Ketamine for Depression

Overseen By Sibilla Masieri

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: Antidepressants

Disqualifiers: Schizophrenia, Bipolar, Substance use, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how ketamine, a medication, affects people with depression, focusing on feelings of pleasure and anxiety. Researchers aim to understand ketamine's impact on the subgenual anterior cingulate cortex, a brain region involved in these emotions. Participants will receive either a ketamine infusion or a placebo (a harmless substance with no effect) for comparison. Those with moderate to severe depression, who have not recently used drugs or certain antidepressants, might be suitable candidates for this study. As a Phase 4 trial, this research seeks to understand how this already FDA-approved and effective treatment benefits more patients.

Will I have to stop taking my current medications?

Yes, if you are taking antidepressant medication, you will need to stop at least 2 weeks before the study begins (4 weeks for fluoxetine).

What is the safety track record for these treatments?

Research has shown that ketamine may help treat depression, particularly for those who haven't improved with other treatments. Studies have found that ketamine is usually safe and well-tolerated. However, some people might experience side effects, such as vivid dreams or hallucinations, occurring in about 12% of patients.

There is also a risk of breathing problems if the dose is too high or administered too quickly. With careful monitoring, these risks can be managed. Overall, ketamine has been used safely in medical and psychiatric settings, supporting its continued study in clinical trials like this one. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike standard antidepressants, which often take weeks to work and typically involve medications like SSRIs, ketamine offers a rapid onset of relief for depression symptoms, often within hours. Researchers are excited about ketamine because it works through a different mechanism, targeting the brain's glutamate system instead of serotonin pathways. This unique action not only provides faster results but also offers hope for treatment-resistant depression, a condition where patients don't respond to traditional therapies.

What is the effectiveness track record for ketamine in treating depression?

Research has shown that ketamine, which participants in this trial may receive, can help treat depression, especially when other treatments have failed. Studies have found that many people feel significantly better within two weeks to a month after just one dose of ketamine. It also improves the quality of life for those with hard-to-treat depression. These findings suggest that ketamine can quickly ease depression symptoms and provide lasting benefits. Overall, ketamine appears to be a promising option for those who haven't found relief with other treatments. ^{2 6 7 8 9}

Who Is on the Research Team?

James M Murrough, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Laurel Morris, PhD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

This trial is for individuals with depression, specifically those who experience a lack of pleasure (anhedonia) or anxiety. Participants must meet certain criteria to join, but these specifics are not provided in the given information.

Inclusion Criteria

I have been diagnosed with major depressive disorder according to DSM-5.

I am either not able to have children or I am using a reliable method of birth control.

MDD Group: Ability for participant to comply with the requirements of the study as determined by the PI

Exclusion Criteria

MDD Group: Positive urine toxicology screen for drugs of abuse at the time of screening, except cannabis

I have significant health issues found in lab tests, physical exams, or heart rhythm tests.

MDD Group: Substance use disorder within the past 2 years*

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of ketamine or placebo

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine
• Placebo

Trial Overview The study is testing the effects of Ketamine compared to a placebo on brain function and symptoms of depression. It focuses on how Ketamine affects a part of the brain called the subgenual anterior cingulate cortex.

How Is the Trial Designed?

Group I: Ketamine Experimental Treatment 1 Intervention

Participants in the ketamine arm will receive a single infusion of ketamine

Group II: Placebo Placebo Group 1 Intervention

Participants in the placebo arm will receive a single placebo infusion of normal saline

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?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

Racemic ketamine and its derivative, S-ketamine, have been shown to provide rapid relief from depressive symptoms, with effects lasting approximately 2-3 weeks after treatment, based on multiple clinical trials.

Further research is needed to optimize dosing strategies, especially for specific populations like obese individuals, and to monitor long-term safety regarding cognitive and organ system effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Key considerations for the use of ketamine and esketamine for the treatment of depression: focusing on administration, safety, and tolerability. Kritzer, MD., Pae, CU., Masand, PS.[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]

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]

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 European clinical trial, a 55-year-old male with treatment-resistant depression and substance use disorder showed significant improvement in depression symptoms after a single intravenous infusion of ketamine, with reductions in Hamilton Depression Rating Scale (HDRS) scores from 36 to 16 and Beck Depression Inventory (BDI) scores from 26 to 9.

