Perampanel + Ketamine for Suicidal Thoughts

Overseen By Margaret Rowland

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

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

Disqualifiers: Neurological disorder, Psychosis, Substance use, others

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: 3

Duration: 6 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the hypothesis that the anti-depressant and anti-suicidal effects of the N-methyl-D-aspartate receptor (NMDAR) antagonist Ketamine is critically dependent on stimulation of Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid receptors (AMPAR).

Will I have to stop taking my current medications?

The trial requires that participants stay on their current medications and dose for at least 4 weeks before joining and continue them throughout the study. However, certain medications like topiramate, memantine, barbiturates, monoamine oxidase inhibitors, and daytime benzodiazepines must be stopped before joining the trial.

Is the combination of Perampanel and Ketamine safe for humans?

Ketamine, when used as a medicine, is considered safe and is listed as an essential medicine by the World Health Organization. It has been used safely in therapeutic settings, particularly for depression, with common side effects including a sense of detachment from reality and increased blood pressure. However, the long-term safety of ketamine, especially in combination with other drugs like Perampanel, requires further study. ^{1 2 3 4 5}

What makes the drug Perampanel + Ketamine unique for treating suicidal thoughts?

The combination of Perampanel and Ketamine is unique because it potentially offers a novel approach to rapidly reducing suicidal thoughts, leveraging Ketamine's fast-acting antidepressant effects and Perampanel's role in modulating brain activity, which is different from traditional antidepressants that often take weeks to show effects. ^{6 7 8 9 10}

Research Team

Naomi Driesen, PhD

Principal Investigator

Yale University / VACHS West Haven

Eligibility Criteria

This trial is for adults with treatment-resistant depression, PTSD, or bipolar disorder who have suicidal thoughts. They must be educated to at least a 12th-grade level, not pregnant or breastfeeding, and agree to birth control if applicable. Participants should be stable on current psychotherapy or medication regimens for four weeks prior to the study and willing to avoid caffeine, drugs, and alcohol before treatments.

Inclusion Criteria

Current depression as indicated by a score greater than 17 on the full Hamilton Depression Rating Scale (HDRS-17) AND current major depressive episode as determined by structured clinical interview (SCID-5)

Have at least a 12th grade education level or equivalent

Current suicidal ideation as indicated by a score ≥ 2 on the HDRS-17 Item #3 ('wishes to be dead (or any thoughts of possible death to self)')

Exclusion Criteria

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

I have a neurological condition, but not migraines or mild head injury.

I am currently being treated with Ketamine.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive oral perampanel or placebo followed by a Ketamine infusion, with infusions at least three weeks apart

6 weeks

2 visits (in-person) for infusions

Follow-up

Participants are monitored for changes in suicidal ideation and antidepressant response 24 hours post-infusion

1 week

Follow-up assessments through interview and electronic diary

Treatment Details

Interventions

• Ketamine
• Perampanel 6 MG

Trial Overview The study tests whether Ketamine's effects on reducing depression and suicidal thoughts depend on AMPA receptors. It involves comparing Perampanel (an AMPA receptor blocker), Ketamine (a known NMDAR antagonist), and a placebo in participants with certain mood disorders.

Participant Groups

Group I: Perampanel + Ketamine Experimental Treatment 2 Interventions

Participants will receive oral perampanel or placebo, in counterbalanced order, 2.5 hours before a standard, subanesthetic Ketamine infusion (0.5 mg/kg over 40 minutes). Ketamine infusions will be at least three weeks apart. Participants will refrain from caffeine and over-the-counter medication seven days before the infusion day.

Group II: Placebo + Ketamine Placebo Group 2 Interventions

Participants will receive oral perampanel or placebo, in counterbalanced order, 2.5 hours before a standard, subanesthetic Ketamine infusion (0.5 mg/kg over 40 minutes). Ketamine infusions will be at least three weeks apart. Participants will refrain from caffeine and over-the-counter medication seven days before the infusion day.

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 Center for PTSD

Collaborator

Trials

13

Recruited

1,200+

American Foundation for Suicide Prevention

Collaborator

Trials

36

Recruited

10,500+

VA Connecticut Healthcare System

Collaborator

Trials

86

Recruited

8,800+

Findings from Research

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 review of 34 articles revealed 312 cases of overdose and 138 deaths related to ketamine use, primarily in recreational settings and often involving polydrug use, highlighting significant risks associated with misuse.

