| Participants |
Inclusion criteria
Only participants from the Ottawa area will be considered Provision of written informed consent before initiation of any study‐ related procedures Documented primary Axis I clinical diagnosis meeting criteria from the DSM‐IV13 for MDD, as confirmed by the MINI.98 Failure to respond adequately to at least two antidepressant medication trials and two augmentation strategies. One augmentation strategy may include a noradrenergic dose of venlafaxine (225 mg/day) or duloxetine (120 mg/day), given their dual mechanism of action99,100 and a 12‐week cognitive behavioural or interpersonal therapy MADRS total score of ≥ 25 at screening and randomisation, with no more than 20% improvement between these two visits Female participants of childbearing potential must have a negative urine pregnancy test at enrolment (Visit 1) and be willing to use a reliable method of birth control (i.e., double‐barrier method, oral contraceptive, implant, dermal contraception, long‐term injectable contraceptive, intrauterine device, or tubal ligation) during the study Abstain from consuming grapefruit juice (a potent 3A4 cytochrome inhibitor) on the day of the infusions as it may slow down the elimination of midazolam and possibly ketamine Be able to understand and comply with the requirements of the study, as judged by the investigator(s)
Exclusion criteria
Particpants with a diagnosis of DSM‐IV Axis II disorder which has a major impact on the participant's current psychiatric status Depression secondary to stroke, cancer or other severe medical illnesses Prior or current substance or alcohol abuse or dependence (except for caffeine or nicotine dependence), as defined in DSM‐IV criteria A positive drug screen Unwilling to maintain their current antidepressant regimen Unwilling or able to hold benzodiazepines on the day prior and that of the infusion. Unwilling to discontinue any narcotic for a minimum of 5 drug half‐lives prior to infusions Pregnant or lactating, or is of childbearing potential and not willing to use an approved method of contraception during the study Evidence of clinically relevant disease, e.g., renal or hepatic impairment, significant coronary artery disease (myocardial infarct within a year prior to initial randomisation), cerebrovascular disease, viral hepatitis B or C, acquired immunodeficiency syndrome A clinical finding that is unstable or that, in the opinion of the investigator(s), would be negatively affected by the study medication or that would affect the study medication (e.g., diabetes mellitus, hypertension, unstable angina) Liver function tests AST and ALT three times the upper normal limit at screening Uncorrected hypothyroidism or hyperthyroidism. Particpants needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for 30 days prior to enrolment (Visit 1) Clinically significant deviation from the reference range in clinical laboratory test results as judged by the investigator(s) ECG results considered clinically significant as determined by the investigator(s) History of seizure disorder, except febrile convulsions Particpants who in the investigator(s) opinion will require psychotherapy (other than supportive psychotherapy) during the study period, unless psychotherapy has been ongoing for a minimum of 2 months prior to Visit 2 Known history of intolerance or hypersensitivity to ketamine or midazolam Any other condition that, in the opinion of the investigator(s) would adversely affect the participant
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