{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:05:58Z","timestamp":1792789558015,"version":"4.5.0"},"reference-count":93,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundaci\u00f3n Hospital Provincial de Castell\u00f3n","id":[{"id":"https:\/\/ror.org\/04dywym46","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04dywym46","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Clozapine is the only evidence-based treatment for treatment-resistant schizophrenia (TRS); however, up to 70% of patients have an inadequate response, leading to clozapine-resistant schizophrenia (CRS) and, in its most severe form, ultra-treatment-resistant schizophrenia (UTRS). Because evidence-based treatment algorithms after clozapine failure remain limited, management requires an individualized, multimodal approach. We present a UTRS complex case alongside a scoping review conducted according to the PRISMA-ScR framework to summarize the current evidence on the diagnosis, neurobiology, and treatment of CRS and UTRS. A 24-year-old man with schizophrenia required 11 months of psychiatric hospitalization due to persistent psychosis, severe aggression, disorganized thinking, prominent negative symptoms, and profound functional impairment. Extensive investigations, including neuroimaging, cerebrospinal fluid analysis, metabolic studies, and genetic testing, ruled out alternative diagnoses. Despite sequential treatment with multiple antipsychotics, optimization of long-acting injectable therapy, clozapine, pharmacological augmentation, two courses of electroconvulsive therapy (ECT), and intensive multidisciplinary rehabilitation, the patient continued to exhibit severe positive, negative, and cognitive symptoms and functional impairment, meeting the criteria for UTRS. This review emphasizes the importance of excluding pseudoresistance by confirming adherence, assessing clozapine exposure when therapeutic drug monitoring is available, and conducting diagnostic reassessment before establishing a diagnosis of CRS or UTRS. Among available interventions, ECT remains the strongest evidence-based augmentation strategy following clozapine failure, while pharmacological augmentation and other neuromodulatory techniques are supported by low-certainty evidence. These findings underscore the need for individualized multimodal management that integrates pharmacological, biological, and psychosocial interventions, and support consideration of precision psychiatry and palliative psychiatry principles as potential future frameworks when evidence-based therapeutic options have been exhausted.<\/jats:p>","DOI":"10.3390\/jcm15187264","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:09:35Z","timestamp":1790075375000},"page":"7264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Beyond Clozapine Failure: Precision Approach and Palliative Psychiatry in Ultra-Treatment-Resistant Schizophrenia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7860-765X","authenticated-orcid":false,"given":"Marc","family":"Peraire","sequence":"first","affiliation":[{"name":"Department of Mental Health, Consorci Hospitalari Provincial Universitari de Castell\u00f3, 12002 Castell\u00f3 de la Plana, Spain"},{"name":"TXP Research Group, Universidad Cardenal Herrera-CEU, 12006 Castell\u00f3 de la Plana, Spain"},{"name":"Fundaci\u00f3n Hospital Provincial, 12002 Castell\u00f3 de la Plana, Spain"},{"name":"Pre-Departmental Medicine Unit, Universitat Jaume I, 12006 Castell\u00f3 de la Plana, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Moreno-Beltr\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Mental Health, Consorci Hospitalari Provincial Universitari de Castell\u00f3, 12002 Castell\u00f3 de la Plana, Spain"},{"name":"TXP Research Group, Universidad Cardenal Herrera-CEU, 12006 Castell\u00f3 de la Plana, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aitana","family":"Fillol","sequence":"additional","affiliation":[{"name":"Department of Mental Health, Consorci Hospitalari Provincial Universitari de Castell\u00f3, 12002 Castell\u00f3 de la Plana, Spain"},{"name":"TXP Research Group, Universidad Cardenal Herrera-CEU, 12006 Castell\u00f3 de la Plana, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"Caba\u00f1\u00e9s-Su\u00f1er","sequence":"additional","affiliation":[{"name":"Department of Mental Health, Consorci Hospitalari Provincial Universitari de Castell\u00f3, 12002 Castell\u00f3 de la Plana, Spain"},{"name":"TXP Research Group, Universidad Cardenal Herrera-CEU, 12006 Castell\u00f3 de la