Clozapine: a review of clinical practice guidelines and prescribing trends

Stephanie Warnez, Silvia Alessi-Severini, Stephanie Warnez, Silvia Alessi-Severini

Abstract

Background: Clozapine effectiveness in the treatment of refractory schizophrenia has been sustained by published evidence in the last two decades, despite the introduction of safer options.

Discussion: Current clinical practice guidelines have strongly recommended the use of clozapine in treatment-resistant schizophrenia, but prescribing trends do not appear to have followed such recommendations. Clozapine is still underutilized especially in patients at risk of suicide. It seems that physicians are hesitant in prescribing clozapine due to concerns about serious adverse effects. Recent reports have highlighted the need to inform health professionals about the benefits of treating patients with clozapine and have voiced concerns about the underutilization of clozapine especially in patients at risk of suicide.

Summary: Guidelines and prescribing patterns reported in various countries worldwide are discussed. Suggestions on how to optimize clozapine utilization have been published but more efforts are needed to properly inform and support prescribers' practices.

References

    1. Crilly J. The history of clozapine and its emergence in the US market: a review and analysis. Hist Psychiatry. 2007;18(1):39–60. doi: 10.1177/0957154X07070335.
    1. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic, A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789–796. doi: 10.1001/archpsyc.1988.01800330013001.
    1. Clozaril. Product Monograph. Health Canada Accessed on January 30, 2014.
    1. Honigfeld G, Arellano F, Sethi J, Bianchini A, Schein J. Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry. J Clin Psychiatry. 1998;59(Suppl 3):3–7.
    1. Hartling L, Abou-Setta A, Dursum S, Mousavi SS, Pasichnyk D, Newton AS. Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications. Ann Int Med. 2012;157:498–511. doi: 10.7326/0003-4819-157-7-201210020-00525.
    1. Leucht S, Cipriani A, Spinelli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple treatments meta-analysis. Lancet. 2013;382:951–962. doi: 10.1016/S0140-6736(13)60733-3.
    1. Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo: a meta-analysis of randomized controlled trials. Schizoph Res. 1999;35:51–68. doi: 10.1016/S0920-9964(98)00105-4.
    1. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with sec- ond-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161:414–425. doi: 10.1176/appi.ajp.161.3.414.
    1. Alessi-Severini S, Biscontri R, Collins D, Kozyrskyj A, Sareen J, Enns M. Utilization and Costs of Antipsychotic Agents: a Canadian Population-Based Study: 1996–2006. Psychiatr Serv. 2008;59(5):547–553. doi: 10.1176/appi.ps.59.5.547.
    1. Pringsheim T, Lam D, Tano DS, Patten SB. The pharmacoepidemiology of antipsychotics for adults with schizophrenia in Canada, 2005 to 2009. Can J Psychiatry. 2011;56(10):630–634.
    1. Aparasu RR, Bhatara V, Gupta S. US national trends in the use of antipsychotics during office visits, 1998–2002. Ann Clin Psychiatry. 2005;17:147–152. doi: 10.1080/10401230591002084.
    1. Trifirò G, Spina E, Brignoli O, Sessa E, Caputi AP, Mazzaglia G. Antipsychotic prescribing pattern among Italian general practitioners: a population- based study during the years 1999–2002. Eur J Clin Pharmacol. 2005;61:47–53. doi: 10.1007/s00228-004-0868-3.
    1. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J. American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2):1–56.
