Action of Ketamine in Treatment-Resistant Depression

NCT01945047 | Completed Phase 2 DMC

• 1 other identifier: REB2012023
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

Depression carries the largest burden of all medical disorders in middle to high income countries, as determined by the World Health Organization. Despite many antidepressant strategies, only a third of patients get well after their first treatment and a third remain ill after several treatments. Moreover, antidepressant treatments all have a delayed action ranging up to several weeks. Ketamine (KET) has been used for decades as a sedative and anesthetic. In treatment-resistant depressed patients(TRD), an intravenous dose much lower than necessary for anesthesia may produce a robust antidepressant effect and may even abolish suicidal thoughts within hours, peaking within 24 hours. But, its antidepressant effect generally lasts only days.Previous studies examining KET in TRD have been critiqued for lack of an effective placebo measure due to brief perceptual experiences associated with KET. Thus, the current study compares KET against a short-acting sedative. The phases of this study compare response to a single KET injection to 6 injections over 2 weeks. Next, KET responders are given 1 injection a week for 3 weeks of either KET or the sedative agent to determine if beneficial effects of KET are maintained, and to assess duration of its benefits after repeated administration. The genetic profile of patients for a substance promoting contacts between cells and brain will be determined to investigate if response to KET could be predicted with that blood test. This substance, as well as several chemicals that produce inflammation, will also be measured in the blood to investigate their role in the effect of KET. Patients will receive, in total, no more than the equivalent of two to three anesthetic dose of KET. Results from this study will help establish the beneficial effects of a single KET injection as a rapid intervention for major depression, and to investigate the possibility of obtaining a prolonged antidepressant effect with repeated injections.

Conditions

Treatment-resistant Depression

Keywords

depression; treatment; ketamine; ottawa; treatment-resistant; infusion

Outcome Measures

Primary Outcomes (1)

• Efficacy of Ketamine over Midazolam in double blind study for efficacy of relief for Major Depressive Disorder

  Phase 1 double blind treatment with Ketamine or Midazolam then crossover. Will assess efficacy of each for relief of Major Depressive Symptoms through assessment using the HAMD17.

  2 weeks

Secondary Outcomes (2)

• Ketamine for use in relief of Major Depressive Disorder over repeated administration

  6 weeks

• To determine the role of genetic polymorphisms in the participants response to ketamine infusion

  2 weeks

Other Outcomes (2)

• Cortisol, melatonin, and inflammatory mediators will be assessed to examine changes occurring during treatment with ketamine

  8 weeks

• Effects of ketamine infusion compared to midazolam

  2 weeks

Study Arms (2)

Ketamine

EXPERIMENTAL

During Phase 1 patients will be randomly assigned to receive ketamine or active placebo.

Drug: Ketamine

Midazolam

ACTIVE COMPARATOR

In phase 1 patients will be randomized to receive active placebo

Drug: Midazolam

Interventions

Ketamine DRUG

Intravenous Bolus infusion Ketamine Hydrochloride 0.50 mg/mL over 40 minutes

Also known as: Ketamine Hydrochloride, Kevlar

Ketamine

Midazolam DRUG

Bolus infusion of Midazolam Hydrochloride 1 mg/mL over 40 minutes

Also known as: Midazolam Hydrochloride, Midazolam HCL

Midazolam

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 randomization, with no more than 20% improvement between these two visits.
• Female subjects 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).

You may not qualify if:

• Subjects with a diagnosis of DSM-IV Axis II disorder which has a major impact on the subject'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. infusions.
• Unwilling or able to hold benzodiazepines on the day prior and that of the 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 randomization), 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. Subjects 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.
• Subjects 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.

Sponsors & Collaborators

• University of Ottawa: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (1)

Institute of Mental Health Research, Royal Ottawa Hospital

Ottawa, Ontario, K1Z 7K4, Canada

Location

Related Publications (3)

• Phillips JL, Van Geel A, Burhunduli P, Vasudev D, Batten LA, Norris S, Talbot J, Ortiz A, Owoeye O, Blier P. Assessment of Objective and Subjective Cognitive Function in Patients With Treatment-Resistant Depression Undergoing Repeated Ketamine Infusions. Int J Neuropsychopharmacol. 2022 Dec 12;25(12):992-1002. doi: 10.1093/ijnp/pyac045.

  PMID: 35931041 DERIVED

• de la Salle S, Phillips JL, Blier P, Knott V. Electrophysiological correlates and predictors of the antidepressant response to repeated ketamine infusions in treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry. 2022 Apr 20;115:110507. doi: 10.1016/j.pnpbp.2021.110507. Epub 2021 Dec 28.

  PMID: 34971723 DERIVED

• Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, Owoeye O, Batten LA, Blier P. Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. Am J Psychiatry. 2019 May 1;176(5):401-409. doi: 10.1176/appi.ajp.2018.18070834. Epub 2019 Mar 29.

  PMID: 30922101 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Depression

Interventions

Ketamine; Midazolam

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Pierre Blier, M.D, Ph.D

  University of Ottawa

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Endowed Chair and Director of Mood Disorders Research Unit

Study Record Dates

• First Submitted: May 22, 2013
• First Posted: September 18, 2013
• Study Start: May 1, 2013
• Primary Completion: December 1, 2017
• Study Completion: December 1, 2017
• Last Updated: June 26, 2018

Record last verified: 2018-06

Locations

CA (1)