Plana, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0385-1618","authenticated-orcid":false,"given":"Rita","family":"Gimeno-Vergara","sequence":"additional","affiliation":[{"name":"Department of Mental Health, Consorci Hospitalari Provincial Universitari de Castell\u00f3, 12002 Castell\u00f3 de la Plana, Spain"},{"name":"TXP Research Group, Universidad Cardenal Herrera-CEU, 12006 Castell\u00f3 de la Plana, Spain"},{"name":"Fundaci\u00f3n Hospital Provincial, 12002 Castell\u00f3 de la Plana, Spain"},{"name":"Pre-Departmental Medicine Unit, Universitat Jaume I, 12006 Castell\u00f3 de la Plana, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S782","DOI":"10.1192\/j.eurpsy.2022.2019","article-title":"Ultra-treatment-resistant schizophrenia: A case report","volume":"65","year":"2022","journal-title":"Eur. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.euroneuro.2024.04.012","article-title":"Overcoming the barriers to identifying and managing treatment-resistant schizophrenia and to improving access to clozapine: A narrative review and recommendation for clinical practice","volume":"84","author":"Agid","year":"2024","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"994425","DOI":"10.3389\/fpsyt.2022.994425","article-title":"Treatment-resistant schizophrenia: How far have we traveled?","volume":"13","author":"Pandey","year":"2022","journal-title":"Front. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1007\/s00406-023-01654-2","article-title":"A network meta-analysis of efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia","volume":"274","author":"Dong","year":"2024","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"111090","DOI":"10.1016\/j.pnpbp.2024.111090","article-title":"Clozapine as a mood stabiliser for schizoaffective disorder: Effectiveness during a three-month follow-up","volume":"135","author":"Peraire","year":"2024","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_6","first-page":"448","article-title":"Treatment resistance in schizophrenia: A meta-analysis of prevalence and correlates","volume":"45","author":"Diniz","year":"2023","journal-title":"Rev. Bras. Psiquiatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"804","DOI":"10.51253\/pafmj.v74i3.11530","article-title":"Delay in clozapine initiation in patients with treatment-resistant schizophrenia presenting tertiary psychiatric facilities","volume":"74","author":"Jan","year":"2024","journal-title":"Pak. Armed Forces Med. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.5498\/wjp.v12.i8.1102","article-title":"Difference between treatment-resistant schizophrenia and clozapine-resistant schizophrenia","volume":"12","author":"Tseng","year":"2022","journal-title":"World J. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jpsychires.2014.07.001","article-title":"New therapeutic approaches for treatment-resistant schizophrenia: A look to the future","volume":"58","author":"Miyamoto","year":"2014","journal-title":"J. Psychiatr. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.schres.2016.01.024","article-title":"Augmentation of clozapine with electroconvulsive therapy in treatment-resistant schizophrenia: A systematic review and meta-analysis","volume":"171","author":"Lally","year":"2016","journal-title":"Schizophr. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1097\/YCT.0000000000000588","article-title":"Continuation electroconvulsive therapy for patients with clozapine-resistant schizophrenia: A pilot study","volume":"35","author":"Braga","year":"2019","journal-title":"J. ECT"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s13643-017-0644-y","article-title":"Optimal database combinations for literature searches in systematic reviews: A prospective exploratory study","volume":"6","author":"Bramer","year":"2017","journal-title":"Syst. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.clinthera.2007.01.002","article-title":"Prevalence, utilization patterns, and predictors of antipsychotic polypharmacy: Experience in a multistate Medicaid population, 1998\u20132003","volume":"29","author":"Morrato","year":"2007","journal-title":"Clin. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1097\/NMD.0b013e3181be7422","article-title":"A preliminary controlled trial of cognitive behavioral therapy in clozapine-resistant schizophrenia","volume":"197","author":"Barretto","year":"2009","journal-title":"J. Nerv. Ment. