{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:49:58Z","timestamp":1793144998419,"version":"4.5.0"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T00:00:00Z","timestamp":1695859200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Purpose<\/jats:title><jats:p>Glaucoma is a leading cause of irreversible blindness worldwide. Retinal ganglion cells (RGC), the neurons that connect the eyes to the brain, specifically die in glaucoma, leading to blindness. Elevated intraocular pressure (IOP) is the only modifiable risk factor, however, many patients progress despite excellent IOP control. Thus, alternative treatment strategies to prevent glaucoma progression are an unmet need. Citicoline has demonstrated neuroprotective properties in central neurodegenerative diseases. However, conclusive evidence of the effect of citicoline on glaucoma progression is missing. This systematic review investigates first-time the therapeutic potential of citicoline in glaucoma patients.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>The present study was conducted according to the PRISMA 2020 statement. PubMed, Web of Science, Google Scholar, and Embase were accessed in July 2023 to identify all clinical studies investigating the efficacy of citicoline on IOP, the mean deviation of the 24\u20132 visual field testing (MD 24\u20132), retinal nerve fibre layer (RNFL), and the pattern electroretinogram (PERG) P50-N95 amplitude in glaucoma patients. The risk of bias was assessed using the Review Manager 5.3 software (The Nordic Cochrane Collaboration, Copenhagen) and the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>Ten studies were eligible for this systematic review, including 424 patients. The mean length of the follow-up was 12.1 \u00b1 11.6 months. The overall risk of bias was low to moderate. The mean age of the patients was 56.7 years. There were no significant differences in the IOP, MD 24\u20132, RNFL, or PERG P50-N95 amplitude between patients receiving citicoline and the control group. There was no improvement from baseline to the last follow-up in IOP, MD 24\u20132, RNFL, or PERG P50-N95 amplitude.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusion<\/jats:title><jats:p>There is a lack of sufficient evidence to support that citicoline slows the progression of glaucoma.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0291836","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T17:30:11Z","timestamp":1695922211000},"page":"e0291836","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Efficacy of citicoline as a supplement in glaucoma patients: A systematic review"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3473-7997","authenticated-orcid":true,"given":"Julia","family":"Prinz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5318-0637","authenticated-orcid":true,"given":"Verena","family":"Prokosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanhan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Fuest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Migliorini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,9,28]]},"reference":[{"issue":"12","key":"pone.0291836.ref001","doi-asserted-by":"crossref","first-page":"e1221","DOI":"10.1016\/S2214-109X(17)30393-5","article-title":"Global causes of blindness and distance vision impairment 1990\u20132020: a systematic review and meta-analysis","volume":"5","author":"SR Flaxman","year":"2017","journal-title":"Lancet Glob Health"},{"issue":"8","key":"pone.0291836.ref002","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1097\/IJG.0000000000001269","article-title":"The Association Between Visual Field Reliability Indices and Cognitive Impairment in Glaucoma Patients","volume":"28","author":"P Raman","year":"2019","journal-title":"J Glaucoma"},{"issue":"11","key":"pone.0291836.ref003","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis","volume":"121","author":"YC Tham","year":"2014","journal-title":"Ophthalmology"},{"issue":"6342","key":"pone.0291836.ref004","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1126\/science.aal5060","article-title":"Regenerating optic pathways from the eye to the brain","volume":"356","author":"B Laha","year":"2017","journal-title":"Science"},{"issue":"9975","key":"pone.0291836.ref005","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/S0140-6736(14)62111-5","article-title":"Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial.","volume":"385","author":"DF Garway-Heath","year":"2015","journal-title":"Lancet"},{"issue":"2","key":"pone.0291836.ref006","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/j.1471-4159.2007.04997.x","article-title":"Mitochondrial dysfunction, oxidative stress, regulation of exocytosis and their relevance to neurodegenerative diseases","volume":"104","author":"DJ Keating","year":"2008","journal-title":"J Neurochem"},{"issue":"1","key":"pone.0291836.ref007","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s00417-011-1887-2","article-title":"DTI parameters of axonal integrity and demyelination of the optic radiation correlate with glaucoma indices","volume":"251","author":"G Michelson","year":"2013","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"1","key":"pone.0291836.ref008","first-page":"Cd006539","article-title":"Neuroprotection for treatment of glaucoma in adults.","volume":"1","author":"DF Sena","year":"2017","journal-title":"Cochrane Database Syst Rev."