Ketamine for Treatment-Resistant Bipolar Depression

(KET-BD-Sustain Trial)

Recruiting at 3 trial locations

Overseen By Amer Burhan, MBChB, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Joshua Rosenblat

Must be taking: Mood stabilizers

Must not be taking: Benzodiazepines, MAOIs, Cannabis

Disqualifiers: Mania, Psychosis, Neurological disorders, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 12 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether ketamine, an anesthetic, can aid individuals with bipolar depression who haven't found relief from other treatments. Researchers aim to determine if repeated ketamine doses can safely and effectively reduce depression symptoms over 12 weeks. Participants will receive ketamine infusions on a flexible schedule to find the optimal balance between benefits and side effects. This trial targets those with bipolar disorder who are currently depressed despite trying at least two standard treatments and have responded well to ketamine in a previous study phase. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you continue taking your current mood stabilizer medication without changes for at least a month before starting. However, you cannot use certain medications like benzodiazepines, monoamine oxidase inhibitors, stimulants, or cannabis during the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that ketamine can be effective and safe for treating depression that resists regular treatments. Most side effects are mild and typically resolve on their own. Studies have found that ketamine works quickly and might help those with bipolar depression, although the evidence remains in the early stages.

The use of ketamine for treatment-resistant cases has been studied, with some early support for its safety and tolerability. This suggests that people generally handle the treatment well, even if the evidence isn't yet robust. Some studies have examined ketamine's impact on mood and found it could be beneficial without causing major safety issues.

In summary, ketamine shows promise as a treatment, with most side effects being mild and temporary. However, as the evidence is still developing, it is important to consider all information before deciding to join a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for treatment-resistant bipolar depression, like antidepressants and mood stabilizers, can take weeks to show effectiveness and often don't work for everyone. But ketamine hydrochloride works differently, targeting NMDA receptors in the brain to provide rapid relief from depressive symptoms, often within hours or days. This quick action is a game-changer, offering hope for those who haven't found success with traditional medications. Additionally, ketamine is administered via infusion, allowing for precise dosing and monitoring, which can be adjusted for optimal benefits with minimal side effects. Researchers are excited about this treatment because it represents a potential breakthrough for individuals struggling with this challenging condition.

What evidence suggests that ketamine might be an effective treatment for treatment-resistant bipolar depression?

Previous studies have shown that ketamine significantly reduces symptoms of depression in people with bipolar disorder. For example, one study found that taking ketamine multiple times led to a greater reduction in symptoms. Another study highlighted that weekly use of ketamine could maintain its antidepressant effects and improve health outcomes. The Montgomery-Åsberg Depression Rating Scale (MADRS), a tool for measuring depression, also showed significant improvement, supporting ketamine's potential effectiveness. Additionally, ketamine has reduced suicidal thoughts, providing extra help for those with severe depression. In this trial, participants will receive open-label ketamine infusions on a flexible schedule to optimize benefits, suggesting that ketamine can effectively manage symptoms of treatment-resistant bipolar depression. ^{2 6 7 8 9}

Who Is on the Research Team?

Joshua Rosenblat, MD, MSc

Principal Investigator

Toronto Western Hospital, Psychiatry

Are You a Good Fit for This Trial?

Adults aged 21-65 with treatment-resistant bipolar depression, who've had no medication changes in the last month and are on a mood stabilizer. They must have participated in an earlier trial phase, responding well to ketamine or still depressed after midazolam control. No recent manic episodes, uncontrolled blood pressure, heart issues, severe liver/renal impairment, pregnancy/breastfeeding without contraception use, certain drug allergies or substance misuse.

Inclusion Criteria

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

I was in the ketamine study for depression and either got much better or my symptoms mostly went away.

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

Exclusion Criteria

Lifetime history of ketamine use disorder

Presence of active suicidality, requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months.

I have not had major neurological issues or strokes in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive open-label ketamine infusions on a flexible schedule to maintain antidepressant effects

12 weeks

Every 2-4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants continue to receive ketamine infusions to maintain antidepressant effects

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine Hydrochloride

Trial Overview The study tests maintenance doses of IV Ketamine Hydrochloride over twelve weeks for those with bipolar depression not improved by standard treatments. Participants receive flexible dosing every 2-4 weeks after showing initial improvement from previous infusions. The focus is on sustained antidepressant effects and impact on quality of life and suicidal thoughts.

How Is the Trial Designed?

Group I: Ketamine Experimental Treatment 1 Intervention

Open-label ketamine infusions will be provided on a flexible schedule (every 2-4 weeks) with flexible dosing (0.5-1.0mg/kg over 40 minutes) titrated to optimize benefits, while minimizing the dosage and frequency over a 12-week extension period

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

In a study of 203 patients with treatment-resistant depression receiving repeat-dose IV ketamine, the treatment was found to be safe and well-tolerated, with less than 5% of patients withdrawing due to tolerability issues.

While transient hypertension occurred in 44.3% of patients during infusion, and some required medication to manage it, no serious psychiatric side effects like psychosis or new onset suicidality were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of IV ketamine in adults with major depressive or bipolar disorder: results from the Canadian rapid treatment center of excellence. Rodrigues, NB., McIntyre, RS., Lipsitz, O., et al.[2021]

In a study of 19 patients with treatment-resistant bipolar depression, repeated ketamine infusions (0.5 mg/kg) led to a significant increase in response rates from 21.1% after the first infusion to 73.7% after the sixth infusion, indicating its potential efficacy as a rapid antidepressant.

