Targeting the Post-Synaptic Proteome in Alzheimer Disease with Psychosis

Sweet, Robert A.; Krivinko, Josh M.; DeChellis-Marks, Michael R.; Zeng, Lang; Fan, Peihao; López, Oscar L.; Ding, Ying; Wang, Lirong; Kofler, Julia; MacDonald, Matthew

doi:10.21203/rs.3.rs-1514870/v1

Cited by 2 publications

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“… 27 A recent study reported that patients with AD+P had reduced postsynaptic density (PSD) proteins compared to patients with AD–P, so we used the only proteome data for AD+P in this study for more accurate results. 28 The PSD proteome was used to build the AD+P network. This proteomic signature was generated by Dr. Sweet's team.…”

Section: Methodsmentioning

confidence: 99%

“…Given that synapse loss is the main neuropathologic indicator of cognitive decline in AD, it has been postulated that the susceptibility to AD+P results from more synaptic impairment in AD+P compared to AD-P. 27 A recent study reported that patients with AD+P had reduced postsynaptic density (PSD) proteins compared to patients with AD-P, so we used the only proteome data for AD+P in this study for more accurate results. 28 The PSD proteome was used to build the AD+P network. This proteomic signature was generated by Dr. Sweet's team.…”

Section: Prediction Of Synergetic Effect Among Antipsychotic-antidepr...mentioning

confidence: 99%

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Combination of antidepressants and antipsychotics as a novel treatment option for psychosis in Alzheimer's disease

Fan

Zeng

Ding

et al. 2023

CPT Pharmacom & Syst Pharma

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Psychotic symptoms are reported as one of the most common complications of Alzheimer's disease (AD), in whom they are associated with more rapid deterioration and increased mortality. Empiric treatments, namely first and second‐generation antipsychotics, confer modest efficacy in patients with AD and with psychosis (AD+P) and themselves increase mortality. Recent studies suggested the use and beneficial effects of antidepressants among patients with AD+P. This motivates our rationale for exploring their potential as a novel combination therapy option among these patients. We included electronic medical records of 10,260 patients with AD in our study. Survival analysis was performed to assess the effects of the combination of antipsychotics and antidepressants on the mortality of these patients. A protein–protein interaction network representing AD+P was built, and network analysis methods were used to quantify the efficacy of these drugs on AD+P. A combined score was developed to measure the potential synergetic effect against AD+P. Our survival analyses showed that the co‐administration of antidepressants with antipsychotics have a significant beneficial effect in reducing mortality. Our network analysis showed that the targets of antipsychotics and antidepressants are well‐separated, and antipsychotics and antidepressants have similar Signed Jaccard Index (SJI) scores to AD+P. Eight drug pairs, including some popular recommendations like aripiprazole/sertraline, showed higher than average scores which suggest their potential in treating AD+P via strong synergetic effects. Our proposed combinations of antipsychotic and antidepressant therapy showed a strong superiority over current antipsychotics treatment for AD+P. The observed beneficial effects can be further strengthened by optimizing drug‐pair selection based on our systems pharmacology analysis.

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Section: Methodsmentioning

confidence: 99%

Section: Prediction Of Synergetic Effect Among Antipsychotic-antidepr...mentioning

confidence: 99%

Combination of antidepressants and antipsychotics as a novel treatment option for psychosis in Alzheimer's disease

Fan

Zeng

Ding

et al. 2023

CPT Pharmacom & Syst Pharma

Self Cite

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“…For the systems pharmacology study, the postsynaptic density (PSD) proteome was used to build the AD+P network. This proteomic signature was generated by Dr. Sweet's team 39 . Information about antipsychotics, antidepressants and their targets were extracted from DrugBank (https://www.drugbank.ca/) 40 .…”

Section: Prediction Of Synergetic Effect Among Antipsychotic-antidepr...mentioning

confidence: 99%

Combination of Antidepressants and Antipsychotics as A Novel Treatment Option for Psychosis in Alzheimer’s Disease

Fan

Zeng

Ding

et al. 2023

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Background: Psychotic symptoms are reported as one of the most common complications of Alzheimer's disease (AD), affecting approximately half of AD patients, in whom they are associated with more rapid deterioration and increased mortality. Empiric treatments, namely first and second-generation antipsychotics, confer modest efficacy in AD patients with psychosis (AD+P) and themselves increase mortality. A recent genome-wide meta-analysis and early clinical trials suggest the use and beneficial effects of antidepressants among AD+P patients. This motivates our rationale for exploring their potential as a novel combination therapy option amongst these patients. Methods: We included University of Pittsburgh Medical Center (UPMC) electronic medical records (EMRs) of 10,260 AD patients from January 2004 and October 2019 in our study. Survival analysis was performed to assess the effects of the combination of antipsychotics and antidepressants on the mortality of these patients. To provide more valuable insights on the hidden mechanisms of the combinatorial therapy, a protein-protein interaction (PPI) network representing AD+P was built, and network analysis methods were used to quantify the efficacy of these drugs on AD+P. An indicator score combining the measurements on the separation between drugs and the proximity between the drugs and AD+P was used to measure the effect of an antipsychotic-antidepressant drug pair against AD+P. Results: Our survival analyses replicated that antipsychotic usage is strongly associated with increased mortality in AD patients while the co-administration of antidepressants with antipsychotics showed a significant beneficial effect in reducing mortality. Our network analysis showed that the targets of antipsychotics and antidepressants are well-separated, and antipsychotics and antidepressants have similar proximity scores to AD+P. Eight drug pairs, including some popular recommendations like Aripiprazole/Sertraline and other pairs not reported previously like Iloperidone/Maprotiline showed higher than average indicator scores which suggest their potential in treating AD+P via strong synergetic effects as seen in our study. Conclusion: Our proposed combinations of antipsychotics and antidepressants therapy showed a strong superiority over current antipsychotics treatment for AD+P. The observed beneficial effects can be further strengthened by optimizing drug-pair selection based on our systems pharmacology analysis.

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Targeting the Post-Synaptic Proteome in Alzheimer Disease with Psychosis

Cited by 2 publications

References 0 publications

Combination of antidepressants and antipsychotics as a novel treatment option for psychosis in Alzheimer's disease

Combination of antidepressants and antipsychotics as a novel treatment option for psychosis in Alzheimer's disease

Combination of Antidepressants and Antipsychotics as A Novel Treatment Option for Psychosis in Alzheimer’s Disease

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