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: Unknown

40 Participants Needed

Trial Summary

What is the purpose of this trial?

For patients with treatment-resistant depression (TRD), a single low dose of intravenous (IV) ketamine can help relieve symptoms as quickly as 24 hours later. 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 treatment, and the safety of long-term, repeated use for depression is unknown. To provide this treatment in a safe and cost-effective way, Investigators must allocate it efficiently to those patients who have the greatest need and probability of benefit. Therefore, this project aims to find clinical features (signs, symptoms, and parts of a patient's history) that will help predict which patients are most likely to respond to a single dose of IV ketamine for TRD. This will help guide patient selection and triaging. Investigators will recruit 40 participants with TRD over one year, and randomize them to one of two conditions (ketamine followed by an active placebo 3-weeks later, or vice versa). With clinical data collected through detailed interviews, questionnaires, actigraphy, speech sampling, electroencephalography (EEG), and computerized tasks, this study design will let us evaluate how well such factors predict (A) rapid response at 24-hours, and (B) sustained response at 7 and 14 days.

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.

What data supports the idea that Ketamine for Treatment-Resistant Depression is an effective drug?

The available research shows that ketamine has rapid and strong effects in reducing depression symptoms in people with treatment-resistant depression. Studies have found that ketamine can significantly decrease depression severity in the short term. It is generally well tolerated with minimal side effects. While more research is needed to understand its long-term effects, ketamine offers a promising alternative to other treatments like electroconvulsive therapy or transcranial magnetic stimulation. ^{1 2 3 4 5}

What safety data exists for ketamine in treating depression?

Existing safety data for ketamine in treating depression includes findings from various studies and reviews. Subcutaneous ketamine has shown rapid antidepressant effects with transient side effects. A systematic review highlighted its efficacy and tolerability, though more research is needed to compare it with other administration routes. An overview of systematic reviews with meta-analyses summarizes the efficacy and safety of ketamine and esketamine. A case report noted apnea as a rare adverse event during intravenous administration, emphasizing the need for careful monitoring. The Ketamine Side Effect Tool (KSET) was developed to improve safety monitoring in clinical practice. Long-term safety data is still being gathered, with esketamine approved by the FDA for treatment-resistant depression in 2019. ^{6 7 8 9 10}

Is the drug Ketamine a promising treatment for people with depression that doesn't respond to other treatments?

Yes, Ketamine is a promising treatment for people with depression that doesn't respond to other treatments. It works quickly to reduce symptoms, including suicidal thoughts, and can be effective when other medications or therapies have failed. Different forms of Ketamine, like intravenous and nasal spray, have shown positive results in maintaining its antidepressant effects. ^{1 3 4 11 12}

Research Team

Abraham Nunes, MD PhD MBA FRCPC

Principal Investigator

Nova Scotia Health Authority

Eligibility Criteria

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Ketamine and Treatment-Resistant Depression. [2020]

3. Greece pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Ketamine for depression. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. [2021]

9. Netherlands pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Long-term safety of ketamine and esketamine in treatment of depression. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

A review of ketamine's role in ECT and non-ECT settings. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Ketamine for the treatment of depression. [2022]