Despite concerns about ketamine's safety in non-medical contexts, no overdoses or deaths were reported from its use as an antidepressant in therapeutic settings, suggesting it can be safely prescribed when used appropriately.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overdoses and deaths related to the use of ketamine and its analogues: a systematic review. Chaves, TV., Wilffert, B., Sanchez, ZM.[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]

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]

In a study involving 97 chronic kidney disease patients with hyperkalemia, both calcium polystyrene sulphonate (CPS) and sodium polystyrene sulphonate (SPS) effectively reduced potassium levels, demonstrating their efficacy in managing this condition.

CPS was associated with fewer side effects compared to SPS, making it a potentially safer option for patients undergoing treatment for hyperkalemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of hyperkalemia in patients with chronic kidney disease: a comparison of calcium polystyrene sulphonate and sodium polystyrene sulphonate. Nasir, K., Ahmad, A.[2022]

A meta-analysis of 5 studies, including 3 randomized controlled trials, found that combining zoledronic acid with percutaneous kyphoplasty (PKP) significantly improves bone mineral density (BMD) and quality of life in patients with osteoporotic vertebral compression fractures (OVCFs).

Patients receiving the combination treatment experienced less severe low back pain and had fewer additional vertebral fractures compared to those who underwent PKP alone, indicating enhanced efficacy and safety of the combined approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoledronic Acid in Osteoporotic Vertebral Compression Fractures Treated With Percutaneous Kyphoplasty: A Meta-Analysis. Tian, P., Liu, Y., Li, ZJ., et al.[2021]

Both percutaneous kyphoplasty (PKP) and short-segment internal fixation combined with vertebroplasty (SSF + VP) are safe and effective treatments for Kummell disease in patients without neurological deficits, based on an analysis of three retrospective studies.

PKP is particularly advantageous as it significantly reduces operation time and blood loss compared to SSF + VP, making it a preferable option for treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of percutaneous kyphoplasty or short-segmental fixation combined with vertebroplasty in the treatment of Kummell disease. Lu, W., Wang, L., Xie, C., et al.[2020]

Percutaneous kyphoplasty (PKP) significantly reduced pain levels in patients with Kümmell disease, as shown by a decrease in the Visual Analog Scale (VAS) scores from 7.00 pre-surgery to 3.14 at 2 years post-surgery, indicating its efficacy as a treatment.

The study found a positive correlation between the volume of cement injected during PKP and the level of pain relief, suggesting that careful dosing of cement may enhance treatment outcomes, while the procedure was deemed safe with no severe complications reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Percutaneous kyphoplasty treatment evaluation for patients with Kümmell disease based on a two-year follow-up. Xia, YH., Chen, F., Zhang, L., et al.[2020]

Both unilateral and bilateral percutaneous kyphoplasty (PKP) are effective and safe treatments for vertebral fragility fractures in elderly patients, with significant improvements in pain and vertebral body height observed postoperatively.

The unilateral approach to PKP is advantageous due to shorter operation times and less trauma compared to the bilateral approach, making it a more ideal option for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Mid and long-term clinical effects of percutaneous kyphoplasty with two methods for vertebral fragility fracture in the elderly]. Yu, HJ., Ma, GP., Guo, QF., et al.[2018]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Overdoses and deaths related to the use of ketamine and its analogues: a systematic review. [2023]

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

Pharmacotherapy: Ketamine and Esketamine. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

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

5. Germany pubmed.ncbi.nlm.nih.gov

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

6. Pakistan pubmed.ncbi.nlm.nih.gov

Treatment of hyperkalemia in patients with chronic kidney disease: a comparison of calcium polystyrene sulphonate and sodium polystyrene sulphonate. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Zoledronic Acid in Osteoporotic Vertebral Compression Fractures Treated With Percutaneous Kyphoplasty: A Meta-Analysis. [2021]

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

Analysis of percutaneous kyphoplasty or short-segmental fixation combined with vertebroplasty in the treatment of Kummell disease. [2020]

9. Greece pubmed.ncbi.nlm.nih.gov

Percutaneous kyphoplasty treatment evaluation for patients with Kümmell disease based on a two-year follow-up. [2020]

10. China pubmed.ncbi.nlm.nih.gov

[Mid and long-term clinical effects of percutaneous kyphoplasty with two methods for vertebral fragility fracture in the elderly]. [2018]