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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore whether ketamine, known for rapid depression relief, can also improve depression and thinking skills in people with mild cognitive issues and depression. Participants will receive a single dose of ketamine through an IV to assess its effects on mood and mental function. This study targets individuals diagnosed with mild cognitive impairment or mild Alzheimer's who are experiencing moderate depression. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that ketamine is generally safe and well-tolerated for treating depression. In a previous study, individuals with mild memory and thinking problems and depression who received a single dose of ketamine through an IV reported feeling better. Importantly, this treatment proved safe for them. Most side effects of ketamine are mild, temporary, and resolve on their own. Additionally, studies have not found ketamine to harm brain function, indicating it does not negatively affect brain performance. Overall, existing evidence suggests ketamine might be a promising and safe option for those with both depression and mild cognitive issues. ^{1 2 3 4 5}

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

Most treatments for depression in mild cognitive impairment involve antidepressants or cognitive therapies that can take weeks to show effects. But ketamine works differently, offering a new approach by targeting the brain's glutamate system rather than the typical serotonin pathways. This unique mechanism allows ketamine to potentially provide rapid relief from depressive symptoms, sometimes within hours. Researchers are excited about ketamine because of its fast-acting nature and potential to help patients who have not responded well to standard treatments.

What evidence suggests that ketamine might be an effective treatment for depression in mild cognitive impairment?

Research has shown that ketamine can quickly improve depression symptoms. Even a single dose can positively affect mood and cognitive skills, such as short-term memory and processing speed, within a few days. In this trial, participants will receive a single IV dose of ketamine at the standard dose for depression treatment (0.5 mg/kg). For individuals with mild cognitive impairment and depression (MCI-D), early findings suggest ketamine might enhance brain adaptability, particularly in the hippocampus. Some small studies have found that ketamine is safe and may help reduce depression in older adults. While more research is needed, these early results are promising for ketamine's use in MCI-D. ^{5 6 7 8 9}

Who Is on the Research Team?

Rachel Fremont, MD, PhD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

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

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1064748125002544

Ket-MCI: An Open-Label Pilot Study Exploring Intavenous ... The findings thus far, although preliminary, suggest that even a single infusion of ketamine at 0.5 mg/kg may improve depression in individuals with MCI-D and ...

2. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.095388

KET‐MCI: An open‐label trial of single‐dose ketamine ... Conclusion. Sub-anesthetic IV ketamine appears to be safe and tolerable in individuals with MCI-D and may improve depressive symptoms. Larger ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10154013/

Efficacy and safety of ketamine for the treatment ... Fan et al.28 demonstrated the treatment efficacy of ketamine against depressive symptoms (more specifically, against suicidal ideation). Compared with placebo, ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0165032724003616

Cognitive outcomes from the randomised, active-controlled ... For example, chronic and high dose recreational ketamine users have shown relatively impaired verbal fluency, episodic memory, attention/working ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12547681/

Serial Ketamine Infusions as Adjunctive Therapy to ... In this randomized clinical trial, serial intravenous ketamine was not significantly more effective than serial midazolam in reducing depressive ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35416105/

Long-term safety of ketamine and esketamine in treatment ... Expert opinion: Based on available data, the most common side effects of ketamine/esketamine are generally transient, mild, and self-limited.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0010440X23000858

The impact of depressive symptoms on cognitive ... Additionally, ketamine users with depressive symptom had significantly higher SDS scores than those without depressive symptom. Table 1. Demographic ...

8. psychiatrist.com psychiatrist.com/jcp/ketamine-cognitive-function-depression-detrimental-neutral-advantageous/

Ketamine and Cognitive Function in Depression There has been little consistent information about whether ketamine is associated with predictably beneficial, detrimental, or neutral effects on cognitive ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4367458/

Neurocognitive Effects of Ketamine and Association with ... Our finding of an absence of adverse effects of ketamine on neurocognitive functioning in this patient population may contribute to a risk-benefit analysis of ...