The antidepressant effects of ketamine were rapid, with the patient reporting improvements just 25 minutes into the infusion, and these effects lasted for at least 7 days, demonstrating ketamine's potential as a fast-acting treatment for depression even in patients with co-occurring substance use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine therapy in a patient with a treatment-resistant major depression. Liebrenz, M., Borgeat, A., Leisinger, R., 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]

In a systematic review of ten randomized controlled trials involving 602 participants, ketamine did not show greater efficacy in improving depressive symptoms or achieving clinical response compared to other induction agents during electroconvulsive therapy (ECT).

The use of ketamine was associated with increased rates of confusion, suggesting potential safety concerns, and the findings do not support its use over traditional anesthetics in ECT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive ketamine in electroconvulsive therapy: updated systematic review and meta-analysis. McGirr, A., Berlim, MT., Bond, DJ., et al.[2022]

This systematic review analyzed 60 studies on the safety of ketamine for treating depression, revealing that acute doses of ketamine led to more frequent side effects, including psychiatric and cardiovascular issues, compared to placebo.

There is a notable lack of data on the long-term safety and effects of repeated ketamine dosing, highlighting the need for large-scale clinical trials to better understand its safety profile over extended use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side-effects associated with ketamine use in depression: a systematic review. Short, B., Fong, J., Galvez, V., et al.[2019]

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 9016 patients receiving ketamine intravenous therapy (KIT) for depression, 53.6% showed a significant response (≥50% reduction in depression scores) within 14-31 days, indicating KIT's efficacy in real-world settings.

While most patients benefited from KIT, a small percentage (8.4%) experienced worsening depressive symptoms, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. McInnes, LA., Qian, JJ., Gargeya, RS., et al.[2023]

In a study of 24 patients with major depressive disorder, activity in the pregenual anterior cingulate cortex (pgACC) was found to predict how well patients would respond to ketamine treatment, suggesting its importance in personalizing depression therapy.

The study also revealed that increased pgACC activity was linked to higher levels of glutamate 24 hours after ketamine infusion, which correlated with better clinical outcomes, indicating a potential biomarker for early treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker. Weigand, A., Gärtner, M., Scheidegger, M., et al.[2023]

Citations

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Efficacy of ketamine therapy in the treatment of depression Results: There was a significant improvement in depression, anxiety, and the severity of illness after 2 weeks and 1 month of the last dose of ketamine.

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK470357/

Ketamine - StatPearls - NCBI Bookshelf - NIH A recent randomized controlled trial demonstrated promising results of ketamine for treatment-resistant depression.[26]. Go to: Adverse ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032725009449

Economic evaluation of subcutaneous ketamine injections ... Ketamine for treatment resistant depression showed significant utility gains. · Quality-adjusted life years were significantly higher in the ketamine group.

4. cda-amc.ca cda-amc.ca/sites/default/files/pdf/htis/2022/RC1420-Ketamine-for-treatment-resistant-depression-and-PTSD.pdf

Ketamine for Adults With Treatment-Resistant Depression ... Seven RCTs22-28 reported both efficacy and safety outcomes, while the retrospective chart review study29 reported only efficacy outcomes. The efficacy outcomes ...

5. aetna.com aetna.com/cpb/medical/data/900_999/0938.html

Ketamine for the Treatment of Depression and Other ... The authors concluded that ketamine was shown in youth to generally improve depressive symptoms, decrease acute suicidality, and reduce mood lability, although ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2017/016812s043lbl.pdf

KETALAR (ketamine hydrochloride) injection Respiratory depression may occur with overdosage or too rapid a rate of administration of KETALAR, in which case supportive ventilation should be employed.

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Pharmacokinetics, Safety, and Tolerability of (R)-Ketamine ... The overall data indicated that (R)-ketamine hydrochloride injection has a favorable safety and tolerability, which can also support further ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2012/016812s039lbl.pdf

Ketalar Label - accessdata.fda.gov SPECIAL NOTE. EMERGENCE REACTIONS HAVE OCCURRED IN APPROXIMATELY 12 PERCENT OF PATIENTS. THE PSYCHOLOGICAL MANIFESTATIONS VARY IN SEVERITY BETWEEN PLEASANT ...

9. mayoclinic.org mayoclinic.org/drugs-supplements/ketamine-injection-route/description/drg-20075559

Ketamine (injection route) - Side effects & uses Ketamine injection is used alone or together with other medicines to produce loss of consciousness before and during surgery or a medical procedure.