The treatment was well-tolerated, with no significant increases in dissociative or psychotic symptoms, suggesting that repeated ketamine infusions at subanaesthetic doses are a safe option for managing severe depressive symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A preliminary study of adjunctive ketamine for treatment-resistant bipolar depression. Zheng, W., Zhou, YL., Liu, WJ., et al.[2021]

In a study involving 16 patients with treatment-resistant bipolar depression, six intravenous infusions of ketamine led to a significant improvement in speed of processing, primarily linked to reductions in depression symptoms.

The study found that patients with lower working memory at baseline experienced a greater antidepressant response to ketamine, suggesting that cognitive function may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurocognitive effects of six ketamine infusions and the association with antidepressant effects in treatment-resistant bipolar depression: a preliminary study. Zheng, W., Zhou, YL., Wang, CY., et al.[2022]

In a study of 201 adults with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD), intravenous (IV) ketamine significantly reduced symptoms of anxiety, irritability, and agitation in those with mixed features, indicating its effectiveness in treating these symptoms.

Participants with anxiety, irritability, and agitation (AIA) experienced greater reductions in overall depressive symptoms and suicidal ideation compared to those without AIA, suggesting that IV ketamine could be a rapid treatment option for adults with mood disorders presenting with mixed features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectiveness of ketamine on anxiety, irritability, and agitation: Implications for treating mixed features in adults with major depressive or bipolar disorder. McIntyre, RS., Lipsitz, O., Rodrigues, NB., et al.[2021]

Approximately 30% of patients with depression experience treatment-resistant depression, which worsens with each episode and significantly impacts quality of life.

Ketamine, a rapid-acting antidepressant with neuroplastic effects, may serve as an effective add-on treatment for resistant major depressive disorder, potentially reversing treatment resistance and improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine. Wilkowska, A., Cubała, WJ.[2022]

In a study of 66 patients with treatment-resistant bipolar depression, repeated intravenous ketamine infusions led to significant reductions in depressive symptoms, with an average decrease of 6.08 points on the Quick Inventory for Depression Symptomatology-Self Report-16 scale after four infusions.

The treatment was generally well tolerated, with only 4.5% of patients experiencing treatment-emergent hypomania, and no cases of mania or psychosis, indicating a favorable safety profile for ketamine in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. Fancy, F., Rodrigues, NB., Di Vincenzo, JD., et al.[2023]

Ketamine hydrochloride has shown rapid and significant antidepressant effects in patients with treatment-resistant mood and anxiety disorders, although the studies supporting this have small sample sizes and limited long-term data.

While ketamine may offer benefits for some patients, there are important safety concerns and limitations in the existing research that must be considered when using it as an off-label treatment for psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. Sanacora, G., Frye, MA., McDonald, W., 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]

In a study involving 97 participants with treatment-resistant depression, ketamine infusions showed a 67% response rate, indicating significant antidepressant effects.

The treatment was found to be safe and well-tolerated, with only a 3.1% attrition rate and no cases of persistent adverse effects, although some participants experienced temporary side effects like drowsiness and dissociation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine safety and tolerability in clinical trials for treatment-resistant depression. Wan, LB., Levitch, CF., Perez, AM., et al.[2022]

Ketamine and esketamine are promising new treatments for adults with treatment-resistant depression, showing rapid-onset efficacy that differs from traditional monoamine-based antidepressants.

Despite their potential benefits, there are ongoing concerns regarding the safety and tolerability of these treatments, as well as uncertainties about their optimal use in clinical practice and the necessary infrastructure for safe administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. McIntyre, RS., Rosenblat, JD., Nemeroff, CB., et al.[2022]

Low-dose intravenous (IV) ketamine has been shown to be effective in the short term for patients with treatment-resistant unipolar or bipolar depression, but its antidepressant effects are typically short-lived, necessitating maintenance treatment after initial response.

There is a lack of controlled evidence to guide psychiatrists on the best practices for maintaining the benefits of ketamine treatment, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next-Step Treatment Considerations for Patients With Treatment-Resistant Depression That Responds to Low-Dose Intravenous Ketamine. Bobo, WV., Riva-Posse, P., Goes, FS., et al.[2021]

Intravenous ketamine has shown rapid improvement in depression symptoms for patients with treatment-resistant bipolar disorder, based on a systematic review of five studies involving 110 subjects.

Common side effects included dissociation and a temporary increase in blood pressure, but ketamine did not exacerbate mania symptoms, indicating a relatively safe profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review on the Efficacy of Intravenous Racemic Ketamine for Bipolar Depression. Joseph, B., Parsaik, AK., Ahmed, AT., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36516343/

Real-world effectiveness of repeated ketamine infusions for ... Real-world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165178125003397

Real World Effectiveness of Maintenance Ketamine ... IV ketamine maintains antidepressant & antisuicidal effects in TRD and TRBD patients · Patients reported feeling health improvements on a weekly ...

3. 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 ...

4. 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 ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S016503272500076X

Symptom modulation and tolerability of intravenous ... Ketamine significantly improves depressive symptoms in bipolar patients, as assessed by the MADRS scale, indicating its potential efficacy.

6. 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 ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05004896

Ketamine for Treatment-Resistant Bipolar Disorder The primary research goal is to determine the acute antidepressant efficacy, safety and tolerability of four repeated sub-anesthetic doses of IV ketamine in ...

8. psychopharmacologyinstitute.com psychopharmacologyinstitute.com/publication/ketamine-guide-pharmacology-indications-dosing-guidelines-and-adverse-effects-2924/

Ketamine Guide: Pharmacology, Indications, Dosing ... Ketamine may be considered for patients with treatment-resistant depression (TRD) who have not responded to other antidepressant therapies.

9. mdpi.com mdpi.com/1424-8247/16/2/173

Safety and Tolerability of the Acute Ketamine Treatment in ... The aim of this study was to investigate the safety of intravenous ketamine treatment in relation to dissociative and psychotic measures in TRD inpatients.