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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how ketamine and perampanel, when used together, might help people with depression unresponsive to other treatments. The research aims to determine if these drugs, particularly by targeting specific brain receptors (AMPAR), can enhance ketamine's antidepressant effects. Participants will be divided into two groups: one will receive ketamine with perampanel, and the other with a placebo. Individuals who have struggled with depression despite other medications might be a good fit, especially if they previously responded positively to ketamine. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this novel combination therapy.

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.

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

Research has shown that ketamine, often used for hard-to-treat depression, is generally safe for most people. Some may experience dizziness or nausea, but these side effects are usually mild. Studies have also found that perampanel, a drug for epilepsy, can help improve depression symptoms. Tested in people with epilepsy, it showed mood improvements. However, both drugs can cause side effects, so researchers continue to study their combined effects.

This clinical trial primarily focuses on safety. It is in an early stage, examining how well people tolerate the combination of ketamine and perampanel. The trial aims to identify any side effects when the two drugs are used together. Since both drugs are already used for other conditions, there is some confidence in their safety. However, this specific combination still requires careful study.

Participants in this trial will be closely monitored for any side effects, ensuring that potential risks are managed safely. ^{1 2 3 4 5}

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

Researchers are excited about using ketamine combined with perampanel for treating depression because this approach targets brain activity in a novel way. Unlike standard antidepressants, which often take weeks to become effective and typically alter serotonin levels, ketamine offers rapid relief by modulating NMDA receptors, a type of glutamate receptor, providing potential benefits within hours. Adding perampanel, which also affects glutamate pathways, might enhance and prolong ketamine’s effects, offering a new mechanism of action and potentially more effective treatment for those not responding well to conventional therapies.

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

Research has shown that ketamine, one of the treatments in this trial, can quickly and significantly improve depression symptoms, especially for those who haven't found relief with other treatments. In some studies, about 55% of patients experienced a significant decrease in their depression symptoms after receiving ketamine. This trial will explore whether combining ketamine with perampanel, another treatment option in this trial, can enhance this effect. Perampanel affects certain brain parts called AMPA receptors. One study suggested that blocking these receptors with perampanel might alter how ketamine works, possibly influencing mood improvements. While more research is needed to confirm the effectiveness of this combination, ketamine alone has shown promise for treating difficult cases of depression. ^{4 6 7 8 9}

Who Is on the Research Team?

John Krystal, MD

Principal Investigator

Yale University Medical School

Naomi R Driesen, Ph.D.

Principal Investigator

Yale University Medical School

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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 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]

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 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]

Citations

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Ketamine + Perampanel for Depression Studies have reported rapid and significant improvements in depression symptoms with ketamine, making it a promising option for those with treatment-resistant ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05786066

The Impact of AMPA Receptor Blockade on Ketamine's Anti ... Perampanel pre-treatment will attenuate Ketamine's reduction of suicidal ideation as assessed 24 hours after drug infusion with a well-established suicidal ...

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Efficacy of single and repeated administration of ketamine in ... At 2–3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD = − 0.70; 95% CI − 1.15; − 0.25 or SMD = − ...

4. 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 ...

5. 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 ...

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

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7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11810691/

Effect of perampanel in reducing depression in patients ... Perampanel reduced depression symptoms in patients with focal epilepsy, although the lack of a control group or the relatively small sample size.

8. emjreviews.com emjreviews.com/neurology/news/ketamine-for-depression-underwhelms-in-new-study/

Ketamine for Depression Underwhelms in New Study A NEW clinical trial has found that serial ketamine infusions offered no greater benefit than placebo in reducing depressive symptoms among ...

9. ibroneuroreports.org ibroneuroreports.org/article/S2667-2421(25)00007-7/pdf

Effect of perampanel in reducing depression in patients with ... Results: The BDI-II score improved significantly compared to before treatment and at 6 and 12 months of follow-up (P < 0.001). The mean total ...