Ketamine + Esketamine for Depression

Overseen By Cristina Cusin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Massachusetts General Hospital

Must not be taking: Benzodiazepines, Opiates, Barbiturates, others

Disqualifiers: Substance use disorder, Bipolar, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 8

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the use of ketamine and esketamine (a nasal spray medication) to treat individuals with Major Depressive Disorder who experience suicidal thoughts. Over 24 weeks, participants will receive a series of ketamine and esketamine treatments to evaluate their effectiveness and safety. The trial seeks individuals currently in a psychiatric unit with ongoing depression and suicidal ideation for at least eight weeks. Participants should not have previously tried IV ketamine and must be in good general health. As a Phase 4 trial, this research aims to understand how these FDA-approved and effective treatments can benefit more patients.

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 currently receiving ECT treatment or taking frequent or high doses of certain medications like benzodiazepines, opiates, or barbiturates.

What is the safety track record for ketamine and esketamine?

Research has shown that both ketamine and esketamine have been studied for their safety in treating depression. These treatments can cause some side effects. For ketamine, side effects may occur immediately, accumulate over time, or persist. Some individuals might experience dizziness or mood changes after use.

Esketamine, administered as a nasal spray, has more side effects than a placebo (a substance with no active drug). Some users of esketamine have reported new thoughts of self-harm.

Despite these concerns, ketamine and esketamine are used because they can help when other treatments fail. The FDA has approved them for treating depression, indicating they have been studied for safety. However, individuals considering these treatments should consult their doctors to understand the risks and benefits. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about ketamine and esketamine for depression because these treatments work much faster than traditional antidepressants. Most antidepressants, like SSRIs, can take weeks to show results, but ketamine and esketamine have the potential to alleviate symptoms within hours or days. Additionally, unlike typical antidepressants that target serotonin, ketamine and esketamine act on the brain's glutamate system, which may offer relief to patients who haven't responded to other treatments. These unique characteristics make them promising alternatives in the fight against depression.

What evidence suggests that ketamine and esketamine could be effective for depression?

Research has shown that both IV ketamine and IN esketamine can effectively reduce depression and suicidal thoughts. In earlier studies, patients who received these treatments experienced significant improvements by the end of the treatment period. Notably, about 24% of patients on ketamine and 29% on esketamine saw their symptoms greatly reduced just one day after treatment. Additionally, both treatments proved effective for depression over four weeks. These findings support using ketamine and esketamine for depression, especially when other treatments have failed. In this trial, all participants will receive a combination of IV ketamine and IN esketamine treatment. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 with Major Depressive Disorder and suicidal thoughts, who are inpatients at a psychiatric unit. They must be in good health, not pregnant or breastfeeding, willing to use birth control if applicable, have internet access and a treating psychiatrist. Excluded are those on certain CNS depressants or with recent substance abuse issues.

Inclusion Criteria

Ability to read, understand, and provide written and dated informed consent prior to screening

I have a psychiatrist who has been treating me.

Access to a mobile phone or computer with internet connection

Exclusion Criteria

Current diagnosis of a moderate to severe substance use disorder, within the last six months prior to screening based on DSM-5 criteria

A status of childbearing potential and is not willing to use birth control during the study

Inability to comply with study safety procedures, including having reliable escorts to and from visits

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous (IV) ketamine and intranasal (IN) esketamine treatments

24 weeks

8 IV ketamine treatments, 13 esketamine treatment visits, 7 long assessment visits, 5 short assessment visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Esketamine
• Ketamine

Trial Overview The study tests the effects of IV ketamine followed by IN esketamine over 24 weeks against historical controls for reducing suicide risk in depression patients. It includes multiple treatment sessions, assessments visits, and daily surveys to evaluate feasibility, tolerability and predictors of response.

How Is the Trial Designed?

Group I: Ketamine and Esketamine Treatment Experimental Treatment 2 Interventions

All study subjects will receive intravenous (IV) ketamine and intranasal (IN) esketamine treatment.

