Ketamine for Bipolar Disorder

(KET-BD Trial)

Recruiting at 2 trial locations

Overseen By Amer Burhan, MBChB, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Joshua Rosenblat

Must be taking: Mood stabilizers, Antipsychotics

Must not be taking: Benzodiazepines, Stimulants

Disqualifiers: Mania, Psychosis, Substance use, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 2 weeks

100 Participants Needed

Trial Summary

What is the purpose of this 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).

Will I have to stop taking my current medications?

You can continue taking your current mood stabilizer or antipsychotic medication as long as it hasn't changed in the last month. However, you must stop using certain medications like benzodiazepines, stimulants, and cannabis during the trial.

What data supports the effectiveness of the drug Ketamine Hydrochloride, Ketalar, Special K, Midazolam Hydrochloride, Midazolam, Versed for treating Bipolar Disorder?

Research shows that ketamine, when used with midazolam, is effective in improving mood disorders, with a significant effect size observed in studies. Additionally, the combination of ketamine and midazolam has been shown to improve cooperation and behavior in children during medical procedures, suggesting potential benefits in managing symptoms. ^{1 2 3 4 5}

Is ketamine safe for use in humans?

Research shows that ketamine, often used with midazolam, is generally safe for sedation and pain management in children, with few side effects that require minor or no intervention. ^{1 5 6 7 8}

How is ketamine different from other drugs for bipolar disorder?

Ketamine is unique for bipolar disorder because it acts rapidly to reduce depressive symptoms and suicidal thoughts, unlike traditional treatments that may take weeks to show effects. It is administered intravenously (through a vein), which allows for quick action, and is often used when other treatments have failed. ^{1 2 9 10 11}

Research Team

Joshua Rosenblat, MD, MSc

Principal Investigator

Toronto Western Hospital, Psychiatry

Eligibility Criteria

This trial is for adults aged 21-65 with moderate to severe bipolar depression that hasn't improved after trying at least two standard treatments. Participants must be on a stable medication regimen and not currently experiencing mania or psychosis. Pregnant or breastfeeding women, those with certain medical conditions, or recent substance abuse are excluded.

Inclusion Criteria

My bipolar depression hasn't improved after trying two or more recommended treatments.

I have been diagnosed with Bipolar I or II and am currently having a major depressive episode without experiencing psychosis.

Patient must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21.

Exclusion Criteria

I do not have allergies or health conditions that make ketamine or midazolam unsafe for me.

I am not using ketamine, benzodiazepines, MAOIs, stimulants, or any form of cannabis.

Lifetime history of ketamine use disorder

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive four repeated sub-anesthetic doses of IV ketamine or midazolam over two weeks

2 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety, effectiveness, and secondary outcomes such as suicidality and quality of life

4 weeks

Treatment Details

Interventions

• Ketamine Hydrochloride
• Midazolam Hydrochloride

Trial Overview The study tests if four doses of IV ketamine can safely reduce depression symptoms in treatment-resistant bipolar disorder (TRBD) patients compared to midazolam, a control drug. It's a phase II trial measuring the change in depression severity over two weeks and monitoring quality of life and suicidal thoughts.

Participant Groups

Group I: Ketamine Experimental Treatment 1 Intervention

Four 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.

Group II: Midazolam Active Control 1 Intervention

Four 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.

Who Is Running the Clinical Trial?

Joshua Rosenblat

Lead Sponsor

Trials

2

Recruited

160+

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Findings from Research

In a study involving 367 patients with mood disorders, ketamine demonstrated significant efficacy in improving clinical outcomes compared to both midazolam and saline, with effect sizes of 0.7 and 1.8 respectively, indicating strong therapeutic potential.

Using midazolam as a control in ketamine studies resulted in smaller observed effects of ketamine compared to using saline, suggesting that midazolam may enhance the perceived effectiveness of ketamine due to its own impact on mood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. Wilkinson, ST., Farmer, C., Ballard, ED., et al.[2021]

A systematic review of five randomized controlled trials involving 346 uncooperative children found that the combination of midazolam and ketamine was significantly more effective for sedation, achieving an 84% success rate compared to midazolam alone.

Children receiving the midazolam and ketamine combination exhibited calmer behavior (50%) compared to those receiving midazolam alone (37%), with only modest adverse effects that did not require special treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Evaluation of Ease of Dental Treatment and Clinical Efficiency of Midazolam vs Midazolam and Ketamine Combination for Sedation in Young Uncooperative Pediatric Patients: A Systematic Review. Rathi, GV., Padawe, D., Takate, V., et al.[2023]

In a study involving 41 healthy children under 36 months, the combination of oral midazolam and ketamine (MK) significantly improved cooperative behavior during dental treatment compared to midazolam alone (MS) or no sedation (PS).

No immediate or post-discharge side effects were observed in the groups receiving midazolam and ketamine, indicating that this sedation method is safe for young children undergoing dental procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined oral midazolam-ketamine better than midazolam alone for sedation of young children: a randomized controlled trial. Moreira, TA., Costa, PS., Costa, LR., et al.[2022]

In a study of 60 children aged 1-10 years requiring laceration repair, the combination of oral midazolam and ketamine provided deeper sedation compared to midazolam alone, as indicated by a higher Sedation Score.

