Esketamine vs. Ketamine for Depression

Recruiting at 5 trial locations

Overseen By Lisa Harding, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Yale University

Disqualifiers: Bipolar, Psychotic disorder, Substance use, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 8

Duration: 4 weeks

400 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores two treatments for individuals with depression that hasn't improved after at least two other antidepressants. It compares racemic ketamine, administered through an IV, with Spravato (esketamine), a nasal spray, to determine which is more effective, easier to use, and has fewer side effects. Participants with moderate to severe depression who have not responded to other treatments might be suitable candidates. The trial also seeks to identify who might benefit more from each treatment. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to the development of potentially groundbreaking treatments.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, a positive urine toxicology screen for prescribed substances like benzodiazepines and stimulants is allowed, suggesting some medications may be continued. It's best to discuss your specific medications with the study team.

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

Research shows that both racemic ketamine and Spravato (esketamine) have been studied for safety in treating treatment-resistant depression (TRD).

Studies suggest racemic ketamine might be effective, but information on its long-term safety is limited. While some psychiatric side effects have been reported, more research is needed to fully understand its safety.

In contrast, the FDA has approved Spravato for TRD, providing more detailed safety information. Long-term studies, up to 4.5 years, have not revealed new safety concerns. Common side effects include nausea and feeling disconnected from reality, but these are usually manageable. Serious mood-related side effects have occurred in a small number of cases.

Overall, Spravato has a more established safety record due to FDA approval and longer-term studies, while racemic ketamine requires further research to confirm its long-term safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for depression because they use ketamine, a well-known anesthetic, in new and potentially more effective ways. Unlike traditional antidepressants that can take weeks to work, both racemic ketamine, given intravenously, and Spravato (esketamine), administered intranasally, have the potential to provide rapid relief from depressive symptoms. Racemic ketamine is a mix of two mirror-image molecules, while Spravato uses only the esketamine part, which may offer similar benefits with potentially fewer side effects. This new approach could be a game-changer for people who haven't responded well to other treatments.

What evidence suggests that this trial's treatments could be effective for treatment-resistant depression?

This trial will compare the effectiveness of racemic ketamine and Spravato (esketamine) for treatment-resistant depression (TRD). Research has shown that racemic ketamine, which participants in this trial may receive, can help with TRD. In one study, 72% of patients felt better, and 38% experienced complete relief from depression after receiving ketamine infusions. Another study found that it reduced self-harm and suicidal thoughts by half. Similarly, esketamine, sold as Spravato, is another treatment option in this trial and is also effective and approved for TRD. It has demonstrated quick and significant improvements in depression symptoms in several studies. Both treatments have evidence supporting their ability to reduce depression symptoms. ^{4 5 6 7 8}

Who Is on the Research Team?

Samuel Wilkinson, MD

Principal Investigator

[e-mail]

Are You a Good Fit for This Trial?

This trial is for individuals with treatment-resistant depression (TRD), meaning their depression hasn't improved after trying other treatments. Participants must be comfortable receiving medication through an IV or as a nasal spray. Specific eligibility criteria are not provided, but typically include factors like age, health status, and prior treatments.

Inclusion Criteria

I have moderate to severe depression.

A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study

Provision of signed and dated informed consent form

Exclusion Criteria

Hypersensitivity to ketamine, esketamine or any of the excipients

Positive urine toxicology at screening visit, except for substances that are prescribed

My blood pressure is not well-controlled.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Spravato® (Esketamine) intranasally or Racemic Ketamine intravenously for treatment-resistant depression

4 weeks

8 treatment sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Racemic Ketamine
• Spravato (Esketamine)

Trial Overview The study compares two forms of ketamine: IV racemic ketamine, which isn't FDA-approved for TRD yet, and Esketamine (Spravato®) nasal spray, which is approved. It will assess how effective they are at easing symptoms of depression, patient comfort with the treatments, and side effect management.

How Is the Trial Designed?

Group I: Spravato (Esketamine) Experimental Treatment 1 Intervention

Spravato® (Esketamine) will be given intranasally. For esketamine, the dose will be between 56 and 84mg, according to the FDA label for the drug. Allowances will be made for patients who have difficulty tolerating these doses to be dosed at 28mg in subsequent treatment sessions.

Group II: Racemic Ketamine Experimental Treatment 1 Intervention

Ketamine will be given intravenously. Per FDA guidance, the max dose of ketamine will be 60mg per day, with a total lifetime limit of 8 doses. Ketamine will be infused over 40 minutes.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

Published Research Related to This Trial

r/s-ketamine has shown rapid and strong antidepressant effects for individuals with treatment-resistant depression, leading to significant advancements in understanding how antidepressants work.

