Peihao, Fan
(2023)
Applying Quantitative Systems Pharmacology Methods to Study Psychosis in Alzheimer’s Disease.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Psychosis is surprisingly common in Alzheimer disease (AD) and can emerge as a part of the neurodegenerative disease process in advance of dementia during the mild cognitive impairment stage or even earlier. Approximately 50% of Alzheimer’s disease patients will develop psychotic symptoms, e.g. hallucination and delusions, and these patients will experience more severe cognitive decline compared with those without psychosis. However, no medication has been approved by the Food and Drug Administration for treating psychosis in AD (AD+P) and second-generation antipsychotics are widely used in clinical practice with modest efficacy and elevated adverse events rate. It is critical to explore and propose more effective and safer treatment options to treat AD+P. Some important advances in recent years provided us opportunities in connecting and comparing the neuropsychiatric symptoms (NPS) in AD with other neurological disorders which will greatly help us understand its mechanisms and further develop appropriate treatments for AD+P. In this thesis, the journey of understanding AD+P starts at comparing it with the similar psychotic symptoms in schizophrenia. We found that the similar psychotic symptoms in AD+P and schizophrenia are supported by distinct genetic associations and pathways which also provided a possible explanation for the decreased efficacy and increased adverse events rate of antipsychotics in AD+P. Multiple approaches, classic and innovative, were applied to identify critical risk factors and possible protective roles in the advancement of AD+P. With the information we have acquired about AD+P from the previous studies, state-of-the-art quantitative systems pharmacology (QSP) approaches are applied to explore and propose alternative treatment options for AD+P. We found out that antidepressants showed a possible beneficial effect against AD+P and they exert their effect through different pathways with antipsychotics which allowed them to form a synergetic effect that may improve therapeutic efficacy or lower the risk of side effects.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
3 April 2023 |
| Date Type: |
Publication |
| Defense Date: |
20 March 2023 |
| Approval Date: |
3 April 2023 |
| Submission Date: |
22 March 2023 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
242 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Alzheimer's Disease; Psychosis; Systems pharmacology; Antipsychotics; Real-world evidence |
| Date Deposited: |
03 Apr 2023 13:32 |
| Last Modified: |
03 Apr 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44307 |
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