Ketamine maintenance treatment for depression: A multicenter open-label randomized controlled trial (PreKET)

This Phase II, multicentre, open-label randomised controlled trial (n=230) will evaluate the long-term efficacy and safety of intravenous ketamine maintenance treatment in adults with treatment-resistant depression (TRD) and a current moderate or severe depressive episode. The primary outcomes are time to relapse after the induction phase and after the final ketamine infusion, assessed using clinician-rated Montgomery–Åsberg Depression Rating Scale (MADRS) scores. Participants will be allocated to monthly ketamine infusions for either 4 or 8 months, or to treatment as usual (TAU) after an initial dose-finding period. Ketamine hydrochloride will be administered by infusion, with a maximum daily dose of 150 mg and maximum total dose of 2700 mg. All participants will be followed for 14 months, with the ketamine groups receiving site-based follow-up after treatment; secondary objectives include assessing the durability of antidepressant effects, safety, and the dose- and duration-related efficacy of ketamine. Shop with Us..

Detailed Description

To examine the long-term efficacy of maintenance therapy with IV ketamine following induction treatment of treatment-resistant depression (TRD).

Study Arms & Interventions

Ketamine 150 mg (8 monthly treatments)

experimental

Monthly ketamine treatments for 8 months, followed by site visits for follow-up purposes for 6 months; a total of 14 months.

Interventions

• Ketamine150 mgvia IV• monthly for 8 months• 8 doses total

Ketamine 150 mg (4 monthly treatments)

experimental

Monthly ketamine treatments for 4 months, followed by site visits for follow-up purposes for 10 months; a total of 14 months.

Interventions

• Ketamine150 mgvia IV• monthly for 4 months• 4 doses total

Treatment as usual

active comparator

Site visits for follow-up purposes for 14 months after the initial dose finding period.

Participants

Ages

18 – ?

Sexes

Male & Female

BMI

–

Psychosis History

–

Inclusion Criteria

• ● Are fluent in spoken and written Norwegian.
• ● Able to provide informed consent to participate in the current study. This may include involuntarily hospitalized patients
• ● Male or female adults aged 18 years or older
• ● Meet DSM-5 criteria for MDD or bipolar-2 disorder as assessed by the MINI version 7.0.2
• ● Have a current MDE of at least moderate severity defined by a Montgomery-Åsberg Depression Rating Scale (MADRS) score of ≥ 20
• ● Meet criteria for treatment-resistant depression, defined by previous treatment for depression included a minimum of two evidence-based treatments (psychopharmacology, psychotherapy, ECT/TMS) without adequate response, in accordance with Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of unipolar or bipolar depression
• ● Women of childbearing potential (WOCBP) as defined in Section 10.4.1 must have a negative pregnancy test at study entry and prior to maintenance ketamine infusion and must agree to use adequate birth control through the last ketamine infusion.
• Only highly effective contraception methods are permitted in this trial. See Section 10.6.2 Contraception guidelines for a list of these methods.

Exclusion Criteria

• ● Women who intend to become pregnant or are breast-feeding
• ● Chronic respiratory failure (requiring LTOT and/or GOLD 3 (severe) or higher)
• ● Obstructive or central sleep apnoea requiring treatment with oxygen, CPAP/BiPAP
• ● Pregnant women as assessed by blood HCG tests
• ● Glaucoma or globe injury
• ● Previous anaphylactic reaction to ketamine
• ● Uncontrolled hypo- or hyperthyroidism
• ● Current or suspected increased intracranial pressure
• ● Acute intermittent porphyria
• ● Any other severe medical or neurological condition that, in the investigator’s judgement, may interfere with the interpretation of the study results or pose a health risk to the participant.
• ● Any use of medication deemed by the trial medical professionals to pose a risk when combined with ketamine or likely to interfere with the study results, and that the participant is unwilling or unable to discontinue before enrolment
• ● Ongoing or previous manic episodes
• ● Electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are not permitted within four weeks prior to enrollment or during the trial.
• ● Ketamine treatment within 6 months preceding enrollment
• ● Not able to provide informed consent to participate in clinical research
• ● BMI under 16 or over 35 or body weight over 150 kg
• ● Outpatients with acute suicide risk as assessed by clinician’s examination
• ● Hospitalized patients with acute suicide risk, unless enrollment doesn’t interfere with clinical security procedures per investigator’s judgement
• ● Ongoing psychotic symptoms unless exclusively explained by the current depressive episode
• ● Ongoing hypomanic episode
• Known hypersensitivity to any ingredients of ketamine
• ● History of any psychotic or bipolar type 1 disorder as assessed by the Mini International Neuropsychiatric Interview (MINI v. 7.0.2)
• ● History of severe personality disorder, severe dissociative disorder, severe obsessive-compulsive disorder, autism-spectrum disorder, or other psyciatric comorbidities, assessed through MINI and/or medical history, that may interfere with the interpretation of the study results or pose a health risk to the participant per investigator’s judgement
• ● Current eating disorder with active purging as assessed by MINI
• ● Current or past severe substance/alcohol use disorder (according to DSM-5 criteria) or substance/alcohol use that, in the investigator’s judgment, may compromise participant safety, study integrity, or compliance with study procedures
• ● Cardiovascular conditions: Heart failure (NYHA class III or IV), recent stroke (< 1 year from enrollment), recent myocardial infarction (< 1 year from enrollment), uncontrolled hypertension (>160/100 mm Hg) or recent clinically significant arrhythmia (< 1 year from enrolment)
• ● Liver failure (Child-Pugh Class C) or impairment of liver function as assessed by medical history, clinical examination and laboratory results at screening (i.e. INR > 1,2 or bilirubin > 30 μmol/L)
• ● Kidney failure (creatinine clearance < 30 mL/min by Cockcroft-Gault)