    1. Addington D, Bouchard RH, Goldberg J, Honer B, Malla A, Norman R, Tempier R, Berzins S. Clinical practice guidelines: treatment of schizophrenia. Can J Psychiatry. 2005;50(Suppl. 1):7S–57S.
    1. Moore TA, Buchanan RW, Buckley PF, Chiles JA, Conley RR, Crismon ML, Essock SM, Finnerty M, Marder SR, Miller DD, McEvoy JP, Robinson DG, Schooler NR, Shon SP, Stroup TS, Miller AL. The Texas Medication Algorithm Project: antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry. 2007;68:1751–1762. doi: 10.4088/JCP.v68n1115.
    1. National Institute of Health and Clinical Excellence: Core intervention in the treatment and management of schizophrenia in primary and secondary care (CG82) 2009. Accessed January 30, 2014.
    1. Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W. Schizophrenia Patient Outcomes Research Team (PORT) The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36(1):71–93. doi: 10.1093/schbul/sbp116.
    1. Clozapine Treatment of Hospitalized Patients: A Review of Clinical Practice Guidelines and Safety. Report December 20, 2010 Accessed on August 10, 2012 +treatment+in+hospitalized.
    1. Barnes TRE. Schizophrenia consensus group of the British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2011;25(5):567–620. doi: 10.1177/0269881110391123.
    1. Osser DN, Roudsari MJ, Manschreck T. The psychopharmacology algorithm project at the Harvard South Shore Program: an update on schizophrenia. Harv Rev Psychiatry. 2013;21(1):18–40. doi: 10.1097/HRP.0b013e31827fd915.
    1. Moore TA, Covell NH, Essock SM, Miller AL. Real-world antipsychotic treatment practices. Psychiatr Clin North Am. 2007;30(3):401–416. doi: 10.1016/j.psc.2007.04.008.
    1. Taylor DM, Young C, Paton C. Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review. J Clin Psychiatry. 2003;64:30–34. doi: 10.4088/JCP.v64n0107.
    1. Wheeler AJ. Treatment pathway and patterns of clozapine prescribing for schizophrenia in New Zealand. Ann Pharmacother. 2008;42:852–860. doi: 10.1345/aph.1K662.
    1. Joober R, Boksa P. Clozapine: a distinct, poorly understood and underused molecule. J Psychiatry Neurosci. 2010;35(3):147–159. doi: 10.1503/jpn.100055.
    1. Howes OD, Vergunst F, Gee S, McGuire P, Kapur S, Taylor D. Adherence to treatment to guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. BJP. 2012;201:481–485. doi: 10.1192/bjp.bp.111.105833.
    1. Alessi-Severini S, LeDorze JA, Nguyen D, Honcharik P, Eleff M. Clozapine prescribing in a Canadian outpatient population. Plos One. 2013;8(12):e83539. doi: 10.1371/journal.pone.0083539.
    1. Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A, Carpenter WT Jr. Effect of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry. 1994;151:20–26.
    1. Essock SM, Hargreaves WA, Covell NH, Goethe J. Clozapine’s effectiveness for patients in state hospitals: results from a randomized trial. Psychopharmacol Bull. 1996;32:683–697.
    1. Rosenheck R, Cramer J, Xu W, Thomas J, Henderson W, Frisman L, Fye C, Charney D. Comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med. 1997;337:809–815. doi: 10.1056/NEJM199709183371202.
    1. Chakos M, Lieberman JA, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry. 2001;158:518–526. doi: 10.1176/appi.ajp.158.4.518.
    1. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31–41. doi: 10.1016/S0140-6736(08)61764-X.
    1. Essali A, Al-Haj HN, Li C, Rathbone J. Clozapine versus typical neuroleptic medications for schizophrenia. Cochrane Database Syst Rev. 2010;20(1):CD000059. pub2.
    1. Lewis SW, Barnes TR, Davies L, Murray RM, Dunn G, Hayhurst KP, Markwick A, Lloyd H, Jones PB. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006;32(4):715–723.
    1. Lieberman JA, Stroup S, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223. doi: 10.1056/NEJMoa051688.