The combination treatment also resulted in fewer children needing intravenous sedation (6% vs. 27%), while pain assessment during local anesthetic injection showed no significant difference between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, randomised, placebo-controlled trial of oral midazolam plus oral ketamine for sedation of children during laceration repair. Barkan, S., Breitbart, R., Brenner-Zada, G., et al.[2022]

A study involving 127 pediatric patients undergoing 295 procedures demonstrated that using ketamine and midazolam for anesthesia and sedation is effective and safe, with only nine minor complications reported.

The procedures were successfully performed outside the operating room by adult critical care practitioners, indicating that this combination can reduce anxiety and discomfort in children while maintaining a low risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sedation for pediatric procedures, using ketamine and midazolam, in a primarily adult intensive care unit: a retrospective evaluation. Slonim, AD., Ognibene, FP.[2019]

In a study involving 92 pediatric oncology patients undergoing 226 procedures, the combination of midazolam and ketamine was found to be safe and effective for managing pain, with no complications reported.

The treatment provided satisfactory analgesia in 89 out of 92 patients and induced brief unconscious sedation lasting an average of ten minutes, demonstrating its efficacy in a clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of intravenous ketamine-midazolam association for pain procedures in children with cancer. A prospective study. Pellier, I., Monrigal, JP., Le Moine, P., et al.[2022]

In a study involving 25 children undergoing 92 invasive procedures, midazolam and ketamine sedation achieved satisfactory sedation levels in 95.7% of cases, demonstrating its efficacy for painful procedures.

There was significant variability in the ketamine dosage needed for sedation among individuals, indicating that dosages should be carefully adjusted for each child to ensure safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inter- and intraindividual variability in ketamine dosage in repetitive invasive procedures in children with malignancies. Meyer, S., Aliani, S., Graf, N., et al.[2013]

A review of four studies involving children in emergency departments found that both ketamine and midazolam provide similar efficacy and safety for conscious sedation.

Despite their comparable profiles, ketamine is favored by both parents and physicians, suggesting a preference for its use in pediatric sedation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midazolam or ketamine for procedural sedation of children in the emergency department. Munro, A., Machonochie, I.[2018]

The study confirmed that intravenous solutions containing ketamine and midazolam remain stable and do not show significant concentration decrease over 100 hours, indicating their efficacy is maintained during this period.

Despite the stability observed, the authors recommend using the prepared intravenous solution within 24 hours to ensure optimal safety and effectiveness, as minor reactions could occur beyond this timeframe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemical compatibility of ketamine and midazolam in infusion solutions]. Lechner, MD., Kreuscher, H.[2013]

In a study of 13 patients with treatment-resistant bipolar depression, intravenous (IV) ketamine showed promising efficacy as an add-on treatment, with response and remission rates of 61.5% and 46.2% after seven infusions, respectively.

Ketamine was found to have a significant antisuicidal effect, with responders showing reduced suicidality, and the treatment was generally safe and well-tolerated, with no serious adverse events reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous Ketamine Infusions in Treatment-Resistant Bipolar Depression: An Open-Label Naturalistic Observational Study. Wilkowska, A., Włodarczyk, A., Gałuszko-Węgielnik, M., et al.[2022]

A pilot study involving 16 participants with bipolar depression indicated that a sub-anesthetic dose of ketamine (0.5 mg/kg) may lead to a greater reduction in suicidal ideation compared to midazolam, with a mean difference of nearly 6 points on the Scale for Suicidal Ideation, although this was not statistically significant.

The study found promising correlations between memory improvement and reduction in suicidal thoughts after ketamine infusion, as well as a decrease in serum brain-derived neurotrophic factor (BDNF) associated with reduced suicidal ideation, suggesting potential biomarkers for future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. Grunebaum, MF., Ellis, SP., Keilp, JG., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. [2021]

2. India pubmed.ncbi.nlm.nih.gov

Comparative Evaluation of Ease of Dental Treatment and Clinical Efficiency of Midazolam vs Midazolam and Ketamine Combination for Sedation in Young Uncooperative Pediatric Patients: A Systematic Review. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Combined oral midazolam-ketamine better than midazolam alone for sedation of young children: a randomized controlled trial. [2022]

4. England pubmed.ncbi.nlm.nih.gov

A double-blind, randomised, placebo-controlled trial of oral midazolam plus oral ketamine for sedation of children during laceration repair. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Sedation for pediatric procedures, using ketamine and midazolam, in a primarily adult intensive care unit: a retrospective evaluation. [2019]

6. France pubmed.ncbi.nlm.nih.gov

Use of intravenous ketamine-midazolam association for pain procedures in children with cancer. A prospective study. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Inter- and intraindividual variability in ketamine dosage in repetitive invasive procedures in children with malignancies. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Midazolam or ketamine for procedural sedation of children in the emergency department. [2018]

9. Germany pubmed.ncbi.nlm.nih.gov

[Chemical compatibility of ketamine and midazolam in infusion solutions]. [2013]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Intravenous Ketamine Infusions in Treatment-Resistant Bipolar Depression: An Open-Label Naturalistic Observational Study. [2022]

11. Denmark pubmed.ncbi.nlm.nih.gov

Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. [2022]