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.schres.2009.01.002","article-title":"The efficacy of lamotrigine in clozapine-resistant schizophrenia: A systematic review and meta-analysis","volume":"109","author":"Tiihonen","year":"2009","journal-title":"Schizophr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.psychres.2010.11.022","article-title":"A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine","volume":"188","author":"Gil","year":"2011","journal-title":"Psychiatry Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.pnpbp.2011.03.011","article-title":"Add-on of aripiprazole improves outcome in clozapine-resistant schizophrenia","volume":"35","author":"Pancheri","year":"2011","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.4081\/mi.2012.e1","article-title":"Antipsychotic polypharmacy in clozapine resistant schizophrenia: A randomized controlled trial of tapering antipsychotic co-treatment","volume":"4","author":"Hallikainen","year":"2012","journal-title":"Ment. Illn."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"394","DOI":"10.4103\/0019-5545.104848","article-title":"Successful use of adjuvant raloxifene treatment in clozapine-resistant schizophrenia","volume":"54","author":"Shivakumar","year":"2012","journal-title":"Indian J. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"pyu117","DOI":"10.1093\/ijnp\/pyu117","article-title":"Glutamatergic neurometabolites in clozapine-responsive and clozapine-resistant schizophrenia","volume":"18","author":"Goldstein","year":"2015","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_21","first-page":"678040","article-title":"Levothyroxine augmentation in clozapine-resistant schizophrenia: A case report and review","volume":"2015","author":"Seddigh","year":"2015","journal-title":"Case Rep. Psychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jpsychires.2015.01.004","article-title":"Efficacy and safety of aripiprazole augmentation of clozapine in schizophrenia: A systematic review and meta-analysis of randomized controlled trials","volume":"62","author":"Srisurapanont","year":"2015","journal-title":"J. Psychiatr. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1080\/17512433.2016.1200971","article-title":"Efficacy and safety of combining clozapine with electrical or magnetic brain stimulation in treatment-refractory schizophrenia","volume":"9","author":"Arumugham","year":"2016","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1007\/s00702-016-1574-x","article-title":"Effects of theta-rhythm transcranial alternating current stimulation (4.5 Hz-tACS) in patients with clozapine-resistant negative symptoms of schizophrenia: A case series","volume":"123","author":"Kallel","year":"2016","journal-title":"J. Neural Transm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1001\/jamapsychiatry.2017.0624","article-title":"Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: Systematic overview and quality appraisal of the meta-analytic evidence","volume":"74","author":"Correll","year":"2017","journal-title":"JAMA Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"58","DOI":"10.4306\/pi.2017.14.1.58","article-title":"Effectiveness of electroconvulsive therapy augmentation on clozapine-resistant schizophrenia","volume":"14","author":"Kim","year":"2017","journal-title":"Psychiatry Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"829","DOI":"10.30773\/pi.2018.05.15","article-title":"Combination of electroconvulsive therapy and clozapine in treatment-resistant schizophrenia","volume":"15","author":"Kim","year":"2018","journal-title":"Psychiatry Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.schres.2017.10.015","article-title":"Functional network dysconnectivity as a biomarker of treatment resistance in schizophrenia","volume":"195","author":"McNabb","year":"2018","journal-title":"Schizophr. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S2215-0366(18)30184-6","article-title":"Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): An assessor-blinded, randomised controlled trial","volume":"5","author":"Morrison","year":"2018","journal-title":"Lancet Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1177\/0004867418772351","article-title":"Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis","volume":"52","author":"Siskind","year":"2018","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jpsychires.2018.08.002","article-title":"ECT augmentation of clozapine for clozapine-resistant schizophrenia: A meta-analysis of randomized controlled trials","volume":"105","author":"Wang","year":"2018","journal-title":"J. Psychiatr. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jpsychires.2018.11.005","article-title":"Adjunctive second-generation antipsychotics for specific symptom domains of schizophrenia resistant to clozapine: A meta-analysis","volume":"108","author":"Bartoli","year":"2019","journal-title":"J. Psychiatr. