Ketamine for Treatment-Resistant Depression

Overseen By Vanessa Pardo, BA (Hons)

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Abraham Nunes

Must be taking: Antidepressants, Augmentation agents

Must not be taking: MAOIs, Narcotics

Disqualifiers: Pregnancy, Substance use disorder, Epilepsy, Hepatic disease, 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

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

Compensation: Varies

Number of Visits: 7

Duration: 6 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether a single low dose of intravenous (IV) ketamine can quickly relieve symptoms of treatment-resistant depression (TRD). Researchers seek to identify which patients are most likely to benefit by examining their clinical features, such as specific signs and symptoms. Participants will receive either ketamine or a similar drug, midazolam, in random order, and researchers will closely monitor their reactions. Those who have tried at least two different antidepressants without success and continue to experience depression symptoms might be suitable for this study. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to a treatment that could soon become widely available.

Do I have to stop taking my current medications for the trial?

You must maintain your current antidepressant management, but you need to abstain from benzodiazepine use within 24 hours of infusion. The protocol does not specify other medication changes, but you cannot use medications that interact with ketamine or midazolam.

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

Research has shown that ketamine is generally safe and well-tolerated for treating depression. One study found that adverse events, or unwanted effects, are usually temporary and resolve on their own. The FDA has approved ketamine as an anesthetic, indicating its safety for human use. However, it is not specifically approved for depression, so it is used "off-label" for this purpose.

Most participants in studies experienced mild side effects like dizziness or nausea. Serious side effects, such as breathing problems, can occur if too much ketamine is administered too quickly. Therefore, it is important to receive ketamine in a controlled setting, like a clinic or hospital. Overall, ketamine shows promise for treating depression that hasn't responded to other treatments, but its long-term safety remains under study. ^{1 2 3 4 5}

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

Researchers are excited about ketamine for treatment-resistant depression because it offers a new mechanism of action compared to traditional antidepressants. Most treatments for depression, like SSRIs and SNRIs, take weeks to work and target neurotransmitters like serotonin. Ketamine, however, acts on the brain's glutamate system and can produce rapid relief of depressive symptoms, often within hours or days. This quick response is particularly promising for individuals who haven’t found success with other medications. Additionally, ketamine's unique pathway could provide relief for those who have struggled with depression for years.

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

Studies have shown that ketamine, which participants in this trial may receive, can quickly reduce depression symptoms in people with treatment-resistant depression (TRD). Improvement can occur within 24 hours after a low dose. However, the relief typically lasts only a few days to two weeks. Despite the short duration, ketamine effectively eases depressive symptoms when other treatments fail. While some research indicates significant improvements, there isn't enough evidence yet to confirm its long-term effectiveness. Overall, ketamine offers promising fast relief in TRD, but its benefits are temporary. ^{6 7 8 9 10}

Who Is on the Research Team?

Abraham Nunes, MD PhD MBA FRCPC

Principal Investigator

Nova Scotia Health Authority

Are You a Good Fit for This Trial?

This trial is for adults with treatment-resistant depression (TRD) who have not responded to at least two different antidepressant medications and one augmentation agent. Participants must be fluent in English, able to understand the study, provide consent, and commit to using birth control if applicable. Exclusions include certain medical conditions like liver disease or recent heart attack, substance abuse issues, use of specific drugs like naltrexone, and previous ketamine therapy.

Inclusion Criteria

I understand and can follow the study's requirements.

Augmentation strategies as per CANMAT depression guidelines

I have been diagnosed with MDD or bipolar disorder without psychosis.

Exclusion Criteria

I am not taking medications that interact with ketamine or midazolam.

Previous or current benzodiazepine abuse history

Allergies to ketamine or midazolam

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment Monitoring

Participants wear a GENEActive accelerometer and complete rating scales and tasks

3 weeks

1 visit (in-person)

Treatment

Participants receive either ketamine or midazolam infusion, followed by a crossover to the other treatment after 21 days

6 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with weekly self-ratings and depression assessments

4 weeks

4 visits (virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine
• Midazolam

Trial Overview The trial tests whether a single low dose of IV ketamine can quickly relieve symptoms of TRD compared to an active placebo (Midazolam). It aims to identify predictors for who will benefit most from this treatment by observing responses at 24 hours and sustained effects up to two weeks after administration.

How Is the Trial Designed?

Group I: Ketamine Experimental Treatment 1 Intervention

Participants will be randomly assigned to receive Ketamine or Midazolam

Group II: Midazolam Active Control 1 Intervention

Participants will receive either Ketamine or Midazolam based on what they initially received

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?

