Treatment-resistant schizophrenia. Whilst seizures have been reported in patients receiving low doses, the risk is increased at higher doses [160], and the FDA label urges caution when prescribing clozapine in patients with a history of seizures or other predisposing risk factors for seizure (e.g., CNS pathology, medications that lower the seizure threshold, alcohol abuse) [62]. Stark A, Scott J. Schoretsanitis G, Kane JM, Correll CU, Marder SR, Citrome L, Newcomer JW, et al. Chan SKW, Chan HYV, Honer WG, Bastiampillai T, Suen YN, Yeung WS, et al. 5). Tiihonen J, Taipale H, Mehtl J, Vattulainen P, Correll CU, Tanskanen A. Clozapine is associated with the risk of rare myocarditis and cardiomyopathy. In the first center, clozapine was started at 25-50 mg followed by 50-100 mg as needed every 6 h on day 1, followed by increases of 50-100 mg/day. Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al. Strategies for optimizing treatment and managing side effects are summarized and a checklist is provided. Older adults should start with 12.5 mg on the first day and daily dosage incrementation by 25 mg [63]. Predictors of clozapine response in patients with treatment-refractory schizophrenia: results from a Danish Register Study. 4.6, Therapeutic Drug Monitoring). The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. Association between n-desmethylclozapine and clozapine-induced sialorrhea: involvement of increased nocturnal salivary secretion via muscarinic receptors by. Every-Palmer S, Inns SJ, Ellis PM. Efficacy, acceptability, and tolerability of antipsychotics in children and adolescents with schizophrenia: A network meta-analysis. Family members and caregivers should be informed of the dangers, risk factors, and signs of aspiration pneumonia. Pillinger T, Rogdaki M, McCutcheon RA, Hathway P, Egerton A, Howes OD. A practical, evidence-based checklist for identifying and managing patients with TRS, such as provided here, should increase confidence in prescribing and monitoring clozapine, reducing treatment delays, and improving outcomes. Delaying initiation of clozapine treatment is associated with higher economic burden [52], and poorer response rates [5356]. official website and that any information you provide is encrypted It is usually titrated up slowly over 14 days from a low starting dose (12.5mg) to limit dose-dependent side effects including sedation and hypotension. Clozapine use during breastfeeding is widely contraindicated because clozapine is excreted into breast milk [63, 76, 7981]. Prof. Crespo-Facorro has received honoraria as a consultant and/or advisor to Angelini, Janssen/J&J, Lundbeck, Otsuka and Viatris. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Cardio Diagnostics, Compass, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Pharmabrain, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. Blackman G, Oloyede E, Horowitz M, Harland R, Taylor D, MacCabe J, et al. Few geriatric patients were included in studies that informed the FDA label, therefore, caution is warranted regarding the side effects of tachycardia and orthostatic hypotension in patients with compromised cardiovascular functioning, and anticholinergic effects of constipation and urinary retention in older adults in general [62]. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. The positive and negative syndrome scale (PANSS) for schizophrenia. According to the reviewed cases, rechallenge may be more successful with slow titration and coadministration of low-dose lithium (300600 mg/day), which stimulates the bone marrow production of leucocytes. Available from: European Agency for the Evaluation of Medicinal Products (EMEA). Studies identifying a clinically relevant change in caffeine intake are lacking, but a relevant change may be > 1 cup of coffee or > 2 cans of caffeinated beverages per day in non-smoking patients (> 3 cups of coffee or > 6 cans of caffeinated beverages in smokers) [82]. Oxford University Press; 2018. Association with hospitalization and all-cause discontinuation among patients with schizophrenia on clozapine vs other oral second-generation antipsychotics: a systematic review and meta-analysis of cohort studies. The decision should consider the substantial risks to the mother and fetus/infant from untreated schizophrenia [78]. From reference [140], permission not required. Prog Neuropsychopharmacol Biol Psychiatry. Lifestyle changes should clearly be promoted [173]. However, the dose is usually not more than 900 mg per day. Dose reduction and/or addition of antiepileptic therapy allows most patients to continue clozapine therapy [161]. Elevated clozapine levels associated with infection: A systematic review. Real-world evidence has confirmed its effectiveness [3941]. Consider prophylactic anticonvulsant, Considercautious dose increase or augmentation. government site. Correll CU, Brevig T, Brain C. Patient characteristics, burden and pharmacotherapy of treatment-resistant schizophrenia: results from a survey of 204 US psychiatrists. Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. Siskind D, Orr S, Sinha S, Yu O, Brijball B, Warren N, et al. Prevalence and predictors of clozapine-associated constipation: a systematic review and meta-analysis. 8600 Rockville Pike Vickers M, Ramineni V, Malacova E, Eriksson L, McMahon K, Moudgil V, et al. Augmentation strategies for clozapine refractory schizophrenia: a systematic review and meta-analysis. Heterogeneity of striatal dopamine function in schizophrenia: meta-analysis of variance. The objective of this review is to provide an overview and guide for clinicians and researchers on clozapine initiation, and to propose a practical checklist for patient selection, clozapine initiation (titration) and maintenance, side-effect monitoring and management, with the aid to facilitate appropriate clozapine use in clinical care. For Initial Dose: 1. However, despite this strong recommendation, clozapine is underutilized in this setting [4446], and many patients initiate clozapine treatment after delays associated with trials of antipsychotic polypharmacy [27, 47, 48]. 1 Overview This Quick Reference Guide provides information for prescribers describing the new enhancements to the Clozapine Management System software in CPRS. Sandarsh S, Bishnoi RJ, Shashank RB, Miller BJ, Freudenreich O, McEvoy JP. ok A, ikrikili U, Karabulut S, Salaj A, ztrk M, Tabak , et al. An official website of the United States government. Conclusion: Orthostatic hypotension is a common side effect during clozapine titration. Less or more frequent monitoring may be appropriate depending on the clinical situation and local guidelines. de Leon J, Sanz EJ, Norn GN, De Las CC. The rate of clozapine titration may influence the occurrence of some adverse events, including benign hyperthermia, tachycardia, orthostatic hypotension, and risk for myocarditis, pneumonia, agranulocytosis, and seizures [65, 82]. Mouchlianitis E, Bloomfield MAP, Law V, Beck K, Selvaraj S, Rasquinha N, et al. Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals. Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy. Clozapine's action at numerous receptors has been implicated in these effects [166, 167], and the presence of one component of the metabolic syndrome is a risk factor for the other components . Clozaril [Internet]. Orthostatic hypotension is defined as a sustained reduction in systolic blood pressure of > 20 or of > 10 mmHg diastolic pressure within 3 min of rising from lying to a standing position and is associated with increased cardiovascular and cerebrovascular mortality, and syncope and falls. Metabolic changes include hyperglycemia, dyslipidemia, and weight gain [62, 164], which predispose patients to diabetes mellitus and cardiovascular disease. Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Clozapine and cardiotoxicitya guide for psychiatrists written by cardiologists. Veronese M, Santangelo B, Jauhar S, DAmbrosio E, Demjaha A, Salimbeni H, et al. Subsequent dose increases can be in increments of up to 100 mg once or twice weekly. The literature on clozapine titrations, including various local guidelines, focuses on initial titration and retitration over a non-standardised duration (SrT), and there is a paucity of evidence examining rapid retitration (RrT) (Nielsen Reference Nielsen, Damkier and Lublin 2011; Ronaldson Reference Ronaldson, Fitzgerald and Taylor 2012 . Benign ethnic neutropenia and clozapine use: a systematic review of the evidence and treatment recommendations. It has a median incidence of 287 (uncertainty interval 246331)/100,000 [2] and median standardized mortality ratio of 2.6 [3]. In a review of case reports, the success rate of clozapine rechallenge after clozapine-associated myocarditis was 64.7% (11/17) [119]. Clozapine is the antipsychotic with the highest risk of weight gain and other metabolic effects [164]. Verdoux H, Quiles C, Bachmann CJ, Siskind D. Prescriber and institutional barriers and facilitators of clozapine use: a systematic review. The World Federation of Societies of Biological Psychiatry does not recommend clozapine treatment during pregnancy because its side-effect profile includes agranulocytosis, metabolic effects, and seizures [76]. Available from: Canada - AA PHARMA. 