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.biopsych.2018.09.009","article-title":"Glutamatergic neurometabolite levels in patients with ultra-treatment-resistant schizophrenia: A cross-sectional 3T proton magnetic resonance spectroscopy study","volume":"85","author":"Iwata","year":"2019","journal-title":"Biol. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.brs.2018.10.002","article-title":"Transcranial direct-current stimulation in ultra-treatment-resistant schizophrenia","volume":"12","author":"Lindenmayer","year":"2019","journal-title":"Brain Stimul."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"104257","DOI":"10.1016\/j.nbd.2018.08.016","article-title":"Treatment-resistant schizophrenia: Clinical, biological, and therapeutic perspectives","volume":"131","author":"Nucifora","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_36","first-page":"76","article-title":"Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: A prospective, randomized study","volume":"17","author":"Petrides","year":"2019","journal-title":"Focus (Am. Psychiatr. Publ.)"},{"key":"ref_37","first-page":"423","article-title":"Clozapine augmentation strategies\u2014A systematic meta-review of available evidence","volume":"33","author":"Wagner","year":"2019","journal-title":"Treat. Options Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1097\/WNF.0000000000000404","article-title":"One plus one sometimes equals more than two: Long-acting injectable aripiprazole adjunction in clozapine-resistant schizophrenia","volume":"43","author":"Balcioglu","year":"2020","journal-title":"Clin. Neuropharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"610","DOI":"10.2174\/1389450120666191011163539","article-title":"Novel treatment for the most resistant schizophrenia: Dual activation of NMDA receptor and antioxidant","volume":"21","author":"Lin","year":"2020","journal-title":"Curr. Drug Targets"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.schres.2020.12.002","article-title":"Characteristics and definitions of ultra-treatment-resistant schizophrenia: A systematic review and meta-analysis","volume":"228","author":"Campana","year":"2021","journal-title":"Schizophr. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"429","DOI":"10.5498\/wjp.v11.i8.429","article-title":"Clozapine resistant schizophrenia: Newer avenues of management","volume":"11","author":"Chakrabarti","year":"2021","journal-title":"World J. Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1080\/08039488.2021.1877349","article-title":"Comparative study of effectiveness of augmentation with ECT in clozapine-resistant schizophrenia and non-clozapine-resistant schizophrenia","volume":"75","author":"Grover","year":"2021","journal-title":"Nord. J. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1503\/jpn.210113","article-title":"Investigating structural subdivisions of the anterior cingulate cortex in schizophrenia, with implications for treatment resistance and glutamatergic levels","volume":"47","author":"Ochi","year":"2022","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"103121","DOI":"10.1016\/j.ajp.2022.103121","article-title":"A case report of clozapine-treatment-resistant schizophrenia successfully managed with brexpiprazole combination therapy","volume":"72","author":"Orsolini","year":"2022","journal-title":"Asian J. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"234","DOI":"10.4212\/cjhp.3178","article-title":"Amisulpride Augmentation of Clozapine in Clozapine-Resistant Schizophrenia: A Case Series","volume":"75","author":"Poonia","year":"2022","journal-title":"Can. J. Hosp. Pharm."},{"key":"ref_46","first-page":"59","article-title":"Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: A 12-week randomized, double-blind, placebo-controlled trial","volume":"9","author":"Zhu","year":"2022","journal-title":"Mil. Med. Res."},{"key":"ref_47","first-page":"380","article-title":"c.4168G>A (p.Ala1390Thr) variation in KMT2D gene detected in an ultra-treatment-resistant schizophrenia patient: A case report and literature review","volume":"60","author":"Alp","year":"2023","journal-title":"Noro Psikiyatr. Ars."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/pcn.13482","article-title":"Decreased cortical gyrification and surface area in the left medial parietal cortex in patients with treatment-resistant and ultra-treatment-resistant schizophrenia","volume":"77","author":"Kitajima","year":"2023","journal-title":"Psychiatry Clin. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"202","DOI":"10.9758\/cpn.2023.21.1.202","article-title":"Cariprazine\u2014An alternative treatment for clozapine-resistant schizophrenia?","volume":"21","author":"Montgomery","year":"2023","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41537-023-00392-7","article-title":"A systematic review of neuroimaging studies of clozapine-resistant schizophrenia","volume":"9","author":"Pang","year":"2023","journal-title":"Schizophrenia"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Peitl, V., Pulji\u0107, A., \u0160krobo, M., Nadalin, S., Fumi\u0107 Dunki\u0107, L., and Karlovi\u0107, D. (2023). Clozapine in treatment-resistant schizophrenia and its augmentation with electroconvulsive therapy in ultra-treatment-resistant schizophrenia. Biomedicines, 11.","DOI":"10.3390\/biomedicines11041072"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/JCP.0000000000001652","article-title":"Ultra-treatment-resistant schizophrenia and clozapine augmentation","volume":"43","author":"Tirupati","year":"2023","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"103375","DOI":"10.1016\/j.ajp.2022.103375","article-title":"Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment","volume":"79","author":"Yeh","year":"2023","journal-title":"Asian J. Psychiatry"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1127508","DOI":"10.3389\/fnimg.2023.1127508","article-title":"Resting-state functional MRI in treatment-resistant schizophrenia","volume":"2","author":"Tuovinen","year":"2023","journal-title":"Front. Neuroimaging"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"232","DOI":"10.9758\/cpn.23.1119","article-title":"Augmentation strategies for partial or non-responders to clozapine in patients with schizophrenia: A Bayesian network meta-analysis of randomized controlled trials","volume":"22","author":"Mishra","year":"2024","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"104029","DOI":"10.1016\/j.ajp.2024.104029","article-title":"Beyond conventional: Feasibility of accelerated tACS in clozapine-resistant schizophrenia\u2014A case report","volume":"95","author":"Pathak","year":"2024","journal-title":"Asian J. Psychiatry"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"171","DOI":"10.9758\/cpn.24.1198","article-title":"Lateral occipital cortex as a novel target for neuromodulation to attenuate auditory and visual hallucinations in a patient with ultra-treatment-resistant schizophrenia: A case report","volume":"23","author":"Bagali","year":"2025","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.euroneuro.2025.07.004","article-title":"Blood-based biomarkers of neuroaxonal and astroglial injury identify ultra-treatment-resistant schizophrenia","volume":"99","author":"Pinto","year":"2025","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_59","first-page":"sbaf209","article-title":"Immune and Long Interspersed Nuclear Element-1 Dysregulation in Schizophrenia: An Exploratory Case-Control Study in a Brazilian Cohort with Ultra-Treatment Resistance","volume":"52","author":"Pinto","year":"2025","journal-title":"Schizophr. Bull."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.jpsychires.2025.09.004","article-title":"Long-term trajectories of treatment-resistant schizophrenia following clozapine or electroconvulsive therapy: A retrospective observational study","volume":"190","author":"Kawashima","year":"2025","journal-title":"J. Psychiatr. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"627","DOI":"10.4103\/indianjpsychiatry.indianjpsychiatry_200_25","article-title":"Exploring adjunctive continuous theta burst stimulation for treatment-resistant auditory hallucinations in schizophrenia: Insights from a case series","volume":"67","author":"Mukherjee","year":"2025","journal-title":"Indian J. Psychiatry"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Prodi, T., Benatti, B., Grecchi, A., Oresti, M., Mazzoni, F., Carnevale, G., Brondino, N., Dell\u2019Osso, B., and Olivola, M. (2025). Lurasidone vs. other antipsychotics as augmentation strategies for clozapine in treatment-resistant schizophrenia: An observational multicenter prospective study. Curr. Neuropharmacol., Advance online publication.","DOI":"10.2174\/011570159X399781250910115949"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"103291","DOI":"10.1016\/j.eclinm.2025.103291","article-title":"Efficacy and tolerability of pharmacological interventions for schizophrenia non-responsive to prior treatment: A systematic review and network meta-analysis","volume":"84","author":"Samara","year":"2025","journal-title":"EClinicalMedicine"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2147\/NDT.S497725","article-title":"Optimal treatment of magnetic seizure therapy (MST) in patients with clozapine-resistant schizophrenia (CRS)","volume":"21","author":"Xiang","year":"2025","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"100396","DOI":"10.1016\/j.scog.2025.100396","article-title":"A clinical control study of modified electroconvulsive therapy and sodium valproate as enhancement strategies for ultra-treatment-resistant schizophrenia","volume":"43","author":"Wang","year":"2025","journal-title":"Schizophr. Res. Cogn."