Psych · Psychopharmacology — clozapine
Clozapine
Also known as Clozaril · Clopine · Treatment-resistant schizophrenia clozapine · Clozapine monitoring · TRS clozapine
Exam-exhaustive fellowship reference on clozapine — TRRIP entry, titration, plasma levels, region-aware haematology principles, myocarditis and cardiomyopathy, constipation/ileus, seizures, hypersalivation, metabolic risk, smoking/CYP1A2, InterSePT, Siskind response rates, rechallenge, elderly slow titration. FRANZCP-primary, globally tagged.
Practise this topic
On this page
Study tools
Your progress
Saved on this device.
Target exams
FRANZCPMRCPsychABPNMD-DNBNEET-SS
Red flags
- Fever, chest pain or unexplained tachycardia in the first month of clozapine — stop and investigate for myocarditis
- Severe constipation, vomiting or abdominal distension — treat as possible ileus; stop clozapine and escalate
- Fever, sore throat or sepsis signs — urgent FBC/ANC before assuming a viral illness
- Seizure on clozapine — ABC, check dose/level/interactions, do not ignore rising levels after smoking cessation
- No recent valid bloods — no dispensing; no bloods, no drug
- Two adequate failed antipsychotic trials with adherence confirmed — do not delay TRRIP-guided clozapine offer
Meet the patient
Day 19 of clozapine. A 27-year-old man on the rehabilitation ward feels "fluey". Temperature 38.4, heart rate 122, mild chest tightness he puts down to anxiety. The overnight note reads "likely viral URTI — push fluids, review Monday."[10][11]
It is not Monday's problem. In the first month of clozapine, fever with unexplained tachycardia is myocarditis until an ECG, CRP and troponin say otherwise — and separately, fever with a sore throat is neutropenia until a full blood count says otherwise.[8][10][11][22]
Two lethal diagnoses hide behind the same three words: "probably a virus". That is why this drug has a topic of its own.[8][11][24]
References24ShowHide
- [1]Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry, 1988.PMID 3046553
- [2]Howes OD, McCutcheon R, Agid O, et al. Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology Am J Psychiatry, 2017.PMID 27919182
- [3]Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT) Arch Gen Psychiatry, 2003.PMID 12511175
- [4]Siskind D, Siskind V, Kisely S Clozapine Response Rates among People with Treatment-Resistant Schizophrenia: Data from a Systematic Review and Meta-Analysis Can J Psychiatry, 2017.PMID 28655284
- [5]Siskind D, McCartney L, Goldschlager R, et al. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis Br J Psychiatry, 2016.PMID 27388573
- [6]Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis Lancet, 2013.PMID 23810019
- [7]Tiihonen J, Lönnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study) Lancet, 2009.PMID 19595447
- [8]Alvir JM, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med, 1993.PMID 8515788
- [9]Pacia SV, Devinsky O Clozapine-related seizures: experience with 5,629 patients. Neurology, 1994.PMID 7991106
- [10]Kilian JG, Kerr K, Lawrence C, et al. Myocarditis and cardiomyopathy associated with clozapine. Lancet, 1999.PMID 10584719
- [11]Ronaldson KJ, Taylor AJ, Fitzgerald PB, et al. Diagnostic characteristics of clozapine-induced myocarditis identified by an analysis of 38 cases and 47 controls. J Clin Psychiatry, 2010.PMID 20361910
- [12]Ronaldson KJ, Fitzgerald PB, Taylor AJ, et al. Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study. Schizophr Res, 2012.PMID 23010488
- [13]Palmer SE, McLean RM, Ellis PM, et al. Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry, 2008.PMID 18452342
- [14]Every-Palmer S, Ellis PM Clozapine-Induced Gastrointestinal Hypomotility: A 22-Year Bi-National Pharmacovigilance Study of Serious or Fatal 'Slow Gut' Reactions, and Comparison with International Drug Safety Advice. CNS Drugs, 2017.PMID 28623627
- [15]Handley SA, Every-Palmer S, Ismail A, et al. Clozapine-induced gastrointestinal hypomotility: presenting features and outcomes, UK pharmacovigilance reports, 1992-2017. Br J Psychiatry, 2022.PMID 35164895
- [16]Rostami-Hodjegan A, Amin AM, Spencer EP, et al. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol, 2004.PMID 14709950
- [17]Haslemo T, Eikeseth PH, Tanum L, et al. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol, 2006.PMID 17089108
- [18]Perry PJ, Miller DD, Arndt SV, et al. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry, 1991.PMID 1670979
- [19]Northwood K, Pearson E, Arnautovska U, et al. Optimising plasma clozapine levels to improve treatment response: an individual patient data meta-analysis and receiver operating characteristic curve analysis. Br J Psychiatry, 2023.PMID 36994656
- [20]de Leon J, Schoretsanitis G, Smith RL, et al. An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels. Pharmacopsychiatry, 2022.PMID 34911124
- [21]Manu P, Lapitskaya Y, Shaikh A, et al. Clozapine Rechallenge After Major Adverse Effects: Clinical Guidelines Based on 259 Cases. Am J Ther, 2018.PMID 29505490
- [22]Cohen D, Bogers JP, van Dijk D, et al. Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy. J Clin Psychiatry, 2012.PMID 23140648
- [23]Hiemke C, Bergemann N, Clement HW, et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry, 2018.PMID 29390205
- [24]Flanagan RJ, Lally J, Gee S, et al. Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals. Br Med Bull, 2020.PMID 32885238