Ketamine for Depression

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Massachusetts General Hospital

Must not be taking: Psychotropics, Fluoxetine

Disqualifiers: Bipolar, Schizophrenia, Substance use, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how a low, controlled dose of ketamine can quickly help treat depression. Researchers seek to understand how ketamine alters specific pathways in the brain and its cells, leading to rapid mood improvements. The study involves an intravenous infusion of ketamine and focuses on identifying the specific molecular targets that make this treatment effective. The trial seeks individuals experiencing a current depressive episode without recent use of certain medications or substances. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking treatment.

Will I have to stop taking my current medications?

Yes, you need to be off psychotropic medications for more than 2 weeks before joining the study, and if you're on fluoxetine, you need to be off it for more than 5 weeks.

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

Research has shown that intravenous ketamine can cause various side effects. These effects may be short-term, develop over time, or persist after treatment. Some individuals may experience these effects more intensely than others. Notably, ketamine is also used to treat other conditions, indicating a certain level of safety.

This study is in an early phase, focusing primarily on assessing ketamine's safety for participants. This step is crucial for understanding how individuals react to the treatment without any prior assumptions. Participants should be aware that the study is still closely examining ketamine's safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Unlike standard treatments for depression, which often include selective serotonin reuptake inhibitors (SSRIs) or psychotherapy that can take weeks to show results, ketamine is unique because it acts quickly, often providing relief within hours. Ketamine works differently by targeting the NMDA receptors in the brain, which is a novel mechanism compared to conventional antidepressants. Additionally, this treatment is administered intravenously, allowing for precise control over dosage and rapid onset of effects, which is particularly exciting for researchers seeking faster relief options for patients with depression.

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

Studies have shown that ketamine can quickly reduce symptoms of depression. In one study, nearly 55% of patients experienced a significant decrease in depression and suicidal thoughts after receiving ketamine treatment. Another study found that just one low-dose infusion of ketamine improved depressive symptoms within a day. Additionally, ketamine proved as effective as electroconvulsive therapy (ECT), with more than half of the patients reporting major improvements. This trial will administer intravenous ketamine, which previous research has shown to offer rapid relief for many patients with depression. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for individuals experiencing depression, self-harm tendencies, or suicidal thoughts. Specific eligibility criteria are not provided but typically include factors like age range, severity of symptoms, and absence of certain medical conditions.

Inclusion Criteria

Able to give voluntary informed consent

Currently in a depressive episode

Satisfy criteria to undergo an MRI scan based on MRI screening questionnaire

Exclusion Criteria

I have not had electroconvulsive therapy in the last year.

Meeting DSM-5 criteria for moderate or severe substance/alcohol use within the past 6 months (excluding caffeine or nicotine)

Meeting DSM-5 criteria for (hypo)mania, bipolar disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, intellectual disability, or pervasive developmental disorder

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

Baseline Assessment

Subjects undergo baseline structural scan, resting state fMRI, and DWI scans, and living neurons are collected from the olfactory epithelium for molecular and gene expression analysis

1 week

1 visit (in-person)

Treatment

Participants receive 3 alternate-day intravenous ketamine treatments at a dose of 0.5 mg/kg over 40 minutes

1 week

3 visits (in-person)

Post-Treatment Assessment

Subjects undergo post-treatment structural scan, resting state fMRI, and DWI scans, and living neurons are collected again for analysis

1 week

1 visit (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 investigates how a low dose of ketamine given through an IV can quickly relieve depression and prevent suicide. It looks at changes in genes within neurons from the nose and links them to brain connectivity improvements observed via imaging techniques.

How Is the Trial Designed?

Group I: Intravenous Ketamine Experimental Treatment 1 Intervention

Intravenous ketamine will be given at a dose of 0.5 mg/kg over 40 minutes with a maximum dose of 60 mg.

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?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Published Research Related to This Trial

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]

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]

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]

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]

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 Phase I study involving 32 patients showed that esketamine (0.5 mg/kg) is generally safe and well-tolerated for use in painless gastroscopy, with no serious adverse events reported.

Esketamine resulted in a shorter recovery time compared to racemic ketamine (9 minutes vs. 13 minutes), making it a potentially more efficient option for anesthesia without gender differences affecting its pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study. Wang, J., Huang, J., Yang, S., 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]

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]

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]

Subanaesthetic doses of ketamine have shown substantial efficacy in treating depression, with response rates averaging 77% and remission rates around 43% within 4 to 72 hours after a single dose.

Despite the rapid improvement in mood for many patients, the effects are often short-lived, highlighting the need for further research on dosing regimens and strategies to maintain the antidepressant response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Katalinic, N., Lai, R., Somogyi, A., et al.[2013]

Intravenous ketamine has been shown to be safe and effective in rapidly reducing depressive symptoms, including suicidal thoughts, in patients with treatment-resistant unipolar or bipolar depression, based on five controlled studies and additional open-label studies.

While ketamine shows promise as a short-term antidepressant therapy, further research is needed to assess its long-term safety and effectiveness, as well as the efficacy of alternative administration routes like oral or intranasal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for the treatment of depression. Howland, RH.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38286230/

Ketamine for major depressive disorder during an inpatient ... Conclusion: Twice weekly racemic ketamine infusion is an effective treatment option for patients hospitalized with MDD. Unmonitored or at home ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0165178124001501

IV low dose ketamine infusions for treatment resistant ... The results showed a significant reduction in depressive symptoms and suicide ideation (SI) by treatment endpoint. 54.93% of patients responded to the treatment ...

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

Ketamine for the treatment of major depression Higher doses reduced depressive symptoms and increased response rates at all stages in a treatment course (initial, ongoing, and lasting effects) ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9010394/

Ketamine treatment for depression: a review - PMC Initial studies found that a single subanesthetic-dose IV ketamine infusion rapidly (within one day) improved depressive symptoms in individuals ...

5. massgeneralbrigham.org massgeneralbrigham.org/en/about/newsroom/press-releases/study-finds-ketamine-effective-as-ect-for-major-depression

Study Finds Ketamine is at Least as Effective as ECT ... The researchers found that 55 percent of those receiving ketamine and 41 percent of those receiving ECT reported at least a 50 percent ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39721099/

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

7. 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 ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36192794/

Real-world depression, anxiety and safety outcomes of ... Patients received a median of 4 (range 1-48) IM ketamine treatments. Median depression scores (PHQ-9) improved 38% from 16.0 (IQR 11.3-21.8) at ...

9. 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 ...

10. 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 ...