Ketamine for Bipolar Depression

No longer recruiting at 1 trial location

Overseen By General Recruitment Contact (Cleveland Clinic Lutheran)

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how ketamine, administered through an intravenous (IV) drip, can treat depression in individuals with bipolar disorder who haven't responded to other treatments. Researchers aim to understand ketamine's effects on the brain using a special brain scan called fMRI. Ideal participants have experienced a depressive episode for at least four weeks and have tried at least two different medications without success. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

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.

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

Research shows that ketamine is generally safe for people with treatment-resistant bipolar depression. Studies have found that it rarely causes manic or hypomanic episodes, which are periods of unusual happiness and energy. Many patients report symptom relief.

In past studies, side effects were manageable. Some experienced mild issues like dizziness or nausea, but these were uncommon. Real-world data also support ketamine's safety, confirming its use in medical settings.

Overall, evidence suggests that ketamine is a safe option for those dealing with treatment-resistant depression. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for bipolar depression, such as mood stabilizers and antidepressants, ketamine offers a unique approach by acting on the brain's glutamate system. Researchers are excited about ketamine because it can potentially provide rapid relief from depressive symptoms, often showing effects within hours or days, compared to the weeks it usually takes for traditional medications to work. Additionally, ketamine is administered intravenously, which allows for precise control over dosing and quick adjustments if needed. This rapid and controlled method can be especially promising for those with treatment-resistant bipolar depression.

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

Research has shown that ketamine can quickly improve depression symptoms, often right after treatment, with effects lasting up to a month. In this trial, participants with treatment-resistant bipolar depression will receive ketamine. For individuals whose depression hasn't responded to other treatments, including bipolar depression, about 44% experienced improvement with ketamine. It works faster than traditional antidepressants, offering a significant advantage. Importantly, ketamine carries a low risk of causing manic episodes in people with bipolar disorder, making it a promising option for those who haven't found relief with other treatments. ^{1 2 3 6 7}

Who Is on the Research Team?

Brian Barnett, MD

Principal Investigator

The Cleveland Clinic

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

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]

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]

Citations

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

The Role of Ketamine in the Treatment of Bipolar Depression Overall, ketamine treatment appeared to be tolerable with minimal risk for manic/hypomanic switching and showed some effectiveness across parameters of ...

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

Oral ketamine for the treatment of major depressive and ... Ketamine, with its rapid onset of efficacy in difficult to treat cases, constitutes a major advancement in antidepressant therapy as mounting ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6767816/

Efficacy of ketamine therapy in the treatment of depression Ketamine has a robust and rapid effect on depression, which was seen immediately after the administration of ketamine and sustained at the end of 1 month.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01944293

Ketamine for Suicidality in Bipolar Depression This study is designed to compare the effectiveness of two medications, Ketamine and Midazolam, for rapidly relieving suicidal thoughts in people suffering from ...

5. frontiersin.org frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1283733/full

Use of ketamine for treatment resistant depression Based on chart review of these first 50 patients treated in our program, 50% had unipolar depression, 40% had bipolar depression, and 10% were unspecified. 44% ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10801061/

Use of ketamine for treatment resistant depression Evidence for the use of ketamine in resistant depression has grown in recent years, with evolving data to support and direct its clinical use.

7. researchgate.net researchgate.net/publication/387291035_Safety_outcomes_of_ketamine_for_treatment-resistant_depression_in_clinical_settings_and_development_of_the_Ketamine_Side_Effect_Tool-Revised_KSET-R

Safety outcomes of ketamine for treatment-resistant ... Real-world clinical data on the long-term effectiveness and safety of generic racemic ketamine treatment. Article. Sep 2025; J AFFECT DISORDERS.