Ketamine + Perampanel for Depression

Overseen By Elizabeth Traester, B.A.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must not be taking: Topiramate, Memantine, Barbiturates, others

Disqualifiers: Suicide risk, Neurological disorder, Psychosis, Diabetes, others

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

Compensation: Varies

Number of Visits: 4

Duration: 2 days

50 Participants Needed

Trial Summary

What is the purpose of this trial?

The proposed study will assess the combined effect of perampanel and ketamine on the anti-depressant response in individuals with treatment resistant depression. The purpose of this study is to test the hypothesis that stimulation of Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid receptors (AMPAR) is critical to the anti-depressant response of ketamine.

Will I have to stop taking my current medications?

Participants must continue their current depression medication and dose for at least 4 weeks before joining the trial and should plan to keep taking it throughout the study. However, if you are currently taking ketamine, topiramate, memantine, barbiturates, monoamine oxidase inhibitors, or using benzodiazepines during the day, you will need to stop these medications before joining the trial.

What data supports the effectiveness of the drug Ketamine for depression?

Research shows that ketamine, when given intravenously or subcutaneously, can quickly and effectively reduce depression symptoms, even in patients who have not responded to other treatments. Studies have reported rapid and significant improvements in depression symptoms with ketamine, making it a promising option for those with treatment-resistant depression. ^{1 2 3 4 5}

Is the combination of Ketamine and Perampanel generally safe for humans?

Ketamine is known to have rapid antidepressant effects but can cause side effects like dissociation (feeling detached from reality) and increased blood pressure. It has been studied in various forms and routes, showing some promise with manageable side effects, but long-term safety still needs more research. Perampanel's safety in combination with ketamine specifically isn't detailed here, so consulting with a healthcare provider is recommended. ^{3 6 7 8 9}

How is the drug Ketamine + Perampanel unique for treating depression?

Ketamine is unique for depression treatment because it acts rapidly and can be administered in various ways, including subcutaneously, which is convenient and cost-effective. It works through multiple pathways, including NMDA receptor blocking and σ1-receptor activation, potentially enhancing its antidepressant effects compared to other treatments. ^{3 4 6 9 10}

Research Team

John Krystal, MD

Principal Investigator

Yale University Medical School

Naomi R Driesen, Ph.D.

Principal Investigator

Yale University Medical School

Eligibility Criteria

This trial is for right-handed individuals with treatment-resistant depression, scoring above 17 on the Hamilton Depression Scale. They must be undergoing or agree to start external therapy and maintain current medication doses throughout the trial. Participants should avoid caffeine, drugs, alcohol before MRI sessions and use birth control if applicable.

Inclusion Criteria

I am receiving treatment besides the ketamine given in this study.

My depression hasn't improved after trying at least one anti-depressant.

I have been in psychotherapy for 4 weeks and plan to continue during the trial.

Exclusion Criteria

I have not donated more than 500 mL of blood or lost a similar amount in the last 56 days.

Psychosis other than psychotic experiences congruent with depressed mood during a period of depression

I have not taken monoamine oxidase inhibitors in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive either ketamine plus perampanel or ketamine plus placebo, followed by MRI scans and symptom assessments

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 hours

1 visit (in-person)

Treatment Details

Interventions

• Ketamine
• Perampanel
• Placebo

Trial Overview The study tests whether activating AMPAR receptors enhances ketamine's anti-depressant effects in those unresponsive to standard treatments. It involves combining perampanel with ketamine versus a placebo to see if this improves depressive symptoms more effectively.

Participant Groups

Group I: ketamine plus perampanel Experimental Treatment 2 Interventions

A screening session is conducted to ensure that the subject can safely receive perampanel and ketamine (physical exam, blood and urine analyses, electrocardiogram, drug and alcohol testing). The participant will then receive 6 milligrams (mg) oral perampanel and intravenous ketamine. Participants will then undergo a 2-hour magnetic resonance imagining (MRI) scan. The following day, participants will return for an additional scan and symptom assessment.

Group II: ketamine plus placebo Placebo Group 2 Interventions

A screening session is conducted to ensure that the subject can safely receive perampanel and ketamine (physical exam, blood and urine analyses, electrocardiogram, drug and alcohol testing). The participant will then receive an oral placebo (in lieu of 6 mg oral perampanel) and intravenous ketamine. Participants will then undergo a 2-hour MRI scan. The following day, participants will return for an additional scan and symptom assessment.

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?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

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 case series involving three hospice patients demonstrated that a single subcutaneous dose of ketamine (0.5 mg/kg) followed by daily oral ketamine (0.5 mg/kg) led to rapid improvement in depression symptoms, as measured by various assessment tools.

This approach offers a potentially effective and convenient method for managing depression in hospice patients, providing quicker relief compared to traditional antidepressant therapies, although further prospective studies are needed to optimize dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single Subcutaneous Ketamine Dose Followed by Oral Ketamine for Depression Symptoms in Hospice Patients: A Case Series. Latuga, NM., Luczkiewicz, DL., Grant, PC., 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]

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 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 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]

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]

Ketamine and esketamine are effective for rapidly alleviating symptoms of treatment-resistant depression, with esketamine being approved for use in the US and EU, while ketamine is often used off-label.

Both treatments may require repeated doses and the addition of standard antidepressants to sustain their effects, but they also carry risks of adverse effects and potential for abuse, highlighting the need for further research on their long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy: Ketamine and Esketamine. Feeney, A., Papakostas, GI.[2023]

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]

S-ketamine, administered as a nasal spray, has demonstrated clear antidepressant effects in patients with major depressive disorder, but its efficacy is less pronounced compared to racemic ketamine given intravenously.

R-ketamine may enhance the antidepressant effects of S-ketamine through its unique mechanism of action involving σ1-receptors, which could explain why the racemic mixture shows superior efficacy compared to S-ketamine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of σ1-Receptors by R-Ketamine May Enhance the Antidepressant Effect of S-Ketamine. Kalkman, HO.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Single Subcutaneous Ketamine Dose Followed by Oral Ketamine for Depression Symptoms in Hospice Patients: A Case Series. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Intravenous ketamine infusion for a patient with treatment-resistant major depression: a 10-month follow-up. [2018]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Intravenous ketamine therapy in a patient with a treatment-resistant major depression. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Pharmacotherapy: Ketamine and Esketamine. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

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

10. Switzerland pubmed.ncbi.nlm.nih.gov

Activation of σ1-Receptors by R-Ketamine May Enhance the Antidepressant Effect of S-Ketamine. [2023]