Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects

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.

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.