},{"issue":"5","key":"pone.0291836.ref009","first-page":"439","article-title":"[The role of citicoline in glaucoma].","volume":"118","author":"AGM J\u00fcnemann","year":"2021","journal-title":"Ophthalmologe"},{"key":"pone.0291836.ref010","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1749-6632.1996.tb34452.x","article-title":"Therapeutic effects of CDP-choline in Alzheimer\u2019s disease. Cognition, brain mapping, cerebrovascular hemodynamics, and immune factors","volume":"777","author":"R Cacabelos","year":"1996","journal-title":"Ann N Y Acad Sci"},{"issue":"6","key":"pone.0291836.ref011","first-page":"664","article-title":"Clinical trial on the use of cytidine diphosphate choline in Parkinson\u2019s disease.","volume":"10","author":"JM Cubells","year":"1988","journal-title":"Clin Ther"},{"key":"pone.0291836.ref012","first-page":"14","article-title":"Citicoline: A Candidate for Adjunct Treatment of Multiple Sclerosis.","author":"P Grieb","year":"2021","journal-title":"Pharmaceuticals (Basel)."},{"issue":"3","key":"pone.0291836.ref013","doi-asserted-by":"crossref","first-page":"390","DOI":"10.3390\/ijms17030390","article-title":"Long-Term Treatment with Citicoline Prevents Cognitive Decline and Predicts a Better Quality of Life after a First Ischemic Stroke","volume":"17","author":"J Alvarez-Sab\u00edn","year":"2016","journal-title":"Int J Mol Sci"},{"key":"pone.0291836.ref014","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1016\/0022-510X(91)90004-Q","article-title":"Biochemical rationale for the use of CDPcholine in traumatic brain injury: pharmacokinetics of the orally administered drug","volume":"103","author":"P Galletti","year":"1991","journal-title":"J Neurol Sci"},{"issue":"2","key":"pone.0291836.ref015","doi-asserted-by":"crossref","first-page":"124","DOI":"10.4103\/0301-4738.128586","article-title":"Effectiveness of the addition of citicoline to patching in the treatment of amblyopia around visual maturity: a randomized controlled trial.","volume":"62","author":"PV Pawar","year":"2014","journal-title":"Indian J Ophthalmol."},{"issue":"7","key":"pone.0291836.ref016","doi-asserted-by":"crossref","first-page":"e0220435","DOI":"10.1371\/journal.pone.0220435","article-title":"Neuroenhancement and neuroprotection by oral solution citicoline in non-arteritic ischemic optic neuropathy as a model of neurodegeneration: A randomized pilot study.","volume":"14","author":"V Parisi","year":"2019","journal-title":"PLoS One."},{"key":"pone.0291836.ref017","doi-asserted-by":"crossref","first-page":"108612","DOI":"10.1016\/j.exer.2021.108612","article-title":"Protective effects of citicoline-containing eye drops against UVB-Induced corneal oxidative damage in a rat model","volume":"208","author":"EO Tokuc","year":"2021","journal-title":"Exp Eye Res"},{"issue":"3","key":"pone.0291836.ref018","first-page":"Pi24","article-title":"Oral citicoline treatment improves visual pathway function in glaucoma","volume":"9","author":"R Rejdak","year":"2003","journal-title":"Med Sci Monit"},{"issue":"1","key":"pone.0291836.ref019","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1385\/JMN:20:1:53","article-title":"CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons","volume":"20","author":"C Mir","year":"2003","journal-title":"J Mol 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Zazueta","year":"2018","journal-title":"Liver Transpl"},{"issue":"1","key":"pone.0291836.ref023","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/2045-824X-4-20","article-title":"Citicoline induces angiogenesis improving survival of vascular\/human brain microvessel endothelial cells through pathways involving ERK1\/2 and insulin receptor substrate-1.","volume":"4","author":"J Krupinski","year":"2012","journal-title":"Vasc Cell."},{"issue":"16","key":"pone.0291836.ref024","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1097\/00001756-200211150-00023","article-title":"Citicoline has a protective effect on damaged retinal ganglion cells in mouse culture retina","volume":"13","author":"T Oshitari","year":"2002","journal-title":"Neuroreport"},{"issue":"5","key":"pone.0291836.ref025","doi-asserted-by":"crossref","first-page":"549","DOI":"10.4103\/0301-4738.133484","article-title":"A preliminary study of the neuroprotective role of citicoline eye drops in glaucomatous optic neuropathy.","volume":"62","author":"G Roberti","year":"2014","journal-title":"Indian J Ophthalmol"},{"issue":"10","key":"pone.0291836.ref026","article-title":"The Effect of Oral Citicoline and Docosahexaenoic Acid on the Visual Field of Patients with Glaucoma: A Randomized Trial.","volume":"12","author":"A Anton","year":"2022","journal-title":"Life (Basel)."},{"key":"pone.0291836.ref027","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.3389\/fphar.2019.01117","article-title":"Morphological and Functional Evaluation of Oral Citicoline Therapy in Chronic Open-Angle Glaucoma Patients: A Pilot Study With a 2-Year Follow-Up.","volume":"10","author":"M Lanza","year":"2019","journal-title":"Front Pharmacol."},{"issue":"4","key":"pone.0291836.ref028","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1159\/000350496","article-title":"Citicoline oral solution in glaucoma: is there a role in slowing disease progression?","volume":"229","author":"L Ottobelli","year":"2013","journal-title":"Ophthalmologica."