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s10143-026-04296-9","article-title":"Deep brain stimulation for clozapine-resistant schizophrenia: A systematic review of target-specific outcomes and stereotactic technical considerations","volume":"49","author":"Armando","year":"2026","journal-title":"Neurosurg. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Barros, F.M.R., Tolentino, A., Smaniotto, L., Lorencetti, P.G., Marques, L.S.K., de Souza, M.G., Marques, R.F., de Ara\u00fajo Bellesi, L.M., da Silva, P.V.P., and Dalgalarrondo, P. (2026). Electroconvulsive therapy as an adjunctive treatment for clozapine-resistant schizophrenia: A systematic review and meta-analysis of randomized controlled trials. J. ECT, Advance online publication.","DOI":"10.1097\/YCT.0000000000001237"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"20451253261433832","DOI":"10.1177\/20451253261433832","article-title":"Adjunctive xanomeline\/trospium in clozapine-resistant schizophrenia: Two case reports demonstrating limited response","volume":"16","author":"Dang","year":"2026","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"112733","DOI":"10.1016\/j.euroneuro.2025.11.010","article-title":"Sodium benzoate treatment linked to increased glutathione levels and improved positive and negative symptoms, global function, and quality of life in patients with clozapine-resistant schizophrenia: Secondary analysis of a randomized clinical trial","volume":"103","author":"Lin","year":"2026","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"MY20096AH1C","DOI":"10.4088\/JCP.MY20096AH1C","article-title":"Treatment-resistant schizophrenia: Definition, predictors, and therapy options","volume":"82","author":"Correll","year":"2021","journal-title":"J. Clin. Psychiatry"},{"key":"ref_71","first-page":"534027","article-title":"A false case of clozapine-resistant schizophrenia","volume":"2010","author":"Pinto","year":"2010","journal-title":"Case Rep. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1176\/appi.ajp.2016.16050503","article-title":"Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group consensus guidelines on diagnosis and terminology","volume":"174","author":"Howes","year":"2017","journal-title":"Am. J. Psychiatry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1093\/schbul\/sbaa145","article-title":"Predictors of treatment-resistant and clozapine-resistant schizophrenia: A 12-year follow-up study of first-episode schizophrenia-spectrum disorders","volume":"47","author":"Chan","year":"2021","journal-title":"Schizophr. Bull."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.schres.2012.03.018","article-title":"Prevalence and correlates of antipsychotic polypharmacy: A systematic review and meta-regression of global and regional trends from the 1970s to 2009","volume":"138","author":"Gallego","year":"2012","journal-title":"Schizophr. Res."},{"key":"ref_75","first-page":"CD006081","article-title":"Transcranial magnetic stimulation (TMS) for schizophrenia","volume":"2015","author":"Dougall","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"552","DOI":"10.4103\/singaporemedj.SMJ-2024-143","article-title":"Association between treatment resistance and cognitive function in schizophrenia","volume":"65","author":"Sun","year":"2024","journal-title":"Singap. Med. