Ketamine for Depression in Mild Cognitive Impairment

Overseen By Rachel Fremont

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Icahn School of Medicine at Mount Sinai

Disqualifiers: Uncontrolled hypertension, Renal impairment, Seizures, Schizophrenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 8

Duration: 1 day

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing ketamine to see if it can quickly improve depression and cognitive functions in people with mild cognitive impairment and depression (MCI-D). The study will also look at how brain changes affect the treatment's effectiveness. The goal is to gather data for a larger study.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. Please consult with the study team for guidance.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the idea that Ketamine for Depression in Mild Cognitive Impairment is an effective drug?

The available research does not provide specific data on the effectiveness of Ketamine for Depression in Mild Cognitive Impairment. Instead, it discusses other treatments like nicotine, Ginkgo biloba extract, and levetiracetam for cognitive issues. Nicotine showed improved cognitive performance in a study, while Ginkgo biloba is noted for its neuroprotective effects. Levetiracetam improved cognitive deficits in Alzheimer's models. However, none of these studies directly address Ketamine's effectiveness for this condition. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Ketamine for treating depression in mild cognitive impairment?

There is no direct evidence from the provided research articles supporting the effectiveness of Ketamine for treating depression in mild cognitive impairment. However, Ketamine is known for its rapid antidepressant effects in other conditions, which might suggest potential benefits for depression in this context. ^{1 2 3 4 5}

What safety data exists for using ketamine to treat depression?

Ketamine and esketamine have been studied for their rapid-onset antidepressant effects, particularly in treatment-resistant depression. Common side effects include dissociation and increased blood pressure. Intranasal esketamine is approved in the US and EU, while intravenous ketamine is used off-label. Studies show ketamine is generally safe with short-term use, but long-term safety and efficacy require further research. Different routes of administration, such as subcutaneous, intravenous, and intranasal, have been explored, with varying side effects and tolerability. More studies are needed to determine the best administration method and to assess long-term safety. ^{6 7 8 9 10}

Is ketamine generally safe for use in humans?

Ketamine has been shown to be generally safe for use in humans, with common side effects including a sense of detachment from reality and increased blood pressure. It is important to note that while ketamine is effective for depression, its long-term safety still needs more research. ^{6 7 8 9 10}

Is the drug Ketamine a promising treatment for depression in people with mild cognitive impairment?

Ketamine could be a promising drug for treating depression in people with mild cognitive impairment because depression is common in these individuals and can lead to more severe memory problems. By addressing depression, Ketamine might help improve their overall mental health and potentially slow down the progression to more serious conditions like Alzheimer's disease. ^{4 11 12 13 14}

How is the drug ketamine unique for treating depression in mild cognitive impairment?

Ketamine is unique because it works quickly to relieve depression symptoms by affecting a different brain pathway than traditional antidepressants, which often take weeks to work. It is usually given as an infusion (a slow injection into a vein), making it different from most oral antidepressants. ^{4 11 12 13 14}

Research Team

Rachel Fremont, MD, PhD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for adults aged 50-90 with moderate depression and mild cognitive impairment or early Alzheimer's. Participants must be able to consent, have a specific score on the MADRS scale indicating depression, and cannot have severe medical issues like uncontrolled high blood pressure, serious heart problems, kidney issues, or a history of certain mental health disorders.

Inclusion Criteria

I have been diagnosed with mild cognitive impairment or mild Alzheimer's Disease.

You have a score of at least 20 on the Montgomery Asberg Depression Rating Scale, indicating moderate depression or higher.

You are capable of offering consent.

Exclusion Criteria

My kidney function is impaired with specific blood test results.

My blood pressure is not controlled by medication.

I do not have any severe, unstable illnesses.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Baseline

Baseline visit includes questionnaires, blood draw, cognitive evaluation, clinical evaluation, neuroimaging, and optional EEG

1 day

1 visit (in-person)

Treatment

Single dose of IV ketamine administered at 0.5 mg/kg

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with follow-up visits including questionnaires, cognitive evaluation, and clinical evaluation

4 weeks

5 visits (in-person)

Treatment Details

Interventions

• Ketamine

Trial Overview The study tests if a single IV dose of Ketamine can improve symptoms of depression and cognitive function in older adults with mild cognitive impairment. It will also look at how brain imaging and amyloid markers relate to treatment response. This pilot study aims to gather data for future larger-scale research.

Participant Groups

Group I: Treatment Experimental Treatment 1 Intervention

Single dose of IV ketamine administered at the standard dose used for depression treatment (0.5 mg/kg)

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?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

Findings from Research

A 6-month pilot clinical trial demonstrated that transdermal nicotine treatment improved cognitive performance in individuals with amnestic mild cognitive impairment (MCI), suggesting a potential new treatment avenue for this condition.

Currently, there are no FDA-approved medications for MCI, highlighting the importance of this study in exploring nicotine as a viable option for improving cognitive function in affected individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible role of nicotine for the treatment of mild cognitive impairment. Roh, S., Evins, AE.[2012]

Ginkgo biloba extract, EGb 761®, has shown symptomatic improvement in cognitive performance and neuropsychiatric symptoms in at least four randomized trials involving individuals with mild cognitive impairment (MCI).

