Ketamine for Bipolar Depression

Recruiting at 1 trial location

Overseen By Amy DiVita

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brian Barnett

Must not be taking: Benzodiazepines, others

Disqualifiers: Schizophrenia, Pregnancy, Substance use, others

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: 9

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a prospective open-label observational study of patients with treatment resistant bipolar depression referred for intravenous ketamine, with an interventional component of fMRI.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking a medication that may significantly interact with ketamine. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug ketamine for treating bipolar depression?

Research shows that ketamine can quickly reduce symptoms of depression, including in people with bipolar depression who haven't responded to other treatments. Studies have found that both intravenous and subcutaneous forms of ketamine can be effective, with many patients experiencing significant improvement. ^{1 2 3 4 5}

Is ketamine safe for treating bipolar depression?

Ketamine has been studied for its safety in treating depression, including bipolar depression. Common side effects include a temporary sense of detachment from reality (dissociation) and increased blood pressure. Overall, it is considered to have a promising safety profile, but more research is needed to fully understand its long-term safety. ^{5 6 7 8 9}

How is the drug ketamine unique in treating bipolar depression?

Ketamine is unique in treating bipolar depression because it provides a rapid and robust antidepressant effect, often within hours, unlike traditional antidepressants that can take weeks to work. It can be administered in various ways, including subcutaneous (under the skin) and intravenous (into a vein), offering flexibility and potential cost-effectiveness, especially in developing countries. ^{1 2 4 5 10}

Research Team

Brian Barnett, MD

Principal Investigator

The Cleveland Clinic

Eligibility Criteria

This trial is for individuals with bipolar depression who haven't improved with standard treatments. Participants will receive intravenous ketamine and undergo brain scans using fMRI. Specific eligibility details are not provided.

Inclusion Criteria

Written informed consent before any study related procedures are performed

I have been diagnosed with a major depressive episode and bipolar disorder.

I have tried at least 2 different mental health medications for 4 weeks each.

Exclusion Criteria

Meet DSM-5 criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder, mental retardation, or pervasive developmental disorder

The patient is pregnant or breastfeeding

I have not taken ketamine in the last 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Acute Treatment

Participants receive twice weekly intravenous ketamine infusions over three weeks

3 weeks

6 visits (in-person)

Continuation Treatment

Responders receive weekly ketamine infusions for three weeks

3 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketamine

Trial Overview The study observes the effects of IV ketamine on patients with treatment-resistant bipolar depression, while also monitoring changes in their brain activity through functional magnetic resonance imaging (fMRI).

Participant Groups

Group I: Open-label Ketamine TRBD Experimental Treatment 2 Interventions

Outpatients with treatment resistant bipolar depression referred by their clinical providers for intravenous ketamine treatment

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Brian Barnett

Lead Sponsor

Trials

1

Recruited

20+

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

Findings from Research

A meta-analysis of 5 studies involving 125 subjects with bipolar depression found that a single dose of intravenous ketamine significantly improved depression symptoms compared to placebo, with a strong effect size (SMD=-1.01).

Ketamine not only showed rapid improvement in depression, peaking 40 minutes post-infusion, but also helped reduce anhedonia and suicidal thoughts, with no serious side effects reported, indicating it is a safe option for treatment-resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Ketamine in Bipolar Depression: Systematic Review and Meta-analysis. Parsaik, AK., Singh, B., Khosh-Chashm, D., et al.[2018]

A 49-year-old woman with severe treatment-resistant major depression experienced significant improvement after receiving 36 sessions of ketamine intravenous therapy over 10 months, resulting in nearly a 50% reduction in her depressive symptoms.

The case suggests that long-term repeated ketamine therapy could be a viable option for patients with treatment-resistant depression, but further research is needed to determine the best treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine infusion for a patient with treatment-resistant major depression: a 10-month follow-up. Kwon, JH., Sim, WS., Hong, JP., et al.[2018]

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]

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]

Subcutaneous (SC) administration of racemic ketamine and esketamine has shown rapid and robust antidepressant effects in both unipolar and bipolar patients, with response and remission rates ranging from 50% to 100% after single or multiple doses.

The studies indicated that SC ketamine is generally well-tolerated, with only transitory side effects, making it a promising and cost-effective treatment option for depression, especially in developing countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. Cavenaghi, VB., da Costa, LP., Lacerda, ALT., et al.[2021]

There is currently no standardized safety monitoring protocol for off-label use of generic ketamine, and safety monitoring for intranasal esketamine varies by jurisdiction, leading to potential gaps in patient safety.

The Ketamine Side Effect Tool (KSET) is recommended as a comprehensive tool for monitoring both acute and long-term side effects of ketamine and esketamine treatments, addressing the lack of agreed frameworks for safety monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. Bayes, A., Short, B., Zarate, CA., et al.[2023]

Ketamine and esketamine demonstrate rapid antidepressant effects, with improvements in clinical response observed within 40 minutes to 1 week for ketamine and 2 hours to 4 weeks for esketamine, along with reductions in depression scores and suicidality.

Despite their effectiveness, the long-term safety and efficacy of ketamine and esketamine remain uncertain, and the overall quality of the studies reviewed was critically low, highlighting the need for more rigorous research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. Lima, TM., Visacri, MB., Aguiar, PM.[2022]

A review of 41 treatment arms from 21 studies found that ketamine formulations that maximize first pass metabolism and delay the time to peak concentration (Tmax) are associated with better safety and tolerability, particularly in reducing side effects like dissociation and increased blood pressure.

The study revealed strong correlations between the ketamine:norketamine ratio and both dissociation ratings and blood pressure changes, suggesting that careful formulation can help minimize adverse effects while maintaining the antidepressant efficacy of ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. Glue, P., Russell, B., Medlicott, NJ.[2021]

An extended release oral ketamine tablet was found to be safe and well tolerated in a study of seven patients with treatment-resistant depression/anxiety, with no significant changes in vital signs and only one brief report of dissociation.

All patients experienced over 50% improvements in mood ratings over 96 hours, suggesting that while the onset of mood improvement is slightly delayed compared to injectable forms, this oral formulation could be a promising option for treating resistant depression and anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. Glue, P., Medlicott, NJ., Neehoff, S., et al.[2022]

In a study involving rats, gallic acid (50 or 100 mg/kg) was found to effectively prevent hyperlocomotion and oxidative brain damage caused by ketamine-induced mania, similar to the effects of lithium (45 mg/kg).

Gallic acid reduced oxidative stress markers and normalized acetylcholinesterase activity in the brain, suggesting it may protect against manic-like behavior by improving brain health and function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gallic acid protects cerebral cortex, hippocampus, and striatum against oxidative damage and cholinergic dysfunction in an experimental model of manic-like behavior: Comparison with lithium effects. Recart, VM., Spohr, L., Soares, MSP., et al.[2021]

References

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

Efficacy of Ketamine in Bipolar Depression: Systematic Review and Meta-analysis. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Intravenous ketamine infusion for a patient with treatment-resistant major depression: a 10-month follow-up. [2018]

3. Denmark pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. [2023]

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

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

5. Switzerland pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. [2022]

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

Gallic acid protects cerebral cortex, hippocampus, and striatum against oxidative damage and cholinergic dysfunction in an experimental model of manic-like behavior: Comparison with lithium effects. [2021]