Dasatinib + Quercetin for Premature Aging in Mental Illness
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Washington University School of Medicine
Must be taking: Antidepressants, Antipsychotics
Must not be taking: CPY3A4 inhibitors, Chemotherapy
Disqualifiers: Dementia, Active SI, others
No Placebo Group
Prior Safety Data
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?This pilot open-label study examines the effects of a combination of dasatinib plus quercetin - two drugs that have known senolytics properties - on physiological aging in older individuals with depression or schizophrenia.
Will I have to stop taking my current medications?
The trial does not specify if you must stop taking your current medications, but it does require that you are already on an adequate dose of medication for schizophrenia/schizoaffective disorder or depression. Some medications, especially those that interact with dasatinib or quercetin, may need to be stopped.
How is the drug Dasatinib + Quercetin unique for treating premature aging in mental illness?
Dasatinib + Quercetin is unique because it targets and removes senescent cells (old or damaged cells that no longer function properly), which may help reduce inflammation and improve symptoms related to aging. This approach is novel as it addresses cellular aging directly, unlike traditional treatments that may not target the underlying cellular mechanisms.
12345Eligibility Criteria
This trial is for people aged 50+ with schizophrenia or 60+ with treatment-resistant major depression. Participants must have three aging-related conditions like hypertension, diabetes, or arthritis, and be on stable medication for their mental disorder. They can't join if they have dementia, recent severe illnesses (like heart attacks), uncontrolled health issues (high blood pressure/diabetes), certain drug interactions, or are at risk of harming themselves.Inclusion Criteria
I have at least three age-related conditions like high blood pressure, heart or lung disease.
I have never been diagnosed with dementia.
I have major depression that hasn't improved with at least 2 treatments, or I have schizophrenia/schizoaffective disorder.
+2 more
Exclusion Criteria
Active suicidal ideation such that participant could not be safely managed in an outpatient clinical trial
I cannot take dasatinib or quercetin due to health reasons.
I am not on strong CPY3A4 drugs, drugs causing cell aging, or drugs interacting with quercetin.
+1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Questionnaires and phone screen
Treatment
Participants receive dasatinib plus quercetin for 4 weeks, with lifestyle education focusing on strength, balance, and nutrition
4 weeks
Weekly visits for medication administration and lifestyle education
Monitoring
Participants undergo MRI scans and blood draws to monitor changes in neuropsychological functioning and physiological markers
10 weeks
MRI at baseline and week 10, blood draws at baseline, weeks 1, 2, 3, 4, 10, and endpoint
Follow-up
Participants are monitored for safety and effectiveness after treatment
Remaining duration of the 1-year involvement
Assessments at baseline, week 10, and study endpoint
Participant Groups
The study tests a combination of dasatinib plus quercetin in older adults with depression or schizophrenia to see if it slows down aging. It's an open-label pilot study where everyone knows what treatment they're getting.
1Treatment groups
Experimental Treatment
Group I: Dasatinib + quercetinExperimental Treatment1 Intervention
open label dasatinib plus quercetin combined as a drug therapy
Dasatinib + Quercetin is already approved in United States, European Union, Canada for the following indications:
πΊπΈ Approved in United States as Sprycel for:
- Chronic Myelogenous Leukemia
- Acute Lymphoblastic Leukemia
πͺπΊ Approved in European Union as Sprycel for:
- Chronic Myelogenous Leukemia
- Acute Lymphoblastic Leukemia
π¨π¦ Approved in Canada as Phyrago for:
- Chronic Myelogenous Leukemia
- Acute Lymphoblastic Leukemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Washington University School of MedicineSaint Louis, MO
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Who Is Running the Clinical Trial?
Washington University School of MedicineLead Sponsor
UConn HealthCollaborator
References
Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease. [2023]Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (AΞ²) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76Β±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of AΞ²42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and AΞ² may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.
Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial. [2023]Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility and efficacy. Five participants (mean age = 76 + 5 years; 40% female) completed the 12-week pilot study. D and Q levels in blood increased in all participants (12.7-73.5 ng ml-1 for D and 3.29-26.3 ng ml-1 for Q). In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) ranging from 0.281 to 0.536 ml-1 with a CSF to plasma ratio of 0.422-0.919%; Q was not detected. The treatment was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment further supporting a favorable safety profile. CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased (t(4) = 3.913, P = 0.008 and t(4) = 3.354, P = 0.028, respectively) with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ42 levels (t(4) = -2.338, P = 0.079). In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability and feasibility in patients with AD. Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies. ClinicalTrials.gov identifier: NCT04063124 .
Natural Products as a Major Source of Candidates for Potential Senolytic Compounds obtained by in silico Screening. [2023]Preclinical studies suggest that senolytic compounds such as quercetin (a natural product) and dasatinib (a synthetic product) decrease senescent cells, reduce inflammation, and alleviate human frailty. This evidence has opened a new field of research for studying the effect of these compounds on age-related dysfunction and diseases.
Dasatinib plus quercetin attenuates some frailty characteristics in SAMP10 mice. [2022]Senolytics are a class of drugs that selectively remove senescent cells. Dasatinib and quercetin have been discovered, and their combination has shown various anti-ageing effects. The SAMP10 mouse strain is a model of brain ageing. Here, we investigated the effect of combination on frailty characteristics in SAMP10. By comparing SAMP10 with SAMR1 mice as normal ageing controls, we investigated some frailty characteristics. Frailty was assessed at 18-38 weeks of age with a clinical frailty index. Motor and cognitive function of these mice were evaluated using behavioral experiments. SAMP10 mice were divided into vehicle and combination, and these functions and histological changes in the brain hippocampus were investigated. Finally, the in vitro effects of combination on oxidative stress-induced senescent muscle and neuronal cells were investigated. As a result, we found that frailty index was higher in SAMP10 than SAMR1. Motor and cognitive function were worse in SAMP10 than SAMR1. Furthermore, combination therapy improved frailty, motor and cognitive function, and the senescent phenotype of the hippocampus compared with vehicle in SAMP10. In summary, SAMP10 showed more marked frailty characteristics than SAMR1, and dasatinib and quercetin attenuated them in SAMP10. From our results, senolytic therapy might contribute protective effects against frailty.
Effect of peripheral cellular senescence on brain aging and cognitive decline. [2023]We examine similar and differential effects of two senolytic treatments, ABT-263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT-263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood-brain barrier (BBB) integrity, and prevented the age-related decline in hippocampal N-methyl-D-aspartate receptor (NMDAR) function associated with impaired cognition. Senolytic treatments decreased senescence-associated secretory phenotype (SASP) and inflammatory cytokines/chemokines in the plasma (IL-1Ξ², IP-10, and RANTES), with some markers more responsive to D + Q (TNFΞ±) or ABT-263 (IFNΞ³, leptin, EGF). ABT-263 was more effective in decreasing senescence genes in the spleen. Both senolytic treatments decreased the expression of immune response and oxidative stress genes and increased the expression of synaptic genes in the dentate gyrus (DG). However, D + Q influenced twice as many genes as ABT-263. Relative to D + Q, the ABT-263 group exhibited increased expression of DG genes linked to cell death and negative regulation of apoptosis and microglial cell activation. Furthermore, D + Q was more effective at decreasing morphological markers of microglial activation. The results indicate that preserved cognition was associated with the removal of peripheral senescent cells, decreasing systemic inflammation that normally drives neuroinflammation, BBB breakdown, and impaired synaptic function. Dissimilarities associated with brain transcription indicate divergence in central mechanisms, possibly due to differential access.