The expert group recommends incorporating EGb 761® into treatment plans for MCI, as it may also help delay progression to dementia, particularly in patients with underlying cerebrovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for the use of Ginkgo biloba extract, EGb 761® , in the treatment and management of mild cognitive impairment in Asia: Expert consensus. Kandiah, N., Chan, YF., Chen, C., et al.[2021]

Levetiracetam, an FDA-approved antiepileptic drug, effectively reduces seizure frequency in patients with epilepsy while preserving cognitive functions, making it a safe option for these individuals.

The drug shows potential cognitive improvement in patients with Alzheimer's disease and in animal models of cognitive decline, suggesting it may be beneficial for preventing or treating Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam might act as an efficacious drug to attenuate cognitive deficits of Alzheimer's disease. Xiao, R.[2019]

Elderly patients with depression are at a higher risk of developing mild cognitive impairment (MCI), which can progress to Alzheimer's disease.

The case study of Mr. P highlights the importance of early diagnosis and treatment of MCI, as well as the use of specific measurements to predict the likelihood of progression to Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying and treating cognitive impairments in elderly patients. Roose, SP.[2019]

In a study of 16,236 patients with mild cognitive impairment (MCI) in France, only 6.1% were prescribed anti-Alzheimer's disease (anti-AD) medications, indicating low off-label use.

Factors associated with the use of anti-AD medications included older age, lower cognitive function (MMSE score), the amnestic subtype of MCI, living at home, and higher education levels, suggesting that these medications are primarily prescribed to those at greater risk of progressing to Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mild cognitive impairment and anti-Alzheimer disease medications: A cross sectional study of the French National Alzheimer Databank (BNA). Tifratene, K., Sakarovitch, C., Rouis, A., et al.[2016]

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]

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 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 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]

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]

The overall prevalence of depression in individuals with mild cognitive impairment (MCI) is estimated to be 32%, based on a systematic review of 57 studies involving 20,892 patients, highlighting a significant mental health concern in this population.

Depression prevalence is notably higher in clinic-based samples (40%) compared to community-based samples (25%), indicating that the setting of diagnosis may influence reported rates of depression in patients with MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevalence of Depression in Patients With Mild Cognitive Impairment: A Systematic Review and Meta-analysis. Ismail, Z., Elbayoumi, H., Fischer, CE., et al.[2022]

A systematic review identified nine validated tools for detecting depression in individuals with mild cognitive impairment (MCI), with several tools showing a high sensitivity of 100%, indicating they are very effective at identifying depressive symptoms.

Despite the promising results, the evidence is limited to single studies for each tool, highlighting the need for further research to confirm their accuracy and effectiveness across different types of MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detecting depression in persons living with mild cognitive impairment: a systematic review. Wong, B., Ismail, Z., Goodarzi, Z.[2022]

In a study of 31 older adults with depression and mild cognitive impairment (MCI), those with amyloid-β (CDAP) showed reduced regional cerebral glucose metabolism (rCMglc) in temporoparietal areas compared to those with normal cognition, indicating potential early signs of Alzheimer's disease.

The group without amyloid-β (CDAN) exhibited lower rCMglc in both frontal and temporoparietal regions, suggesting different metabolic patterns in depression-related MCI, which could help in assessing the risk of cognitive decline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regional glucose metabolism due to the presence of cerebral amyloidopathy in older adults with depression and mild cognitive impairment. Youn, H., Lee, ES., Lee, S., et al.[2019]

In a study of 400 patients with Type 2 diabetes, 76% were found to have varying degrees of depression, while 56.8% had mild cognitive impairment (MCI), highlighting a high prevalence of these comorbid conditions in this population.

Factors such as low HDL-cholesterol levels and high anxiety scores were significant predictors of depression, while increased total cholesterol and low HDL-cholesterol levels were linked to anxiety, indicating that managing cholesterol levels may be important for mental health in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of comorbid mild cognitive impairment and depression in patients with type 2 diabetes mellitus. Abd Elaaty, TA., Ismail, AA., Sheshtawy, HA., et al.[2019]

References

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

Possible role of nicotine for the treatment of mild cognitive impairment. [2012]

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

Strategies for the use of Ginkgo biloba extract, EGb 761® , in the treatment and management of mild cognitive impairment in Asia: Expert consensus. [2021]

3. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Levetiracetam might act as an efficacious drug to attenuate cognitive deficits of Alzheimer's disease. [2019]

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

Identifying and treating cognitive impairments in elderly patients. [2019]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Mild cognitive impairment and anti-Alzheimer disease medications: A cross sectional study of the French National Alzheimer Databank (BNA). [2016]

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

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

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

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

8. Germany pubmed.ncbi.nlm.nih.gov

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

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

Pharmacotherapy: Ketamine and Esketamine. [2023]

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

Ketamine for the treatment of depression. [2022]

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

Prevalence of Depression in Patients With Mild Cognitive Impairment: A Systematic Review and Meta-analysis. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Detecting depression in persons living with mild cognitive impairment: a systematic review. [2022]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Regional glucose metabolism due to the presence of cerebral amyloidopathy in older adults with depression and mild cognitive impairment. [2019]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Assessment of comorbid mild cognitive impairment and depression in patients with type 2 diabetes mellitus. [2019]