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Bipolar DisorderPhase 2KET-BDNCT05004896

Ketamine for Treatment-Resistant Bipolar Disorder

A Phase 2 study testing Ketamine Hydrochloride and Midazolam Hydrochloride in people with Bipolar Disorder and Bipolar Depression, run by Joshua Rosenblat at 3 sites in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Growing evidence has supported rapid and robust antidepressant effects with subanesthetic doses of intravenous (IV) ketamine for treatment resistant depression (TRD). However, no completed or ongoing randomized control trials (RCTs) have evaluated the effects of repeated doses of IV ketamine for a homogenous sample of… Read more about this study

Who is it for?
Ages 21 to 65 years
What is being tested?
Ketamine Hydrochloride and Midazolam Hydrochloride
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
71 participants
Where
3 sitesCanada
Study dates
4 Jul 2022to 14 Nov 2025
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • Male or female between the age of 21 to 65, inclusive.
  • 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.
  • Patient must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21.
  • 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.
  • Patient must be receiving guideline-concordant pharmacotherapy without changes in the last month, including a therapeutic dose of a guideline-concordant mood stabilizer/antipsychotic.

Who cannot join

  • Currently exhibiting symptoms of mania, hypomania, or mixed state bipolar, as determined by the Young Mania Rating Scale (YMRS) score greater than 12.
  • 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.
  • 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)
  • Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder)
  • Lifetime history of ketamine use disorder
  • Presence of active suicidality, requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months.
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  • 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
  • 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).
  • 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.
  • Use of ketamine in the 30 days leading up to the patient's entry in the trial.
  • Use of monoamine oxidase inhibitors (MAOIs) at least two weeks prior to receiving study treatment.

Trial locations and contacts

3 sites in 1 country.

Canada3 sites

  • Toronto General Hospital

    Toronto, Ontario, M5G 2C4

  • Toronto Western Hospital

    Toronto, Ontario, M5T 2S8

  • Ontario Shores Centre for Mental Health Sciences

    Whitby, Ontario, L1N 5S9

Other trials in Canada

About this study

Official title: Repeated Ketamine Infusions for Treatment-Resistant Bipolar Disorder: A Randomized, Double-blind, Midazolam-controlled, Phase II Clinical Trial

Growing evidence has supported rapid and robust antidepressant effects with subanesthetic doses of intravenous (IV) ketamine for treatment resistant depression (TRD). However, no completed or ongoing randomized control trials (RCTs) have evaluated the effects of repeated doses of IV ketamine for a homogenous sample of patients with treatment-resistant bipolar disorder (TRBD). The primary research goal is to determine the acute antidepressant efficacy, safety and tolerability of four repeated sub-anesthetic doses of IV ketamine in moderate to severe TRBD. Secondary aims include evaluating effects of IV ketamine on suicidal ideations, quality of life, function and duration of effects. Herein, a two-site (University Health Network and Ontario Shores Centre for Mental Health Sciences), phase II, double-blinded, midazolam-controlled, two-week RCT evaluating the efficacy, safety and tolerability of four flexibly-dosed adjunctive ketamine infusions (0.5-0.75mg/kg infused over 40 minutes) for acute treatment of moderate to severe TRBD (type I \& II) is proposed. The primary outcome will be Montgomery-Åsberg Depression Rating Scale (MADRS) scores, determining the between group difference in change from baseline to day 14, using analysis of covariance (ANCOVA), with 14-day MADRS as the outcome and baseline MADRS and stratification variables (sex, bipolar type) as covariates. Secondary outcomes include evaluating response and remission rates, safety, tolerability (including treatment-emergent mania), and effects on suicidality, anxiety, quality of life, function and the duration of effects (to day 28).