The FDA has approved the s-isomer of ketamine, known as Esketamine (Spravato), marking it as the first new treatment for depression in over 60 years, highlighting its importance in modern psychiatric care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A New Rapid-Acting Antidepressant. Krystal, JH., Charney, DS., Duman, RS.[2020]

This clinical trial aims to compare the efficacy and safety of esketamine and racemic ketamine in treating treatment-resistant depression, involving adults aged 18 and older who will receive either esketamine (0.25 mg/kg) or ketamine (0.5 mg/kg) in a controlled setting.

The primary outcome will assess remission rates at 24 and 72 hours post-infusion, providing crucial data on whether esketamine is noninferior to ketamine, which could enhance treatment accessibility for depression globally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial. Correia-Melo, FS., Leal, GC., Carvalho, MS., 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]

Esketamine, approved for treatment-resistant depression, has been shown to have generally mild and transient side effects, such as dissociation and nausea, with no severe bladder issues reported when used according to guidelines.

Long-term use of esketamine does not appear to impair cognition, contrasting with high doses of racemic ketamine, which can lead to cognitive impairments, indicating that esketamine may be safer for long-term use in treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of ketamine and esketamine in treatment of depression. Nikayin, S., Murphy, E., Krystal, JH., et al.[2022]

This study is the first randomized controlled trial investigating the efficacy and safety of repeated oral administration of esketamine in patients with treatment-resistant depression (TRD) over a 6-week period, followed by a 4-week follow-up.

If effective, oral esketamine could offer significant advantages over intravenous administration, potentially improving treatment accessibility and patient comfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial. Smith-Apeldoorn, SY., Veraart, JKE., Kamphuis, J., et al.[2020]

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 36 studies involving 2903 participants found that both racemic ketamine and esketamine significantly improve response and remission rates in patients with depression compared to placebo, with a response rate ratio of 2.14 and a remission rate ratio of 1.64.

The treatments were found to be safe, with no significant increase in treatment retention issues or dropouts due to adverse events, indicating that ketamine and esketamine are acceptable options for managing depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. Bahji, A., Zarate, CA., Vazquez, GH.[2023]

In a Phase 2b study involving 202 Japanese patients with treatment-resistant depression, esketamine nasal spray did not show a statistically significant improvement in depressive symptoms compared to placebo, despite reductions in MADRS scores across all esketamine doses.

Esketamine was found to be safe and well-tolerated, although it was associated with a higher incidence of certain side effects, such as increased blood pressure and dissociation, compared to the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study. Takahashi, N., Yamada, A., Shiraishi, A., et al.[2021]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2302399

Ketamine versus ECT for Nonpsychotic Treatment ... These trials showed that remission with ketamine was inferior to that with ECT. Our trial differs from these reports in that it included only ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36112599/

Clinical Effectiveness of Intravenous Racemic Ketamine ... Response and remission rates were 72% and 38%, respectively, after 10 infusions, and there was a 50% reduction in self-harm/suicidal ideation ( ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2666915325000848

Intranasal racemic ketamine in treatment-resistant ... Intranasal racemic ketamine is an effective, well-tolerated treatment for TRD, with favorable safety outcomes and substantial antidepressant effects.

4. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00304-8/fulltext

Ketamine for the treatment of major depression Multivariable mixed effects meta-regression analyses showed that racemic ketamine had numerically greater efficacy than esketamine. Higher doses ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7704936/

Comparative efficacy of racemic ketamine and esketamine for ... Fortunately, ketamine appears to ameliorate the symptoms of depression at subanesthetic doses among individuals with major depressive disorder as well as ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40930174/

Real-world clinical data on the long-term effectiveness and ... There is minimal data on the effectiveness and safety of generic racemic ketamine treatment of >4 weeks duration. The aim of this study was to report the ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032725016349

Real-world clinical data on the long-term effectiveness and ... Data suggested effectiveness, with response rates of 35 % at 8 weeks (16/45) and 44.2 % at 6 months (19/43). Suicidality scores improved in 73.3 ...

8. bmcpsychiatry.biomedcentral.com bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-022-04268-5

Real-world depression, anxiety and safety outcomes of ... Patients receiving IM ketamine treatment had a mean of 2.8 (SD 1.4) psychiatric diagnoses. 420 (93%) patients had a diagnosis of major ...