at time 2)<br>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<br>* . 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).<br>Drug: sirolimus<br>* 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.<br>* Other names: Rapamune;Drug: Placebo<br>* Placebo oral dose<br>|
| Placebo Comparator: ketamine + placebo (sirolimus at time 2)<br>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<br>* . 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).<br>Drug: sirolimus<br>* 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.<br>* Other names: Rapamune;Drug: Placebo<br>* Placebo oral dose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Pretreatment and 2 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Pretreatment and 2 week | 
| 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). | Pretreatment and 2 week | 
| 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). | During infusion, approximately 40 mins | 
| 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). | During infusion, approximately 40 mins | 
| Rapamycin Level | Plasma level of rapamycin (a.k.a. sirolimus). | During infusion, approximately 0 mins | 
| Ketamine Level | Plasma level of ketamine | During infusion, approximately 40 mins |