    1. Stroup TS, Lieberman JA, McEvoy JP, Davis SM, Swartz MS, Keefe RS, Miller AL, Rosenheck RA, Hsiao JK. CATIE Investigators. Results of phase 3 of the CATIE schizophrenia trial. Schizophr Res. 2009;107(1):1–12. doi: 10.1016/j.schres.2008.10.011.
    1. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK. CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetipine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600–610. doi: 10.1176/appi.ajp.163.4.600.
    1. Asenjo Lobos C, Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Leucht S. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010. p. CD006633.
    1. Souza JS, Kayo M, Tassel I, Martins CB, Elkis H. Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from systematic review and meta-analyses. CNS Spectrums. 2013;18(2):82–89. doi: 10.1017/S1092852912000806.
    1. Duggan A, Wagner J, Knapp M, Kerwin R. Modelling the impact of clozapine on suicide in patients with treatment-resistant schizophrenia. BJP. 2003;182:505–508. doi: 10.1192/bjp.182.6.505.
    1. Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, Haukka J. 11-year follow up of mortality in patients with schizophrenia: a population-based cohort study (FIN 11 study) Lancet. 2009;374:620–627. doi: 10.1016/S0140-6736(09)60742-X.
    1. Kasckow J, Felmet K, Zisook S. Managing suicide risk in patients with schizophrenia. CNS Drugs. 2011;25(2):129–143. doi: 10.2165/11586450-000000000-00000.
    1. Wasserman D, Rihmer Z, Rujescu D, Sarchiapone M, Sokolowski M, Titelman D, Zalsman G, Zemishlany Z, Carli V. European Psychiatric Association. The European Psychiatric Association (EPA) guidance on suicide treatment and prevention. Eur Psychiatry. 2012;27:129–141. doi: 10.1016/j.eurpsy.2011.06.003.
    1. Conley RB, Kelly DL, Lambert TJ, Love RC. Comparison of clozapine use in Maryland and in Victoria, Australia. Psychiatr Serv. 2005;56:320–323. doi: 10.1176/appi.ps.56.3.320.
    1. Goren JL, Meterko M, Williams S, Young GJ, Baker E, Chou CH, Kilbourne AM, Bauer MS. Antipsychotic prescribing pathways, polypharmacy, and clozapine use in treatment of schizophrenia. Psychiatr Serv. 2013;64(6):527–533. doi: 10.1176/appi.ps.002022012.
    1. Latimer E, Wynant W, Clark R, Malla A, Moodie E, Tamblyn R, Naidu A. Underprescribing of clozapine and unexplained variations in use across hospitals and regions in the Canadian province of Quebec. Clin Schizophr Relat Psychoses. 2013;7(1):33–41. doi: 10.3371/CSRP.LAWY.012513.
    1. Malalagama G, Bastiampillai T, Dhillon R. Clozapine use in Australia. Australas Psychiatry. 2011;19(2):175.
    1. Frogley C, Taylor D, Dickens G, Picchioni M. A systematic review of the evidence of clozapine’s anti-aggressive effects. Int J Neuropsychopharmacol. 2012;15:1351–1371. doi: 10.1017/S146114571100201X.
    1. “Clozaril” Prescribing information Accessed January 30, 2014.
    1. Woerner MG, Robinson DG, Alvir JM, Sheitman BB, Lieberman JA, Kane JM. Clozapine as a first treatment for schizophrenia. Am J Psychiatry. 2003;160(8):1514–1526. doi: 10.1176/appi.ajp.160.8.1514.
    1. Lieberman JA, Phillips M, Gu H, Stroup S, Zhang P, Kong L, Ji Z, Koch G, Hamer RM. Atypical and conventional antipsychotic drugs in treatment-naïve first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology. 2003;28(5):995–1003.
    1. Agid O, Remington G, Kapur S, Arenovich T, Zipursky RB. Early use of clozapine for poorly responding first-episode psychosis. J Clin Psychopharmacol. 2007;27(4):369–373. doi: 10.1097/jcp.0b013e3180d0a6d4.
