Clinical TrialBipolar DisorderKetaminePlaceboCompleted

Ketamine for Treatment-Resistant Bipolar Disorder

Phase II, double-blind, randomized, quadruple-masked RCT (n=72) testing four IV ketamine infusions (0.5–0.75 mg/kg over 40 minutes) versus midazolam (0.02–0.03 mg/kg) as adjunctive treatment for moderate to severe treatment-resistant bipolar depression.

Target Enrollment
72 participants
Study Type
Phase II interventional
Design
Randomized, quadruple Blind

Detailed Description

This two-site (University Health Network and Ontario Shores) phase II double-blind randomised trial evaluates four repeated sub-anaesthetic IV ketamine infusions versus active midazolam comparator for acute treatment of moderate to severe treatment-resistant bipolar disorder (types I and II).

Ketamine is given at 0.5 mg/kg for the first two infusions with flexible dosing to 0.75 mg/kg for infusions 3–4, each infused over 40 minutes; midazolam is dosed 0.02–0.03 mg/kg on the same schedule.

Primary outcome is change in MADRS score from baseline to day 14; secondary outcomes include response/remission rates, safety and tolerability (including treatment-emergent mania), suicidality, anxiety, quality of life, function and durability of effect to day 28.

Study Protocol

Preparation

sessions

Dosing

4 sessions
40 min each

Integration

sessions

Study Arms & Interventions

Ketamine

experimental

Four IV infusions over two weeks; first two at 0.5 mg/kg, infusions 3–4 flexibly dosed 0.5–0.75 mg/kg depending on response.

Interventions

  • Ketamine0.5 - 0.75 mg/kg
    via IV• four infusions over two weeks• 4 doses total

    Infused over 40 minutes; flexible dosing for infusions 3–4 (0.5–0.75 mg/kg).

Midazolam

active comparator

Four IV midazolam infusions over two weeks as active comparator; first two at 0.02 mg/kg, infusions 3–4 flexibly 0.02–0.03 mg/kg.

Interventions

  • Placebo0.02 - 0.03 mg/kg
    via IV• four infusions over two weeks• 4 doses total

    Midazolam hydrochloride 0.02–0.03 mg/kg infused over 40 minutes (active comparator; recorded under notes).

Participants

Ages
21 – 65
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria
  • 1. Provide written, voluntary informed consent prior to study enrollment. Substitute decision makers will not be allowed to consent to study on a potential patient's behalf.
  • 2. Male or female between the age of 21 to 65, inclusive.
  • 3. Meets DSM-5 criteria for Bipolar I or II Disorder, currently experiencing a Major Depressive Episode without psychotic features. Diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI) conducted by a delegated physician or trained research study while assessing eligibility.
  • 4. Patient must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21.
  • 5. Current depressive episode has inadequate response to two or more adequate first-line treatment trials for bipolar depression, as per the 2018 CANMAT Bipolar Disorder Guidelines. First line treatment trials include the use of lithium, valproate, carbamazepine, lamotrigine and/or any antipsychotic medication.
  • 6. Patient must be receiving guideline-concordant pharmacotherapy without changes in the last month, including a therapeutic dose of a guideline-concordant mood stabilizer/antipsychotic.

Exclusion Criteria

  • Exclusion Criteria
  • 1. Currently exhibiting symptoms of mania, hypomania, or mixed state bipolar, as determined by the Young Mania Rating Scale (YMRS) score greater than 12.
  • 2. Current symptoms of psychosis or a substance use disorder within the past 3 months. History of psychotic features during a mood episode will not be excluded.
  • 3. History of neurological disorders (including, but not limited to, uncontrolled seizure disorder, history of stroke within past 12 months, major head injuries, aneurysmal vascular disease [including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels], arteriovenous malformation, or intracerebral hemorrhage)
  • 4. Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder)
  • 5. Lifetime history of ketamine use disorder
  • 6. Presence of active suicidality, requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months.
  • 7. Presence of a contraindication to ketamine or midazolam, including a drug allergy, uncontrolled hypertension (baseline systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg), low or labile blood pressure, myocardial infarction within past 12 months, cardiac arrhythmia, moderate to severe hepatic impairment (i.e., Child-Pugh score of B or C), moderate or severe renal impairment (glomerular filtration rate (GFR) < 45 milliliters/min) , heart failure, or coronary artery disease
  • 8. Pregnant or breastfeeding women or women who intend to get pregnant. Patients who are sexually active must agree to use a highly effective contraceptive method (as outlined in section 5.11).
  • 9. Use of prohibited concomitant medications, including other forms of ketamine or esketamine, benzodiazepines, stimulants, alcohol, and medical or recreational cannabis taken during the trial at a specific prohibited time.
  • 10. Use of ketamine in the 30 days leading up to the patient's entry in the trial.
  • 11. Use of monoamine oxidase inhibitors (MAOIs) at least two weeks prior to receiving study treatment.

Study Details

  • Status
    Completed
  • Phase
    Phase II
  • Type
    interventional
  • Design
    Randomizedquadruple Blind
  • Target Enrollment72 participants
  • Timeline
    Start: 2022-04-30
    End: 2024-12-31
  • Compounds
    KetaminePlacebo
  • Topic
    Bipolar Disorder

Locations

Toronto General Hospital — Toronto, Ontario, Canada
Toronto Western Hospital — Toronto, Ontario, Canada
Ontario Shores Centre for Mental Health Sciences — Whitby, Ontario, Canada

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