5) [31]. Mortality and self-harm in association with clozapine in treatment-resistant schizophrenia. Clozapine is the only treatment approved for TRS, and patients should be treated as soon as possible to improve their chances of achieving remission. Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Glucagon-like peptide receptor agonists can increase insulin secretion while decreasing glucagon secretion and food intake, and have a larger effect on weight loss than metformin [172]. Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Therapies targeting postsynaptic dopamine receptors are not effective in all cases, especially regarding negative symptoms and in patients with treatment-resistant schizophrenia (TRS). The .gov means its official. Correlation between delay in initiating clozapine and symptomatic improvement. for a community titration schedule [90]). Moreover, TDM may potentially increase prescriber confidence [107]. However, if the inducer is necessary, it may be necessary to increase the clozapine dose. Jackson A, Seneviratne U. EEG changes in patients on antipsychotic therapy: a systematic review. Patients not responding to these should be referred to gastroenterology. Note: this is a sample titration schedule. The FDA requires weekly monitoring during the first 6 months of treatment; if absolute neutrophil count remains 1500/L ( 1000/L for BEN), then monitoring may be reduced to every 2 weeks for the next 6 months, and monthly thereafter (Tables (Tables66 and and7)7) [62]. Lally J, Ajnakina O, Di Forti M, Trotta A, Demjaha A, Kolliakou A, et al. World federation of societies of biological psychiatry (WFSBP) guidelines for biological treatment of schizophrenia. Nielsen J, Dahm M, Lublin H, Taylor D. Psychiatrists attitude towards and knowledge of clozapine treatment. Remington G, Agid O, Foussias G, Ferguson L, McDonald K, Powell V. Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold? Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Lifestyle interventions for weight management in people with serious mental illness: a systematic review with meta-analysis, trial sequential analysis, and meta-regression analysis exploring the mediators and moderators of treatment effects. Monitor for decreased effectiveness. Renzenbrink M, Wand APF. This project was supported by an unconditional grant from Viatris to support medical writing provided by EDRA S.p.A.; the sponsor had no role in study design, collection of evidence, interpretation of data, writing the manuscript, or the decision to publish. Antipsychotic drugs and obesity. Clozapine tablets are indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia. In most cases clozapine will be discontinued once myocarditis or cardiomyopathy develops, but there may be circumstances where the benefits outweigh the risks. Clozapine-associated myocarditis: a protocol for monitoring upon clozapine initiation and recommendations for how to conduct a clozapine rechallenge. Turrion MC, Perez J, Bernardo M, Fernandez-Egea E. Intra-individual variation of clozapine and norclozapine plasma levels in clinical practice. Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if well-tolerated. As a library, NLM provides access to scientific literature. Nielsen J, Correll CU, Manu P, Kane JM. 14-16 The incidence of clozapine-induced orthostatic hypotension is around 9%. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthj B, Gattaz WF, et al. Kay SR, Fiszbein A, Opler LA. Target 200 mg/day at the end of the second week. Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective. Treatment resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestones. 2021. Brugger SP, Angelescu I, Abi-Dargham A, Mizrahi R, Shahrezaei V, Howes OD. sharing sensitive information, make sure youre on a federal Hjorthj C, Strup AE, McGrath JJ, Nordentoft M. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. 17-19 However, common . Proactive measures might include the co-prescription of prophylactic laxatives in patients with risk factors (e.g., advanced age, history of constipation). Clozapine use can cause gastrointestinal hypomotility in any part of the digestive tract and, depending on the location, this can lead to constipation with increased risk of paralytic ileus and pseudo-obstruction, gastroparesis, or dysphagia and aspiration pneumonia and death [134]. He served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, and Teva. A systematic review of maternal and infant outcomes after clozapine continuation in pregnancy. Bernardo M, Rico-Villademoros F, Garca-Rizo C, Rojo R, Gmez-Huelgas R. Real-world data on the adverse metabolic effects of second-generation antipsychotics and their potential determinants in adult patients: a systematic review of population-based studies. This highlights the importance of reducing the chances of side effects by using the lowest effective clozapine dosage, while remaining vigilant for signs of respiratory tract infection. Nielsen J, Nielsen RE, Correll CU. It is associated with higher disease burden [26, 27] and poorer outcomes [28], especially involving persistent positive symptoms despite adherence with treatment [29]. Moreover, patients receiving clozapine are recommended to have hematological monitoring, particularly in the first 6 months of treatment when the risk of agranulocytosis is highest [64]. Abidi S, Mian I, Garcia-Ortega I, Lecomte T, Raedler T, Jackson K, et al. The risk is highest during the first 4 months of treatment, but remains throughout treatment [138]. The original online version of this article was revised. Myles N, Myles H, Xia S, Large M, Kisely S, Galletly C, et al. Clozapine ODT tablets rapidly disintegrate after placement in the mouth and may be chewed if desired. This may be due to the side-effect profile of clozapine, the monitoring requirements associated with its use, and a lack of prescribing experience [49, 50]. Gren JL, Rose AJ, Smith EG, Ney JP. ChildrenUse and dose must be determined by your doctor. (Fig.5)5) [131]. Prediabetic increase in hemoglobin A1c compared with impaired fasting glucose in patients receiving antipsychotic drugs. Kaar SJ, Natesan S, McCutcheon R, Howes OD. B-type natriuretic peptide (BNP) and N-terminal proBNP are sensitive and specific markers for heart failure and cardiomyopathy. Wang G, Zheng W, Li X-B, Wang S-B, Cai D-B, Yang X-H, et al. A meta-analysis of 32 studies (n = 2,013 patients) showed that the pooled prevalence of constipation associated with clozapine was 31.2% [135]. Clozapine is associated with side effects of varying severity, including FDA black box warnings for severe neutropenia, orthostatic hypotension, bradycardia, and syncope, seizure, myocarditis, cardiomyopathy, and mitral valve incompetence, as well as increased mortality in older adults with dementia-related psychosis (see prescribing information for complete list) [62]. The use of granulocyte colony-stimulating factor in clozapine rechallenge: a systematic review. An exception is made for patients with Duffy-null associated neutrophil count (DANC) who are subject to a lower ANC level. Mouchlianitis E, McCutcheon R, Howes OD. Yoshimura B, Yada Y, So R, Takaki M, Yamada N. The critical treatment window of clozapine in treatment-resistant schizophrenia: secondary analysis of an observational study. Take temperature, pulse, respiration (TPR), and lying and standing blood pressure (BP) prior to administration of clozapine 2. Tanzer T, Warren N, McMahon L, Barras M, Kisely S, Brooks E, et al. There may be high intra-individual variation in plasma levels even in stable patients [105], and some patients only respond after achieving blood clozapine levels above the reference range (350600 ng/mL) [106]. Seizures during clozapine therapy. Several lines of evidence indicate that it has a different neurobiology to schizophrenia that responds to dopamine D2 receptor blockers [11, 12]. McMillan SC, Williams FA. Psychopharmacology in pregnancy and breastfeeding. Schneider C, Corrigall R, Hayes D, Kyriakopoulos M, Frangou S. Systematic review of the efficacy and tolerability of clozapine in the treatment of youth with early onset schizophrenia. It has been hypothesized that TRS could represent aneurobiologically distinct sub-type of schizophrenia [13, 14]. Consider prophylactic anticonvulsant in both cases, Decrease dose slowly, monitor to remain in the reference range, if possible, Continue to monitor concentrations. Steinlechner S, Klein C, Moser A, Lencer R, Hagenah J. Botulinum toxin B as an effective and safe treatment for neuroleptic-induced sialorrhea. HHS Vulnerability Disclosure, Help The blank clozapine titration chart can be used for this purpose. British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017. Ruan C-J, Zang Y-N, Wang C-Y, Cheng Y-H, Sun C, Spina E, et al. Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-responsive. Clinical validation of ratings on the six-item positive and negative syndrome scale obtained via the simplified negative and positive symptoms interview. National Inpatient Medication Chart (NIMC) - Clozapine Titration guide Download PDF (78.34 KB) Accessibility - We aim to provide documents in an accessible format. Based on evidence from nearly 50,000 patients, the risk ratio for hospitalization in patients taking clozapine relative to patients taking other antipsychotics was 0.817 (95% CI 0.7250.920; P = 0.001) [42]. Altered glutamatergic response and functional connectivity in treatment resistant schizophrenia: the effect of riluzole and therapeutic implications. The validity and sensitivity of PANSS-6 in treatment-resistant schizophrenia. Accessibility Dixon LB, Dickerson F, Bellack AS, Bennett M, Dickinson D, Goldberg RW, et al. Target 100 mg/day at the end of the second week. Findings from genomic studies suggest the involvement of multiple genes, including the solute carrier organic anion transporter 1B3/1B7 and members of the human leukocyte antigen complex [116]. A summary of 259 cases of clozapine rechallenge after major adverse events reported a success rate of 63.0% (128/203) for patients with neutropenia, and 17.7% (3/17) for those with agranulocytosis [119]. The US Food and Drug Administration (FDA) indications for clozapine include TRS and suicidal behavior in patients with schizophrenia or schizoaffective disorder [62], while the European Medicines Agency (EMA) indication includes TRS and schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including second-generation antipsychotics, as well as psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed [63], whereas clozapine is indicated only for treating TRS in Australia, Japan, and Canada [6668]. Varma S, Bishara D, Besag FMC, Taylor D. Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Major factors influencing blood clozapine concentrations include those significantly elevating clozapine blood levels, such as female sex (estrogen), older age, Asian/Amerindian ancestry, obesity, inflammation (from infection, rapid clozapine titration), high levels of caffeine use, coadministration of valproic acid, low CYP1A2 expression, and coadministration of CYP1A2 inhibitors; conversely, clozapine blood levels are lowered by smoking and other CYP1A2 inducers, including phenobarbital, phenytoin, and topiramate dosage > 400 mg/day (Table (Table1)1) [62, 8286]. Psychosis and Schizophrenia in Adults: Treatment and Management: Updated Edition 2014 [Internet]. Update and maintain vaccination against seasonal influenza and COVID-19. Repeat observations: Half hourly for 2 hours 1 hourly for 4 hours 4. See Sect. AGRANULOCYTOSIS BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT, CLOZARIL (CLOZAPINE) SHOULD BE RESERVED FOR USE IN (1) THE TREATMENT OF. Hynes C, Keating D, McWilliams S, Madigan K, Kinsella A, Maidment I, et al. International trends in clozapine use: a study in 17 countries. However, it can be useful during initial titration of clozapine and during maintenance when there are signs of relapse, onset of side effects that are known to be dose dependent, or changes in factors known to influence blood levels, such as concomitant medications or cigarette use [103, 104]. Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, et al. Maher S, Cunningham A, OCallaghan N, Byrne F, Mc Donald C, McInerney S, et al. Shimomura Y, Kikuchi Y, Suzuki T, Uchida H, Mimura M, Takeuchi H. Antipsychotic treatment strategies for acute phase and treatment resistance in schizophrenia: a systematic review of the guidelines and algorithms. Guidelines on prescribing psychotropic medication during the perinatal period. Despite its effectiveness, concern over side effects, monitoring requirements, and inexperience with prescribing often result in long delays that . Background Clozapine is the gold standard intervention for treatment resistant schizophrenia. Clozapine is the most efficacious antipsychotic for treatment-resistant schizophrenia (TRS) [] and when patients respond, clozapine should not be discontinued [], unless continuation poses a risk to the patient.Leucht et al. Rechallenge after recovery from clozapine-induced neutropenia is envisioned in guidance from the FDA. Dr. de Bartolomeis has participated in advisory boards, lectures and unrestricted presentations sponsored by Trivia- Mylan. stergaard SD, Lemming OM, Mors O, Correll CU, Bech P. PANSS-6: a brief rating scale for the measurement of severity in schizophrenia. A review of the use of clozapine levels to guide treatment and determine cause of death. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? Clozapine is the only drug approved for TRS by regulators in North America, Europe, and many other jurisdictions. The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements. An audit conducted in UK mental health services found that patient-compiled rating scales may be underutilized [111]. Stokes I, Griffiths SL, Jones R, Everard L, Jones PB, Fowler D, et al. (Fig.5)5) [90, 131133]. A Correction to this paper has been published: 10.1007/s40263-022-00946-w, National Library of Medicine The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. 9 This study used a rapid titration defined as a starting dose of 25 mg and increased by 25-50 mg every 6 hours, no more than 100 mg daily, until control of symptoms. Tiihonen J, Lnnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, et al. Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, Stone JM, et al. Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ. Rating scales to measure side effects of antipsychotic medication: a systematic review. Available from: Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. It occurs most frequently during the first month of treatment and affects approximately 1% of treated patients [113, 114]. A validated, clozapine-specific version of the GASS (GASS-C) has been developed [110]. The clozapine dose required to achieve and maintain blood levels in the therapeutic range varies greatly among patients. In conducting this review, we have searched Medline using the query (((algorithm OR checklist OR tool OR recommendation OR guide* OR policy)) AND ((review OR systematic OR meta-analysis OR metaanalysis))) AND ((clozapine AND (resistan* OR refractor* OR treatment-resistant schizophrenia OR TRS OR "treatment failure"))) to identify systematic reviews, meta-analyses, guidelines, and treatment algorithms related to TRS published in English before March 2022; we manually searched the reference lists of retrieved recent publications for additional relevant publications. Temperature- pre-dose and hourly for 6 hours. Risk-benefit considerations should be weighed against the fact that clozapine is the only approved treatment for TRS and that clozapine treatment significantly lowers all-cause mortality [3436]. Its low affinity for D2 dopamine receptors may explain its relative lack of extrapyramidal side effects [30], whilst its actions to modulate glutamate levels may contribute to its superior efficacy in TRS [32]. Taylor DM, Young C, Paton C. Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review. Seizure associated with clozapine: incidence, etiology, and management. Lally J, Malik S, Krivoy A, Whiskey E, Taylor DM, Gaughran FP, et al. Treatment may include clozapine dose reduction, when possible, and anticholinergics. Manu P, Correll CU, Wampers M, van Winkel R, Yu W, Mitchell AJ, et al. The reference citation was corrected from 103 to 104 in few occurrences. Where available, treatment should take place in a context that supports the psychosocial needs of the patient and provides care for psychiatric comorbidities and any medical problems, as well as providing access to psychiatric pharmacotherapy and monitoring [6971]. A systematic review of evidence-based guidelines for antipsychotic treatment of patients with schizophrenia found that all 17 of the guidelines reviewed recommend initiating treatment with the antipsychotic drug clozapine when patients are diagnosed with TRS [43]. The risk of myocarditis is higher among patients commencing clozapine treatment while receiving valproate [130]. Clozapine treatment is not contraindicated by the EMA or FDA for pregnant women who clearly require treatment (FDA pregnancy class B) [62, 63]; however, caution and additional monitoring are warranted because of the relative lack of studies. Blood pressure (standing and lying)- pre-dose and hourly for 6 hours. Iasevoli F, Giordano S, Balletta R, Latte G, Formato MV, Prinzivalli E, et al. Clozapine is the only treatment approved for TRS, and patients should be treated as soon as possible to improve their chances of achieving remission. These conditions do not appear to be dose dependent. 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