Lirong Wang1, Jian Ying2, Peihao Fan1, Elise A Weamer3, Mary Ann A DeMichele-Sweet4, Oscar L Lopez5, Julia K Kofler6, Robert A Sweet7. 1. Department of Pharmaceutical Sciences (LW, PF), Computational Chemical Genomics Screening, University of Pittsburgh School of Pharmacy, Pittsburgh. 2. Department of Internal Medicine (JY), University of Utah, Salt Lake City. 3. Department of Neurology (EAW, OLL, RAS), University of Pittsburgh School of Medicine, Pittsburgh. 4. Department of Psychiatry (MAADS, OLL, RAS), University of Pittsburgh School of Medicine, Pittsburgh. 5. Department of Neurology (EAW, OLL, RAS), University of Pittsburgh School of Medicine, Pittsburgh; Department of Psychiatry (MAADS, OLL, RAS), University of Pittsburgh School of Medicine, Pittsburgh. 6. Department of Pathology (JKK), University of Pittsburgh School of Medicine, Pittsburgh. 7. Department of Neurology (EAW, OLL, RAS), University of Pittsburgh School of Medicine, Pittsburgh; Department of Psychiatry (MAADS, OLL, RAS), University of Pittsburgh School of Medicine, Pittsburgh; VISN 4 Mental Illness Research, Education and Clinical Center (RAS), VA Pittsburgh Healthcare System, Pittsburgh. Electronic address: sweetra@upmc.edu.
Abstract
OBJECTIVE: To identify medications that may prevent psychosis in patients with Alzheimer disease (AD). METHODS: The authors compared the frequency of medication usage among patients with AD with or without psychosis symptoms (AD + P versus AD - P). The authors also conducted survival analysis on time to psychosis for patients with AD to identify drugs with beneficial effects. The authors further explored the potential molecular mechanisms of identified drugs by gene-signature analysis. Specifically, the gene expression profiles induced by the identified drug(s) were collected to derive a list of most perturbed genes. These genes were further analyzed by the associations of their genetic variations with AD or psychosis-related phenotypes. RESULTS: Vitamin D was used more often in AD - P patients than in AD + P patients. Vitamin D was also significantly associated with delayed time to psychosis. AD and/or psychosis-related genes were enriched in the list of genes most perturbed by vitamin D, specifically genes involved in the regulation of calcium signaling downstream of the vitamin D receptor. CONCLUSION: Vitamin D was associated with delayed onset of psychotic symptoms in patients with AD. Its mechanisms of action provide a novel direction for development of drugs to prevent or treat psychosis in AD. In addition, genetic variations in vitamin D-regulated genes may provide a biomarker signature to identify a subpopulation of patients who can benefit from vitamin D treatment.
OBJECTIVE: To identify medications that may prevent psychosis in patients with Alzheimer disease (AD). METHODS: The authors compared the frequency of medication usage among patients with AD with or without psychosis symptoms (AD + P versus AD - P). The authors also conducted survival analysis on time to psychosis for patients with AD to identify drugs with beneficial effects. The authors further explored the potential molecular mechanisms of identified drugs by gene-signature analysis. Specifically, the gene expression profiles induced by the identified drug(s) were collected to derive a list of most perturbed genes. These genes were further analyzed by the associations of their genetic variations with AD or psychosis-related phenotypes. RESULTS:Vitamin D was used more often in AD - P patients than in AD + P patients. Vitamin D was also significantly associated with delayed time to psychosis. AD and/or psychosis-related genes were enriched in the list of genes most perturbed by vitamin D, specifically genes involved in the regulation of calcium signaling downstream of the vitamin D receptor. CONCLUSION:Vitamin D was associated with delayed onset of psychotic symptoms in patients with AD. Its mechanisms of action provide a novel direction for development of drugs to prevent or treat psychosis in AD. In addition, genetic variations in vitamin D-regulated genes may provide a biomarker signature to identify a subpopulation of patients who can benefit from vitamin D treatment.
Authors: O L Lopez; J T Becker; W Klunk; J Saxton; R L Hamilton; D I Kaufer; R A Sweet; C Cidis Meltzer; S Wisniewski; M I Kamboh; S T DeKosky Journal: Neurology Date: 2000-12-26 Impact factor: 9.910
Authors: O L Lopez; J T Becker; W Klunk; J Saxton; R L Hamilton; D I Kaufer; R A Sweet; C Cidis Meltzer; S Wisniewski; M I Kamboh; S T DeKosky Journal: Neurology Date: 2000-12-26 Impact factor: 9.910
Authors: M A Harris; J Clark; A Ireland; J Lomax; M Ashburner; R Foulger; K Eilbeck; S Lewis; B Marshall; C Mungall; J Richter; G M Rubin; J A Blake; C Bult; M Dolan; H Drabkin; J T Eppig; D P Hill; L Ni; M Ringwald; R Balakrishnan; J M Cherry; K R Christie; M C Costanzo; S S Dwight; S Engel; D G Fisk; J E Hirschman; E L Hong; R S Nash; A Sethuraman; C L Theesfeld; D Botstein; K Dolinski; B Feierbach; T Berardini; S Mundodi; S Y Rhee; R Apweiler; D Barrell; E Camon; E Dimmer; V Lee; R Chisholm; P Gaudet; W Kibbe; R Kishore; E M Schwarz; P Sternberg; M Gwinn; L Hannick; J Wortman; M Berriman; V Wood; N de la Cruz; P Tonellato; P Jaiswal; T Seigfried; R White Journal: Nucleic Acids Res Date: 2004-01-01 Impact factor: 16.971
Authors: R A Sweet; B G Pollock; D L Sukonick; B H Mulsant; J Rosen; W E Klunk; K B Kastango; S T DeKosky; R E Ferrell Journal: Int Psychogeriatr Date: 2001-12 Impact factor: 3.878
Authors: M M Bassiony; M S Steinberg; A Warren; A Rosenblatt; A S Baker; C G Lyketsos Journal: Int J Geriatr Psychiatry Date: 2000-02 Impact factor: 3.485
Authors: Zahinoor Ismail; Byron Creese; Dag Aarsland; Helen C Kales; Constantine G Lyketsos; Robert A Sweet; Clive Ballard Journal: Nat Rev Neurol Date: 2022-01-04 Impact factor: 44.711