Being tested
Ketamine Hydrochloride, Midazolam Hydrochloride
Medical subject headings
Bipolar Disorder

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ketamine HydrochlorideDrug

    36 patients will receive ketamine hydrochloride, over four infusions, flexibly dosed between 0.5 mg/kg to 0.75 mg/kg

  • Midazolam HydrochlorideDrug

    36 patients will receive midazolam hydrochloride, over four infusions, flexibly dosed between 0.02 mg/kg to 0.03 mg/kg

Study groups in NCT05004896
Study groupRoleWhat they receive
KetamineExperimentalFour infusions of ketamine will be administered over two weeks. The first two infusions will be dosed at 0.5mg/kg over a period of 40 minutes. For infusions 3 and 4, patients will be flexibly dosed between 0.5 mg/kg to 0.75 mg/kg, depending on clinical response to first two infusions.
Receives: Drug: Ketamine Hydrochloride
MidazolamActive comparatorFour infusions of midazolam will be administered over two weeks. The first two infusions will be dosed at 0.02mg/kg over a period of 40 minutes. For infusions 3 and 4, patients will be flexibly dosed between 0.02 mg/kg to 0.03 mg/kg, depending on clinical response to first two infusions.
Receives: Drug: Midazolam Hydrochloride

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in depression severity using the Montgomery Asberg Depression Rating Scale (MADRS)

    The MADRS is a clinician-rated scale measuring depression severity. It consists of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60. A higher score is indicative of greater depressive severity. Response rates are defined as > 50% decrease and Remission ≤ 12 actual score.

    Measured: 4 weeks

Secondary outcomes (5)

  1. Recruitment and Retention Rate

    The feasibility of ketamine as a treatment in bipolar disorder will be measured by recruitment and retention rates.

    Measured: 4 weeks

  2. Treatment-Emergent Adverse Events

    Treatment-emergent adverse events will be assessed using patient-reported adverse events.

    Measured: 4 weeks

  3. Suicidality

    Suicidality will be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS) which is a clinical assessment used to assess suicidal ideation and suicidal behaviour. It measures the incidence of suicidality via "yes" or "no" questions as well as the severity of suicidal ideation if present on a scale of 1 to 5 with 5 being the most severe.

    Measured: 4 weeks

  4. Treatment-Emergent Mania

    Treatment-emergent mania will be assessed using the Young Mania Rating Scale (YMRS) which is a clinical assessment used to evaluate manic symptoms and their severity. It consists of 11 items with a maximum possible score of 60, with higher scores indicating more severe manic symptoms.

    Measured: 4 weeks

  5. Quality of Life (QOL)

    Quality of life will be assessed using the Quality of Life-BD (QOL.BD) scale, which contains 56 questions over 12 domains. It uses a 5-component scale that evaluates mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. This scale is numbered from 56 to 280, 280 indicating a high quality of life, while 56 denotes a low quality of life.

    Measured: 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Aug 2021
  2. Study start4 Jul 2022
  3. Primary completion14 Nov 2025
  4. Study completion14 Nov 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
71 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05004896
Sponsor's protocol ID
21-5560
Acronym
KET-BD
Status last verified
Mar 2026
First submitted
6 Aug 2021
Last updated
5 Mar 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Orsini DK, Di Luch S, Tomlinson G, Lovell GFM, Vasudeva S, Rodrigues NB, Johnson DE, Flint AJ, Llach CD, McIntyre RS, Mansur RB, Karkouti K, Burhan AM, Kaczmarek E, Chisamore N, Bhatia A, Soneji N, Joshi A, Grewal D, Laframboise R, Rosenblat JD. Serial Ketamine Infusions for Treatment-Resistant Bipolar Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2026 Sep 2:e262658. doi: 10.1001/jamapsychiatry.2026.2658. Online ahead of print.

    PubMed 42684694

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ketamine Hydrochloride and Midazolam Hydrochloride in people with Bipolar Disorder and Bipolar Depression, run by Joshua Rosenblat at 3 sites in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in depression severity using the Montgomery Asberg Depression Rating Scale (MADRS) (time frame: 4 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05004896, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Mar 2026.

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