{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:01:45Z","timestamp":1789542105148,"version":"build-2803163510"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Introduction<\/jats:title>\n Neuropsychiatric toxicity is a recognized complication of calcineurin inhibitor (CNI) therapy; however, large-scale comparative assessments across tacrolimus immediate-release (IR), once-daily LCP-tacrolimus (LCPT), and cyclosporine remain limited.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We performed a decade-long pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database from 2015 to 2025 to characterize the spectrum, seriousness, temporal trends, and drug-specific reporting signals of neuropsychiatric adverse events (AEs) in transplant recipients in whom tacrolimus IR, LCPT, or cyclosporine was listed as a suspect agent. Events were categorized as neurological, psychiatric, or combined neuropsychiatric. Disproportionality was assessed using reporting odds ratios (RORs) and proportional reporting ratios (PRRs).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n A total of 5,437 neuropsychiatric AE reports were identified, involving tacrolimus IR (71.9%), cyclosporine (23.7%), and LCPT (4.5%). Most reports were neurological (74.1%), followed by psychiatric (17.1%) and combined neuropsychiatric events (8.8%). Serious outcomes were frequently reported (92.5%), including hospitalization (52.1%) and reported death (16.2%). Combined neuropsychiatric events had the highest hospitalization rate (62.1%); however, such outcomes should be interpreted in the context of complex clinical illness and treatment exposure rather than as directly attributable to CNI-related neuropsychiatric toxicity alone. Tremor demonstrated elevated reporting disproportionality for tacrolimus IR (ROR 1.97; PRR 1.78) and LCPT (ROR 2.42; PRR 1.97). In contrast, cyclosporine showed no tremor signal but demonstrated elevated disproportionality for encephalopathy (ROR 1.73; PRR 1.45), insomnia (ROR 1.87; PRR 1.76), and anxiety (ROR 1.50; PRR 1.48). Reporting increased from 2015 to 2019 and remained elevated through 2025.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n These findings suggest distinct drug-specific neuropsychiatric reporting patterns among CNIs in FAERS. However, given the inherent limitations of spontaneous reporting systems and differences in real-world utilization across CNIs, these findings should be interpreted as hypothesis-generating pharmacovigilance signals rather than evidence of causation, incidence, or comparative risk. They highlight the potential clinical relevance of neuropsychiatric tolerability when individualizing CNI selection, monitoring, and formulation strategies, and support further integration of pharmacovigilance data with pharmacokinetic and registry-level evidence to improve individualized risk assessment.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1795626","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:19:02Z","timestamp":1774588742000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Comparative neuropsychiatric safety signals of tacrolimus versus cyclosporine in solid organ transplantation: ten-year FAERS pharmacovigilance study"],"prefix":"10.3389","volume":"17","author":[{"given":"Bassem A.","family":"Almalki","sequence":"first","affiliation":[{"name":"College of Pharmacy, Imam Abdulrahman Bin Faisal University","place":["Dammam, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid A.","family":"Alamer","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Imam Abdulrahman Bin Faisal University","place":["Dammam, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trre.2013.04.003","article-title":"The impact of calcineurin inhibitors on graft survival","volume":"27","author":"Rush","year":"2013","journal-title":"Transplant Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1159\/000515933","article-title":"Calcineurin inhibitor toxicity in solid organ transplantation","volume":"106","author":"Karolin","year":"2021","journal-title":"Pharmacology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"bcr2013201099","DOI":"10.1136\/bcr-2013-201099","article-title":"Tacrolimus-induced encephalopathy and polyneuropathy in a renal transplant recipient","volume":"2013","author":"Wu","year":"2013","journal-title":"BMJ Case Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.proghi.2004.04.001","article-title":"Cyclosporine A and adverse effects on organs: histochemical studies","volume":"39","author":"Rezzani","year":"2004","journal-title":"Prog Histochem Cytochem"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s40268-023-00428-4","article-title":"Tremor induced by cyclosporine, tacrolimus, sirolimus, or everolimus: A review of the literature","volume":"23","author":"Wagle Shukla","year":"2023","journal-title":"Drugs RD"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e3173","DOI":"10.1097\/MD.0000000000003173","article-title":"Calcineurin inhibitors associated\u00a0posterior reversible encephalopathy syndrome in solid organ transplantation: report of 2 cases and literature review","volume":"95","author":"Song","year":"2016","journal-title":"Med (Baltimore)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.5500\/wjt.v14.i2.91146","article-title":"Tacrolimus-induced