},{"issue":"4","key":"pone.0291836.ref029","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1007\/s12325-019-0897-z","article-title":"Enhancement of Retinal Function and of Neural Conduction Along the Visual Pathway Induced by Treatment with Citicoline Eye Drops in Liposomal Formulation in Open Angle Glaucoma: A Pilot Electrofunctional Study.","volume":"36","author":"V Parisi","year":"2019","journal-title":"Adv Ther."},{"issue":"3","key":"pone.0291836.ref030","doi-asserted-by":"crossref","first-page":"483","DOI":"10.18240\/ijo.2022.03.17","article-title":"Effect of oral citicoline therapy on retinal nerve fiber layer and ganglion cell-inner plexiform layer in patients with primary open angle glaucoma.","volume":"15","author":"AK Sahin","year":"2022","journal-title":"Int J Ophthalmol."},{"key":"pone.0291836.ref031","article-title":"The 2011 Oxford CEBM evidence levels of evidence (introductory document).","author":"J Howick","year":"2011","journal-title":"Oxford Center for Evidence Based Medicine."},{"key":"pone.0291836.ref032","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"MJ Page","year":"2021","journal-title":"BMJ"},{"issue":"2","key":"pone.0291836.ref033","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1023\/A:1002016531591","article-title":"Standard for clinical electroretinography (1999 update). International Society for Clinical Electrophysiology of Vision","volume":"97","author":"MF Marmor","year":"1998","journal-title":"Doc Ophthalmol."},{"issue":"11","key":"pone.0291836.ref034","first-page":"2520","article-title":"Correlation between morphological and functional retinal impairment in multiple sclerosis patients","volume":"40","author":"V Parisi","year":"1999","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0291836.ref035","article-title":"Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021).","author":"J Higgins","year":"2021","journal-title":"Cochrane"},{"issue":"6","key":"pone.0291836.ref036","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/S0161-6420(99)90269-5","article-title":"Cytidine-5\u2019-diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma.","volume":"106","author":"V Parisi","year":"1999","journal-title":"Ophthalmology"},{"issue":"8","key":"pone.0291836.ref037","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1007\/s00417-015-3044-9","article-title":"Treatment with citicoline eye drops enhances retinal function and neural conduction along the visual pathways in open angle glaucoma","volume":"253","author":"V Parisi","year":"2015","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"7","key":"pone.0291836.ref038","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1097\/IJG.0000000000001565","article-title":"Can Treatment With Citicoline Eyedrops Reduce Progression in Glaucoma? The Results of a Randomized Placebo-controlled Clinical Trial","volume":"29","author":"L Rossetti","year":"2020","journal-title":"J Glaucoma"},{"issue":"1\u20132","key":"pone.0291836.ref039","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/BF02028649","article-title":"Therapeutic value of citicoline in the treatment of glaucoma (computerized and automated perimetric investigation).","volume":"13","author":"J Pecori Giraldi","year":"1989","journal-title":"Int Ophthalmol"},{"issue":"232","key":"pone.0291836.ref040","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1600-0420.2000.tb01107.x","article-title":"The protective effect of citicoline on the progression of the perimetric defects in glaucomatous patients (perimetric study with a 10-year follow-up).","author":"M Virno","year":"2000","journal-title":"Acta Ophthalmol Scand Suppl"},{"issue":"1","key":"pone.0291836.ref041","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s10633-005-7348-7","article-title":"Electrophysiological assessment of glaucomatous visual dysfunction during treatment with cytidine-5\u2019-diphosphocholine (citicoline): a study of 8 years of follow-up.","volume":"110","author":"V. Parisi","year":"2005","journal-title":"Doc Ophthalmol"},{"key":"pone.0291836.ref042","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/S0079-6123(08)01137-0","article-title":"Evidence of the neuroprotective role of citicoline in glaucoma patients","volume":"173","author":"V Parisi","year":"2008","journal-title":"Prog Brain Res"},{"issue":"11","key":"pone.0291836.ref043","doi-asserted-by":"crossref","first-page":"e0224982","DOI":"10.1371\/journal.pone.0224982","article-title":"Human vitreous concentrations of citicoline following topical application of citicoline 2% ophthalmic solution.","volume":"14","author":"C Carnevale","year":"2019","journal-title":"PLoS One"},{"issue":"6","key":"pone.0291836.ref044","doi-asserted-by":"crossref","first-page":"2770","DOI":"10.1167\/iovs.12-9476","article-title":"Intervals between visual field tests when monitoring the glaucomatous patient: wait-and-see approach","volume":"53","author":"DP Crabb","year":"2012","journal-title":"Invest Ophthalmol Vis Sci"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0291836","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,23]],"date-time":"2023-12-23T00:13:50Z","timestamp":1703290430000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0291836"}},"subtitle":[],"editor":[{"given":"Osamudiamen Cyril","family":"Obasuyi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,9,28]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0291836","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,28]]}}}