Examining the Impact of Sirolimus on Ketamine’s Antidepressant Effects
Randomised, triple-blind, placebo-controlled crossover trial (n=23) testing whether a single 6 mg oral dose of sirolimus alters the antidepressant response to two ketamine infusions (0.5 mg/kg IV over ~40 minutes) in participants with antidepressant-resistant depressive symptoms.
Detailed Description
This double-blind, randomized crossover study (n=23) evaluates whether sirolimus (6 mg oral) modifies the acute and short-term antidepressant effects of ketamine (0.5 mg/kg IV infused over ~40 minutes), with each participant receiving two ketamine infusions separated by two weeks.
Primary population includes adults 21–65 with antidepressant-resistant major depressive episodes; outcomes include MADRS change and safety/tolerability, with sirolimus/placebo administered ~2 hours prior to infusions.
Study Protocol
Preparation
Dosing
Integration
Study Arms & Interventions
Ketamine + Sirolimus
experimentalTwo ketamine infusions (one with sirolimus, one with placebo) in a randomized crossover.
Interventions
- Ketamine0.5 mg/kgvia IV• two sessions• 2 doses total
Infusion over ~40 minutes; one infusion paired with sirolimus, the other with placebo.
- Compound6 mgvia Oral• single dose• 1 doses total
Sirolimus 6 mg oral ~2 hours prior, given in 6 oz orange juice.
- Placebovia Oral• single dose• 1 doses total
Placebo oral dose matching sirolimus; given in 6 oz orange juice.
Ketamine + Placebo
inactiveCrossover comparator: ketamine infusion paired with placebo at one timepoint and sirolimus at the other.
Interventions
- Ketamine0.5 mg/kgvia IV• two sessions• 2 doses total
Infusion over ~40 minutes.
- Compound6 mgvia Oral• single dose• 1 doses total
Sirolimus 6 mg oral ~2 hours prior, given in 6 oz orange juice.
- Placebovia Oral• single dose• 1 doses total
Placebo oral dose matching sirolimus; given in 6 oz orange juice.
Participants
Inclusion 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 utilise 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
- 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.
Primary Results(1 publication)
Participants
Adverse Events (from all publications)
| Arm / Group | n | Any TEAE | Severe | Serious | Discont. |
|---|---|---|---|---|---|
| Ketamine + Sirolimusexperimental | 20 | — | — | 0(0.0%) | 0(0.0%) |
| Ketamine + Placeboinactive | 20 | — | — | 0(0.0%) | 1(5.0%) |
* Safety data is for the cross-over study. nAtRisk is the total number of participants who received this treatment. No participant counts for 'any TEAE' per arm are explicitly provided, only event counts in Table S2. Adverse events were described as 'mostly mild and transient', so severe TEAE count is not explicitly zero.
* Safety data is for the cross-over study. nAtRisk is the total number of participants who received this treatment. No participant counts for 'any TEAE' per arm are explicitly provided, only event counts in Table S2. One patient was discontinued due to worsening of symptoms in the placebo session. Adverse events were described as 'mostly mild and transient', so severe TEAE count is not explicitly zero.
Study Details
- StatusCompleted
- PhasePhase II
- Typeinterventional
- DesignRandomizedtriple Blind
- Target Enrollment23 participants
- TimelineStart: 2016-01-03End: 2020-01-01
- Compounds
- Topic
Study Team
Sponsors & Collaborators
- Yale UniversityPrimary Sponsor