Abraham Nunes

Lead Sponsor

Trials

2

Recruited

290+

Nova Scotia Health Authority

Collaborator

Trials

302

Recruited

95,300+

Published Research Related to This Trial

Ketamine, at sub-anesthetic doses, shows promise as a rapid-acting treatment for patients with treatment-resistant depression (TRD), potentially improving response rates to electroconvulsive therapy (ECT) when used alone or as an adjunct.

While ketamine can enhance the effectiveness of ECT, it may also increase seizure duration and has been associated with cardiovascular and psychotomimetic side effects, necessitating careful monitoring and consideration of concurrent medications to mitigate risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of ketamine's role in ECT and non-ECT settings. Jankauskas, V., Necyk, C., Chue, J., et al.[2020]

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]

Maintenance ketamine treatment, delivered through various methods such as intravenous and intranasal, shows promise in sustaining antidepressant effects for patients with treatment-resistant depression, based on a review of multiple studies including three randomized controlled trials.

The treatment appears to have a favorable safety profile, with serious side effects like addiction and renal issues being uncommon, although further long-term studies are needed to fully establish its efficacy and role in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Smith-Apeldoorn, SY., Veraart, JK., Spijker, J., 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]

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]

Ketamine shows promise as a treatment for treatment-resistant depression (TRD), but its use can lead to common adverse events, which are usually temporary.

A case of apnea during a slow sub-anesthetic infusion of ketamine highlights a rare but serious potential side effect, emphasizing the need for careful monitoring and management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. Gómez-Revuelta, M., Fernández-Rodríguez, M., Boada-Antón, L., et al.[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]

In a study of 53 older adults with treatment-resistant depression, repeated intravenous (IV) ketamine infusions led to significant reductions in depressive symptoms, with 27% of participants showing a response and 10% achieving remission after 4 infusions.

While ketamine was effective, 69% of participants experienced transient hypertension during treatment, highlighting the need for monitoring and potential intervention for this side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series. Lipsitz, O., Di Vincenzo, JD., Rodrigues, NB., 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]

The FDA has approved S-ketamine nasal spray as a new treatment option for patients with treatment-resistant depression, marking a significant advancement in psychiatric therapies.

Intravenous ketamine has been researched for depression treatment since the 1990s, and this paper outlines the current protocol for its use in patients who do not respond to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ketamine infusion therapy in treatment-resistant depression]. Christodoulakis, ΤΕ.[2022]

Ketamine infusions have shown significant short-term efficacy in reducing depression severity in patients with treatment-resistant depression, as supported by evidence from 10 systematic reviews and randomized controlled trials.

The treatment is generally well tolerated with minimal side effects, but more large-scale studies are needed to evaluate long-term effects and optimal dosing schedules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine and Treatment-Resistant Depression. Lent, JK., Arredondo, A., Pugh, MA., et al.[2020]

Ketamine, an NMDA receptor antagonist, has shown rapid and significant antidepressant effects in treatment-resistant depression (TRD), with an (S)-ketamine nasal spray now approved for use alongside oral antidepressants in the U.S. and Europe.

Despite its effectiveness, challenges such as maintaining response, potential side effects, and abuse risk remain, highlighting the need for further research to develop safer, next-generation rapid-acting antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for depression. Jelen, LA., Stone, JM.[2021]

Citations

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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.

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Ketamine for Adults With Treatment-Resistant Depression or ... A 2022 CADTH report 24 on the use of ketamine for PTSD or TRD found insufficient evidence to provide definitive conclusions about its clinical effectiveness.

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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.

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Ketamine and chronic treatment-resistant depression Ketamine has shown a rapid but short-lived antidepressant effect in several studies involving TRD patients with different demographic and clinical profiles.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05625555

Predictors of Intravenous Ketamine Response in TRD The main problem with IV ketamine for TRD is that the effect is short-lived, lasting only days to 1 or 2 weeks. Furthermore, IV ketamine is a resource-intensive ...

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

Ketamine - StatPearls - NCBI Bookshelf - NIH Ketamine is a medication approved by the United States Food and Drug Administration (FDA) for use as a general anesthetic either on its own or in combination ...

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Pharmacokinetics, Safety, and Tolerability of (R)-Ketamine ... The adverse events of (R)-ketamine hydrochloride injection were temporary and recovered spontaneously without treatment. Conclusions: In summary ...

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Ketamine for Adults With Treatment-Resistant Depression ... Findings suggest overall safety and tolerability of ketamine for treatment of post-traumatic stress disorder or treatment-resistant depression. Most frequent ...

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2018/016812s040lbl.pdf

ketamine - accessdata.fda.gov 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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Ketamine: Uses, Dosage, Side Effects, Warnings Ketamine is not FDA-approved for depression; it is used off-label for this condition. Ketamine Therapy. Ketamine infusion therapy has been used ...