Esketamine is already approved in United States for the following indications:

Approved in United States as Spravato for:

• Treatment-resistant depression
• Major depressive disorder with suicidal ideation or behavior

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

American Foundation for Suicide Prevention

Collaborator

Trials

36

Recruited

10,500+

Published Research Related to This Trial

The pharmacokinetics of esketamine and its metabolite noresketamine were characterized in a study involving over 820 individuals, revealing that 54% of an intranasal dose is absorbed, with significant differences in absorption and clearance rates based on race and age.

Esketamine's bioavailability was quantified, showing that its effectiveness can be influenced by factors such as hepatic blood flow and demographic characteristics, which may lead to higher concentrations in certain populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression. Perez-Ruixo, C., Rossenu, S., Zannikos, P., et al.[2022]

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]

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]

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 involving 156 participants with suicidal ideation, ketamine treatment led to a significantly higher rate of full remission of suicidal thoughts at day 3 compared to placebo, with 63% of those receiving ketamine achieving remission versus 31.6% in the placebo group.

The study found that ketamine was safe in the short term, with limited side effects and no occurrences of manic or psychotic symptoms, suggesting it could be a rapid and effective option for acute care in suicidal patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. Abbar, M., Demattei, C., El-Hage, W., et al.[2022]

A 65-year-old male cancer patient experienced significant improvement in depression symptoms and achieved remission within 7 days after receiving subcutaneous esketamine, indicating its rapid antidepressant effect.

Subcutaneous administration of esketamine appears to be a safe and effective option for managing both pain and depression in palliative care, suggesting it could be a valuable alternative to traditional intravenous methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated subcutaneous esketamine administration for depressive symptoms and pain relief in a terminally ill cancer patient: A case report. Barbosa, MG., Delfino, RS., Sarin, LM., et al.[2021]

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 hydrochloride (Spravato) is an effective treatment for adults with treatment-resistant major depressive disorder, specifically for those who have not responded to at least two different antidepressants during their current episode.

The treatment involves a nasal spray formulation, starting with a dose of 56 mg for adults under 65 and 28 mg for those 65 and older, with a structured dosing schedule that includes twice-weekly doses for the first month, followed by weekly or biweekly maintenance, and is recommended for at least 6 months after symptom improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Esketamine for treatment-resistant depression. [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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39128167/

IN Esketamine and IV Ketamine: Results of a multi-site ... Both IV ketamine and IN esketamine significantly reduced depressive symptoms and suicidal ideation by treatment endpoint.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0165178124004104

IN Esketamine and IV Ketamine: Results of a multi-site ... Both IV ketamine and IN esketamine significantly reduced depressive symptoms and suicidal ideation by treatment endpoint.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9922941/

Esketamine for treatment‑resistant depression: A review of ... The results collected 24 h post-infusion showed that 24.1% of patients who received ketamine and 29.4% of those treated with esketamine obtained remission, ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2666144624000224

Benefits and risks of esketamine nasal spray continuation ... Preliminary results of a prospective observational study found both IV ketamine and ESK to be similarly effective for depression at 4 weeks, although IV ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06713616

NCT06713616 | PCORI Comparative Effectiveness Study ... The purpose of this study is to compare the relative effectiveness, acceptability, and side effects of ketamine delivered through an IV (a drip into the ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12450024/

Spravato for Treatment-Resistant Depression: Efficacy and ... In terms of safety and tolerability, intranasal esketamine showed greater number of adverse effects than the placebo group. In particular, there ...

7. jamanetwork.com jamanetwork.com/journals/jamapsychiatry/fullarticle/2836115

Esketamine Monotherapy in Adults With Treatment ... Treatment-emergent suicidal ideation was reported at least once during the double-blind phase for 7 of 105 participants (6.7%) in the 56-mg ...

8. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.20241177

Six Years After Approval of Esketamine Nasal Spray for ... Hence, there is still no evidence that esketamine nasal spray (or ketamine) actually reduces the risk of suicide attempts or suicide. What are ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S016517812400619X

Safety outcomes of ketamine for treatment-resistant ... Ketamine can give rise to acute, cumulative and longer-term side effects (SEs) across a treatment course. The Ketamine Side Effect Tool (KSET) examines adverse ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11607365/

Personalized use of ketamine and esketamine for treatment ... Despite preliminary reports indicating that ketamine may be safe and effective in psychotic depression [150], the available data are still ...