Clinical TrialTreatment-Resistant Depression (TRD)KetaminePlaceboKetaminePlaceboCompleted

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.

Target Enrollment
23 participants
Study Type
Phase II interventional
Design
Randomized, triple Blind

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

sessions

Dosing

2 sessions
40 min each

Integration

sessions

Study Arms & Interventions

Ketamine + Sirolimus

experimental

Two ketamine infusions (one with sirolimus, one with placebo) in a randomized crossover.

Interventions

  • Ketamine0.5 mg/kg
    via IV• two sessions• 2 doses total

    Infusion over ~40 minutes; one infusion paired with sirolimus, the other with placebo.

  • Compound6 mg
    via Oral• single dose• 1 doses total

    Sirolimus 6 mg oral ~2 hours prior, given in 6 oz orange juice.

  • Placebo
    via Oral• single dose• 1 doses total

    Placebo oral dose matching sirolimus; given in 6 oz orange juice.

Ketamine + Placebo

inactive

Crossover comparator: ketamine infusion paired with placebo at one timepoint and sirolimus at the other.

Interventions

  • Ketamine0.5 mg/kg
    via IV• two sessions• 2 doses total

    Infusion over ~40 minutes.

  • Compound6 mg
    via Oral• single dose• 1 doses total

    Sirolimus 6 mg oral ~2 hours prior, given in 6 oz orange juice.

  • Placebo
    via Oral• single dose• 1 doses total

    Placebo oral dose matching sirolimus; given in 6 oz orange juice.

Participants

Ages
21 – 65
Sexes
Male & Female

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.

Study Details

Locations

Yale New Haven Hospital — New Haven, Connecticut, United States
West Haven Veterans Affairs — West Haven, Connecticut, United States

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