    1. Swartz MS, Perkins DO, Stroup TS, Davis SM, Capuano G, Rosenheck RA, Reimherr F, McGee MF, Keefe RS, McEvoy JP, Hsiao JK, Lieberman JA. CATIE Investigators. Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study. Am J Psychiatry. 2007;164(3):428–436. doi: 10.1176/appi.ajp.164.3.428.
    1. Meltzer HY, Bobo WV, Lee MA, Cola P, Jayathilake K. A randomized trial comparing clozapine and typical neuroleptic drugs in non-treatment-resistant schizophrenia. Psychiatry Res. 2010;177(3):286–293. doi: 10.1016/j.psychres.2010.02.018.
    1. Ascher-Svanum H, Nyhuis AW, Faries DE, Kinon BJ, Baker RW, Shekhar A. Clinical, functional, and economic ramifications of early nonresponse to antipsychotics in the naturalistic treatment of schizophrenia. Schizophr Bull. 2008;34(6):1163–1171. doi: 10.1093/schbul/sbm134.
    1. Chang YC, Lane HY, Yang KH, Huang CL. Optimizing early prediction for antipsychotic response in schizophrenia. J Clin Psychopharmacol. 2006;26(6):554–559. doi: 10.1097/01.jcp.0000246211.95905.8c.
    1. Correll CU, Malhotra AK, Kaushik S, McMeniman M, Kane JM. Early prediction of antipsychotic response in schizophrenia. Am J Psychiatry. 2003;160(11):2063–2065. doi: 10.1176/appi.ajp.160.11.2063. Erratum in: Am J Psychiatry 2005, 162(9):1774.
    1. Gallego JA, Robinson DG, Sevy SM, Napolitano B, McCormack J, Lesser ML, Kane JM. Time to treatment-response in first –episode schizophrenia: should acute treatment trials last several months? J Clin Psychiatry. 2011;72:1691–1696. doi: 10.4088/JCP.10m06349.
    1. Agid O, Arenovich T, Sajeev G, Kipursky RB, Kapur S, Foussias G, Remington G. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry. 2011;72(11):1439–1444. doi: 10.4088/JCP.09m05785yel.
    1. Netherlands Clozapine Collaboration Group. Guideline for the use of clozapine [English version] 2009. [Cited 14 July 2010] .
    1. Schulte PF, Cohen D, Bogers JPAM, van Dijk D, Bakker B. A Dutch guideline for the use of clozapine. Aust N Z J Psychiatry. 2010;44:1055–1056.
    1. Van-Kammen DP, Marder SR. In: Comprehensive Textbook of Psychiatry. 7. Kaplan HI, Sadock BJ, editor. Baltimore, Md: Lippincott Williams & Wilkins; 2000. Serotonin/dopamine antagonists; pp. 2455–2473.
    1. Hermes E, Resenheck. Choice of randomization to clozapine versus other second-generation antipsycotics in the CATIE schizophrenia trial. J Psychopharmacol. 2012;26:1194–1200. doi: 10.1177/0269881112443744.
    1. Meltzer HY. Clozapine: balancing safety with superior antipsychotic efficacy. Clin Schizophr Relat Psychoses. 2012;6(3):134–144. doi: 10.3371/CSRP.6.3.5.
    1. Phanthunane P, Vos T, Whitefors H, Bertram M. Cost-effectiveness of pharmacological and psychosocial interventions for schizophrenia. Cost Eff Resour Alloc. 2011;9:6. doi: 10.1186/1478-7547-9-6. doi:10.1186/1478-7547-9-6.
    1. Attard A, Taylor DM. Comparative Effectiveness of Atypical Antipsychotics in Schizophrenia. CNS Drugs. 2012;26(6):491–508. doi: 10.2165/11632020-000000000-00000.
    1. Sinyor M, Remington G. Is psychiatry ignoring suicide? J Clin Psychopharmacol. 2012;32(3):307–308. doi: 10.1097/JCP.0b013e31825501fb.
    1. Hill M, Freudenreich O. Clozapine: key discussion points for prescribers. Clin Schizophr Relat Psychoses. 2013;6(4):177–185. doi: 10.3371/CSRP.HIFR.01062013.
    1. Damkier NJ, Taylor LH. Optimizing clozapine treatment. Acta Psychiatric Scand. 2011;123:411–422. doi: 10.1111/j.1600-0447.2011.01710.x.
    1. Beck K, Howes O. Optimising treatment of refractory schizophrenia. Psychopharmacology. 2013;227:373–374. doi: 10.1007/s00213-013-3076-y.
    1. Williams T, Purvis TL. Development of an outpatient pharmacist-managed clozapine clinic. Am J Health-Syst Pharm. 2012;69:1192–1195. doi: 10.2146/ajhp110461.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe