Ketamine + Perampanel for Depression
Recruiting in Palo Alto (17 mi)
Overseen byJohn Krystal, MD
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Yale University
Must not be taking: Topiramate, Memantine, Barbiturates, others
Disqualifiers: Suicide risk, Neurological disorder, Psychosis, Diabetes, others
Approved in 5 Jurisdictions
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.12345
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.36789
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.346910
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.
See 10 more
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.
See 23 more
Trial 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 (Glutamate Receptor Modulator)
- Perampanel (Glutamate Receptor Modulator)
- Placebo (Placebo)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Placebo Group
Group I: ketamine plus perampanelExperimental Treatment2 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 placeboPlacebo Group2 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, 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Yale UniversityNew Haven, CT
Loading ...
Who Is Running the Clinical Trial?
Yale UniversityLead Sponsor
National Institute of Mental Health (NIMH)Collaborator
References
A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. [2023]Outcomes of ketamine intravenous therapy (KIT) for depression in real-world care settings have been minimally evaluated. We set out to quantify treatment response to KIT in a large sample of patients from community-based practices.
Single Subcutaneous Ketamine Dose Followed by Oral Ketamine for Depression Symptoms in Hospice Patients: A Case Series. [2021]Management of depression symptoms in hospice patients is complicated by the fact that an appropriate trial of antidepressant therapy requires 4-6 weeks and most hospice patients receive hospice services for less than 8 weeks. Intravenously administered ketamine has been shown to produce rapid improvement in depression symptoms but is not an ideal route for hospice patients and oral ketamine appears to have a slower onset of antidepressant activity. We present a case series that illustrates the use of a single subcutaneous dose of ketamine (0.5 mg/kg) followed by daily oral ketamine (0.5 mg/kg daily) therapy to manage depression symptoms in three hospice patients. Clinical improvement of depression symptoms occurred quickly for all patients as measured by the PHQ-4, numeric ratings, and subjective reporting. A single subcutaneous dose of ketamine followed by oral therapy presents itself as an option to quickly reduce depression symptoms in hospice patients that do not also require additional pain management. Combining the use of the subcutaneous and oral routes takes advantage of the possibly faster onset, home administration, and milder side effects than intravenous dosing. Prospective studies are needed to determine which dosing strategy would be the most beneficial for hospice patients.
Subcutaneous Ketamine in Depression: A Systematic Review. [2021]Background: Ketamine has been shown to produce a rapid and robust antidepressant effect. Though numerous routes of administration have been studied, subcutaneous (SC) has proven to be a convenient and cost-effective route making its use particularly relevant in developing countries. Here we provide a systematic review covering the use of SC racemic ketamine and esketamine in depression, including its efficacy, safety and tolerability. Methods: A systematic literature search was carried out, from inception through March, 2021, using PubMed/MEDLINE, EMBASE and Web of Science, with no limits of language. After identifying 159 potentially relevant articles, 12 articles were selected after applying our inclusion/exclusion criteria. These comprised two randomized clinical trials, five case-reports and five retrospective studies. Given the small number of studies found and their heterogeneous nature, a meta-analysis was not considered appropriate. Here we provide a synthesis of these data including participant characteristics, dose range, efficacy, safety/ tolerability. Risk of bias was accessed using the Cochrane risk of bias tool. Results: SC Ketamine was administered to unipolar and bipolar patients a single or multiple doses, weekly or twice-weekly, a dose-titration approach was made in major studies, dose ranged from 0.1 to 0.5 mg/Kg of racemic ketamine and 0.5-1 mg/Kg of esketamine. Across all studies, SC ketamine showed a rapid and robust antidepressant effect, with response/ remission rates from 50 to 100% following both single or multiple doses, with transitory side effects. Conclusion: SC racemic ketamine and esketamine in depression is a promising strategy showing beneficial efficacy and tolerability. Future studies exploring the SC route, its cost-effectiveness, and a direct comparison with IV and intranasal (IN) protocols are warranted. Systematic Review Registration: CRD42019137434.
Intravenous ketamine infusion for a patient with treatment-resistant major depression: a 10-month follow-up. [2018]Ketamine in a subanaesthetic dose has been shown to produce rapid antidepressant effects. Here, we describe a long-term follow-up case of a Korean patient with severe major depression who received repeated ketamine intravenous therapy (KIT).
Intravenous ketamine therapy in a patient with a treatment-resistant major depression. [2022]Recently, reports from North America have indicated that the intravenous infusion of ketamine hydrochloride (an N-methyl-d-aspartate receptor antagonist) results in a sudden and robust improvement of depression symptoms.
Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. [2021]Ketamine has rapid-onset antidepressant effects in patients with treatment-resistant depression. Common side effects include dissociation (a sense of detachment from reality) and increases in systolic and diastolic blood pressure. The objective of this structured review was to examine the effect of ketamine formulation and route of administration on its pharmacokinetics, safety and tolerability, to identify formulation characteristics and routes of administration that might minimise side effects.
The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]On a background of the rapidly expanding clinical use of ketamine and esketamine for treatment of depression and other conditions, we examined safety monitoring, seeking to identify knowledge gaps relevant to clinical practice.
Pharmacotherapy: Ketamine and Esketamine. [2023]Ketamine and esketamine have rapid-onset antidepressant effects and may be considered for the management of treatment-resistant depression. Intranasal esketamine has regulatory approval in the United States and European Union. Intravenous ketamine is often administered off-label as an antidepressant, though no standard operating procedures exist. Repeated administrations and the use of a concurrent standard antidepressant may maintain antidepressant effects of ketamine/esketamine. Possible adverse effects of ketamine and esketamine include psychiatric, cardiovascular, neurologic and genitourinary effects, and the potential for abuse. The long-term safety and efficacy of ketamine/esketamine as antidepressants require further study.
Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022]To summarize the evidence of efficacy and safety of the use of ketamine and esketamine for depression.
Activation of σ1-Receptors by R-Ketamine May Enhance the Antidepressant Effect of S-Ketamine. [2023]Ketamine is a racemic mixture composed of two enantiomers, S-ketamine and R-ketamine. In preclinical studies, both enantiomers have exhibited antidepressant effects, but these effects are attributed to distinct pharmacological activities. The S-enantiomer acts as an NMDA-channel blocker and as an opioid μ-receptor agonist, whereas the R-enantiomer binds to σ1-receptors and is believed to act as an agonist. As racemate, ketamine potentially triggers four biochemical pathways involving the AGC-kinases, PKA, Akt (PKB), PKC and RSK that ultimately lead to inhibitory phosphorylation of GSK3β in microglia. In patients with major depressive disorder, S-ketamine administered as a nasal spray has shown clear antidepressant activity. However, when compared to intravenously infused racemic ketamine, the response rate, duration of action and anti-suicidal activity of S-ketamine appear to be less pronounced. The σ1-protein interacts with μ-opioid and TrkB-receptors, whereas in preclinical experiments σ1-agonists reduce μ-receptor desensitization and improve TrkB signal transduction. TrkB activation occurs as a response to NMDA blockade. So, the σ1-activity of R-ketamine may not only enhance two pathways via which S-ketamine produces an antidepressant response, but it furthermore provides an antidepressant activity in its own right. These two factors could explain the apparently superior antidepressant effect observed with racemic ketamine compared to S-ketamine alone.