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

72 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether ketamine, an anesthetic, can alleviate depressive symptoms in individuals with bipolar disorder who haven't found relief with other treatments. It examines the effectiveness and safety of repeated ketamine doses, administered through an IV, in reducing depression and improving quality of life. The trial compares ketamine to midazolam to determine which is more effective. Suitable participants have bipolar I or II disorder and currently experience moderate to severe depression despite trying at least two other treatments. As a Phase 2 trial, this research measures ketamine's effectiveness in an initial, smaller group, exploring new treatment possibilities.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ketamine can be a safe and effective treatment for bipolar disorder. Studies have found that ketamine is usually well-tolerated when used for treatment-resistant bipolar disorder (TRBD), with most side effects being mild and resolving on their own.

However, some safety concerns exist, including the risk of misuse, potential increases in blood pressure, and changes in mood or behavior. Despite these concerns, ketamine is often seen as promising because it can quickly improve depression symptoms.

Prospective trial participants should understand both the benefits and risks. Discuss with a healthcare provider to determine if it’s the right choice. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for bipolar disorder?

Unlike the standard treatments for bipolar disorder, which often include mood stabilizers and antipsychotics, ketamine works differently by targeting the brain's NMDA receptors. This action can lead to rapid mood improvements, sometimes within hours, which is a significant departure from traditional medications that can take weeks to show effects. Researchers are excited about ketamine because it offers the potential for fast relief from depressive symptoms, providing hope for individuals who struggle with the delayed effects of conventional treatments.

What evidence suggests that this trial's treatments could be effective for bipolar disorder?

Studies have shown that ketamine can significantly reduce symptoms of depression in people with bipolar disorder. In this trial, participants in the ketamine arm will receive four infusions over two weeks, with doses adjusted based on clinical response. One study reported a 6.08-point drop in depression symptoms on a commonly used scale after repeated ketamine treatments. Research also suggests that ketamine can decrease suicidal thoughts in people with bipolar depression. These studies have reported that ketamine is well-tolerated, with no serious side effects. While more research is needed specifically for bipolar disorder, these findings suggest ketamine could be a promising treatment option. ^{4 5 6 7 8}

Who Is on the Research Team?

Joshua Rosenblat, MD, MSc

Principal Investigator

Toronto Western Hospital, Psychiatry

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10296406/

The Role of Ketamine in the Treatment of Bipolar Depression There was an estimated decrease of 5.84 points on SSI at day 1 for patients on ketamine compared to the midazolam group (p = 0.074). Similar results were ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0165032725019081

Oral ketamine for the treatment of major depressive and ... Treatment was well-tolerated, with no serious adverse events reported, potentially due to the lower exposure to ketamine compared to its ...

3. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.focus.23021022

Real-World Effectiveness of Repeated Ketamine Infusions ... We observed a clinically and statistically significant reduction in depressive symptoms (6.08±1.39 point reduction in QIDS-SR16 score) following ...

4. journals.sagepub.com journals.sagepub.com/doi/10.1177/20451253231202723

Ketamine for bipolar depression: an updated systematic ... This systematic review aimed to summarize findings on the use of ketamine for the treatment of BD by assessing its efficacy, safety, and tolerability.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01944293

Ketamine for Suicidality in Bipolar Depression Change in suicidal ideation in Bipolar Disorder during a Major Depressive Episode (MDE), with moderate to severe suicidal thoughts, from the pre-infusion ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10524067/

Ketamine for bipolar depression: an updated systematic review Based on the analysis of the eight included studies, our results suggest that IV ketamine is a promising, safe, and effective treatment option for BD and TRBD.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7073997/

Safety and Tolerability of Ketamine Use in Treatment ... The literature shows that treatment with ketamine is efficacious and safe, and the majority of adverse drug reactions are mild and tend to mostly disappear ...

8. fda.gov fda.gov/drugs/human-drug-compounding/fda-warns-patients-and-health-care-providers-about-potential-risks-associated-compounded-ketamine

FDA warns about compounded ketamine for psychiatric ... Known safety concerns associated with the use of ketamine products include abuse and misuse, psychiatric events, increases in blood pressure, ...