Depression
Conditions
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.
Interventions
DRUGKetamine
. 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).
DRUGsirolimus
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.
DRUGPlacebo
Placebo oral dose
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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). |
| 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 |
| 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketamine + Sirolimus First, Then Ketamine + Placebo Participants received ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of sirolimus 6 mg orally. After two weeks, they received another infusion of ketamine, and a single dose of placebo. | 11 |
| Ketamine + Placebo First, Then Ketamine + Sirolimus Participants received ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of placebo. After two weeks, they received another infusion of ketamine, and a single dose of sirolimus 6 mg. | 10 |
| Total | 21 |
Baseline characteristics
| Characteristic | Ketamine + Sirolimus First, Then Ketamine + Placebo | Total | Ketamine + Placebo First, Then Ketamine + Sirolimus |
|---|---|---|---|
| Age, Continuous | 40.09 years STANDARD_DEVIATION 13.22 | 42 years STANDARD_DEVIATION 12.79 | 44.1 years STANDARD_DEVIATION 12.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 10 Participants | 16 Participants | 6 Participants |
| Region of Enrollment United States | 11 Participants | 21 Participants | 10 Participants |
| Sex: Female, Male Female | 6 Participants | 14 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 6 / 20 | 6 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
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).
Time frame: Pretreatment and 2 week
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine + Sirolimus | Montgomery-Asberg Depression Rating Scale | Pretreatment | 27.9387 score on a scale | Standard Error 1.9 |
| Ketamine + Sirolimus | Montgomery-Asberg Depression Rating Scale | At 2 weeks | 16.5482 score on a scale | Standard Error 2.3 |
| Ketamine + Placebo | Montgomery-Asberg Depression Rating Scale | Pretreatment | 26.5756 score on a scale | Standard Error 1.9 |
| Ketamine + Placebo | Montgomery-Asberg Depression Rating Scale | At 2 weeks | 20.9065 score on a scale | Standard Error 2.3 |
Secondary
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).
Time frame: During infusion, approximately 40 mins
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine + Sirolimus | Clinician Administered Dissociative States Scale (CADSS) | 12.1 score on a scale | Standard Error 3.1 |
| Ketamine + Placebo | Clinician Administered Dissociative States Scale (CADSS) | 13.95 score on a scale | Standard Error 3.1 |
Secondary
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).
Time frame: Pretreatment and 2 week
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine + Sirolimus | Hamilton Anxiety Rating Scale (HAMA) | Pretreatment | 12.9678 score on a scale | Standard Error 1.4 |
| Ketamine + Sirolimus | Hamilton Anxiety Rating Scale (HAMA) | At 2 weeks | 9.8755 score on a scale | Standard Error 1.4 |
| Ketamine + Placebo | Hamilton Anxiety Rating Scale (HAMA) | Pretreatment | 13.8222 score on a scale | Standard Error 1.4 |
| Ketamine + Placebo | Hamilton Anxiety Rating Scale (HAMA) | At 2 weeks | 10.8669 score on a scale | Standard Error 1.6 |
Secondary
Ketamine Level
Plasma level of ketamine
Time frame: During infusion, approximately 40 mins
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine + Sirolimus | Ketamine Level | 115 ng/mL | Standard Error 16 |
| Ketamine + Placebo | Ketamine Level | 125 ng/mL | Standard Error 13 |
Secondary
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).
Time frame: During infusion, approximately 40 mins
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine + Sirolimus | Positive and Negative Symptom Scale (PANSS) - Positive | 9.1537 score on a scale | Standard Error 0.59 |
| Ketamine + Placebo | Positive and Negative Symptom Scale (PANSS) - Positive | 8.9444 score on a scale | Standard Error 0.6 |
Secondary
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).
Time frame: Pretreatment and 2 week
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine + Sirolimus | Quick Inventory of Depressive Symptoms (QIDS) | Pretreatment | 12.6342 score on a scale | Standard Error 1.4 |
| Ketamine + Sirolimus | Quick Inventory of Depressive Symptoms (QIDS) | At 2 weeks | 9.1193 score on a scale | Standard Error 1.2 |
| Ketamine + Placebo | Quick Inventory of Depressive Symptoms (QIDS) | Pretreatment | 11.3942 score on a scale | Standard Error 1.4 |
| Ketamine + Placebo | Quick Inventory of Depressive Symptoms (QIDS) | At 2 weeks | 10.6699 score on a scale | Standard Error 1.3 |
Secondary
Rapamycin Level
Plasma level of rapamycin (a.k.a. sirolimus).
Time frame: During infusion, approximately 0 mins
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine + Sirolimus | Rapamycin Level | 26.5 ng/mL | Standard Error 2.4 |
| Ketamine + Placebo | Rapamycin Level | 0 ng/mL | Standard Error 0 |