posterior reversible encephalopathy syndrome following liver\u00a0transplantation","volume":"14","author":"Dilibe","year":"2024","journal-title":"World J Transplant"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/cimb47010002","article-title":"Tacrolimus- and mycophenolate-mediated toxicity: clinical considerations and options in management of post-transplant patients","volume":"47","author":"Kaye","year":"2024","journal-title":"Curr Issues Mol Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.12955","article-title":"Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of phase III, double-blind, randomized trial","volume":"14","author":"Budde","year":"2014","journal-title":"Am J Transplant"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.12659\/AOT.943498","article-title":"Use of LCP-tacrolimus (LCPT) in kidney transplantation: A delphi consensus survey of expert clinicians","volume":"29","author":"Wiseman","year":"2024","journal-title":"Ann Transplant"},{"key":"B11","article-title":"Causes of death in renal transplant recipients: a study of 102 autopsies from 1968 to 1991","volume":"88","author":"Reis","year":"1995","journal-title":"J R Soc Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4103\/aian.aian_614_24","article-title":"Neurotoxicity of calcineurin inhibitors","volume":"28","author":"Bajon","year":"2025","journal-title":"Ann Indian Acad Neurol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199410273311702","article-title":"A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation","volume":"331","year":"1994","journal-title":"N Engl J Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1136\/bmj.38569.471007.AE","article-title":"Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomized trial data","volume":"331","author":"Webster","year":"2005","journal-title":"BMJ"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.94637","article-title":"Balancing\u00a0graft survival and neural outcomes: insights from a systematic review of tacrolimus-induced neurotoxicity","volume":"17","author":"Dathi","year":"2025","journal-title":"Cureus"},{"key":"B16","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1111\/ctr.12581","article-title":"Switching ST udy of Kidney TRansplant\u00a0PA tients with Tremor to LCP -TacrO (STRATO): an\u00a0open-label, multicenter, prospective phase 3b study","volume":"29","author":"Langone","year":"2015","journal-title":"Clin Transplant"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/ti.2024.11571","article-title":"Impact of switching from immediate- or prolonged-release to once-daily extended-release tacrolimus (LCPT) on tremor in stable kidney transplant recipients: the observational ELIT study","volume":"37","author":"Giral","year":"2024","journal-title":"Transpl Int Off J Eur Soc Organ Transplant"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.trre.2023.100815","article-title":"The association between tacrolimus exposure and tremor, headache and insomnia in adult kidney transplant recipients: A systematic review","volume":"38","author":"King","year":"2024","journal-title":"Transplant Rev"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/ph18101488","article-title":"Tacrolimus-associated tremor in renal transplant patients: potential impact of the galenic formulation","volume":"18","author":"Rovira","year":"2025","journal-title":"Pharmaceuticals"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.5125\/jkaoms.2023.49.6.311","article-title":"Review of two immunosuppressants: tacrolimus and cyclosporine","volume":"49","author":"Lee","year":"2023","journal-title":"J Korean Assoc Oral Maxillofac Surg"},{"key":"B21","doi-asserted-by":"publisher","first-page":"23","DOI":"10.5812\/jnp.6","article-title":"Nephro and neurotoxicity of calcineurin inhibitors and mechanisms of rejections: A review on tacrolimus and cyclosporin in organ transplantation","volume":"1","author":"Tolou-Ghamari","year":"2012","journal-title":"J Nephropathol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14238530","article-title":"Early conversion to once-daily meltDose\u00ae Extended-release tacrolimus (LCPT) in liver transplant patients","volume":"14","author":"Jochheim","year":"2025","journal-title":"J Clin Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1055\/s-0033-1334471","article-title":"Calcineurin inhibitor encephalopathy","volume":"32","author":"Mammoser","year":"2013","journal-title":"Semin Neurol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1002\/jmd2.12088","article-title":"Neurotoxicity including posterior reversible encephalopathy syndrome after initiation of calcineurin inhibitors in transplanted methylmalonic acidemia patients: Two case reports and review of the literature","volume":"51","author":"Molema","year":"2020","journal-title":"JIMD Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1795626\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:19:03Z","timestamp":1774588743000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1795626\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":24,"alternative-id":["10.3389\/fimmu.2026.1795626"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1795626","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]},"article-number":"1795626"}}