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1541469","DOI":"10.3389\/fpsyt.2025.1541469","article-title":"Exploring the role of autistic traits in treatment-resistant and clozapine-resistant schizophrenia: A comparative study","volume":"16","author":"Koparal","year":"2025","journal-title":"Front. Psychiatry"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"115338","DOI":"10.1016\/j.bbr.2024.115338","article-title":"Glutamate, GABA and NAA in treatment-resistant schizophrenia: A systematic review of the effect of clozapine and group differences between clozapine responders and non-responders","volume":"479","author":"Kristensen","year":"2025","journal-title":"Behav. Brain Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S2215-0366(15)00540-4","article-title":"Brain-imaging studies of treatment-resistant schizophrenia: A systematic review","volume":"3","author":"Mouchlianitis","year":"2016","journal-title":"Lancet Psychiatry"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"pyaf025","DOI":"10.1093\/ijnp\/pyaf025","article-title":"Moving toward precision and personalized treatment strategies in psychiatry","volume":"28","author":"Comai","year":"2025","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"104059","DOI":"10.1016\/j.nsa.2024.104059","article-title":"Biomarkers of treatment-resistant schizophrenia: A systematic review","volume":"3","author":"Pisanu","year":"2024","journal-title":"Neurosci. Appl."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1176\/ajp.156.11.1822","article-title":"D-serine added to clozapine for the treatment of schizophrenia","volume":"156","author":"Tsai","year":"1999","journal-title":"Am. J. Psychiatry"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1176\/ajp.156.1.145","article-title":"Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia","volume":"156","author":"Potkin","year":"1999","journal-title":"Am. J. Psychiatry"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"742058","DOI":"10.3389\/fpsyt.2021.742058","article-title":"Directly and indirectly targeting the glycine modulatory site to modulate NMDA receptor function to address unmet medical needs of patients with schizophrenia","volume":"12","author":"Pei","year":"2021","journal-title":"Front. Psychiatry"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1056\/NEJMoa2017015","article-title":"Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia","volume":"384","author":"Brannan","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"107510","DOI":"10.1016\/j.phrs.2024.107510","article-title":"IUPHAR review on muscarinic M1 and M4 receptors as drug treatment targets relevant to the molecular pathology of schizophrenia","volume":"210","author":"Dean","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/S0140-6736(23)02190-6","article-title":"Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: Results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial","volume":"403","author":"Kaul","year":"2024","journal-title":"Lancet"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.schres.2025.12.015","article-title":"Long-term efficacy, safety, and tolerability of xanomeline and trospium chloride in schizophrenia: A 52-week, open-label trial (EMERGENT-5)","volume":"288","author":"Kaul","year":"2026","journal-title":"Schizophr. Res."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2020). The American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia, American Psychiatric Association.","DOI":"10.1176\/appi.books.9780890424841"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1097\/PRA.0000000000000645","article-title":"Psychiatric futility and palliative care for a patient with clozapine-resistant schizophrenia","volume":"28","author":"Rosenbaum","year":"2022","journal-title":"J. Psychiatr. Pract."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"433","DOI":"10.21037\/apm-23-586","article-title":"Palliative psychiatry for a patient with treatment-refractory schizophrenia and severe chronic malignant catatonia: Case report","volume":"13","author":"Elgudin","year":"2024","journal-title":"Ann. Palliat. Med."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Peraire, M., and Echeverria, I. (2025). Beyond clinical remission: The foundations and rationale of palliative psychiatry. Span. J. Psychiatry Ment. Health, Advance online publication.","DOI":"10.1016\/j.sjpmh.2025.10.002"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1186\/s12888-016-0970-y","article-title":"Palliative psychiatry for severe persistent mental illness as a new approach to psychiatry? Definition, scope, benefits, and risks","volume":"16","author":"Trachsel","year":"2016","journal-title":"BMC Psychiatry"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/18\/7264\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:27:55Z","timestamp":1790076475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/18\/7264"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,18]]},"references-count":93,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jcm15187264"],"URL":"https:\/\/doi.org\/10.3390\/jcm15187264","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,18]]}}}