{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:04:50Z","timestamp":1784887490255,"version":"3.55.0"},"reference-count":45,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epileptic Disorders"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>Focal epilepsy constitutes 60\u201370% of epilepsy, and up to half of patients do not achieve seizure freedom with their first antiseizure medication (ASM). When the first ASM fails, evidence guiding whether to switch or add\u2010on another ASM and which ASMs to use is limited. This review synthesized evidence from randomized controlled trials (RCTs) on the comparative effectiveness of subsequent ASMs after first ASM failure in focal epilepsy. Following a pre\u2010registered protocol (PROSPERO: CRD42025603003) and PRISMA guidelines, we included RCTs involving children or adults with focal epilepsy who failed first ASM therapy for any reason. The primary outcomes were seizure remission and responder rate (\u226550% reduction in seizure frequency). Searches were conducted across major databases in February 2025. Risk ratios with 95% confidence intervals were calculated in R. Meta\u2010analysis was not performed due to heterogeneity. Six RCTs (961 participants) published between 1998 and 2012 met inclusion criteria, assessing seven ASMs under add\u2010on or switch strategies. Trial duration ranged from 12 to 52\u2009weeks; most were judged high risk of bias (ROB\u20102). Seizure remission end\u2010point was assessed at a short\u2010term endpoint of 3\u2009months. Remission rates ranged from 11 to 43% for add\u2010on and 8\u201343% for switch trials; response rates were 34\u201363% and 38\u201376%, respectively. Valproate showed higher responder rates than primidone (RR 1.52, 95% CI 1.01\u20132.28) in an add\u2010on trial, while lamotrigine had a lower responder rate than valproate (RR 0.74, 95% CI 0.55\u20130.99) in one trial. In a switch strategy, lamotrigine showed lower treatment failure rates than valproate (RR 0.61; 95% CI 0.45\u20130.83) and fewer adverse effects than carbamazepine and valproate. Evidence guiding treatment decisions after the first ASM failure remains limited and outdated. Seizure outcomes were modest and comparable across treatment strategies, with few significant differences between ASMs. The small number of trials, short follow\u2010up for endpoints, and methodological heterogeneity across trials constrain interpretation and clinical applicability. Leveraging observational data with causal inference methods, alongside pragmatic trials evaluating machine\u2010learning\u2010guided ASM selections, is needed to address this evidence gap and improve seizure management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epd2.70353","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T09:31:22Z","timestamp":1784885482000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The effectiveness of adding on or switching antiseizure medications after the first fails to control focal epilepsy: A\u00a0systematic review of randomized controlled trials"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0483-1517","authenticated-orcid":false,"given":"Isaac J.","family":"Egesa","sequence":"first","affiliation":[{"name":"Department of Health Data Science Institute of Population Health, University of Liverpool  Liverpool UK"},{"name":"Mayuge Institute for Global Health Science Research and Innovation  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gashirai","family":"Mbizvo","sequence":"additional","affiliation":[{"name":"Liverpool Interdisciplinary Neuroscience Centre University of Liverpool  Liverpool UK"},{"name":"Liverpool Centre for Cardiovascular Science University of Liverpool  Liverpool UK"},{"name":"The Walton Centre NHS Foundation Trust  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Maden","sequence":"additional","affiliation":[{"name":"Department of Health Data Science Institute of Population Health, University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2617-9201","authenticated-orcid":false,"given":"Thomas","family":"Spain","sequence":"additional","affiliation":[{"name":"Department of Health Data Science Institute of Population Health, University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Emsley","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry, Psychology and Neuroscience, King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6981-9212","authenticated-orcid":false,"given":"Laura J.","family":"Bonnett","sequence":"additional","affiliation":[{"name":"Department of Health Data Science Institute of Population Health, University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony G.","family":"Marson","sequence":"additional","affiliation":[{"name":"Liverpool Interdisciplinary Neuroscience Centre University of Liverpool  Liverpool UK"},{"name":"The Walton Centre NHS Foundation Trust  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catrin Tudur","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Health Data Science Institute of Population Health, University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1474-4422(18)30454-X","article-title":"Global, regional, and national burden of epilepsy, 1990\u20132016: a systematic analysis for the global burden of disease study 2016","volume":"18","author":"Beghi E","year":"2019","journal-title":"Lancet Neurol"},{"issue":"393","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S0140-6736(18)32596-0","article-title":"Epilepsy in adults","volume":"16","author":"Thijs RD","year":"2019","journal-title":"Lancet"},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1111\/epi.12605","article-title":"An 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