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Clozapine: a review of clinical practice guidelines and prescribing trends

†Contributed equally
BMC Psychiatry201414:102

https://doi.org/10.1186/1471-244X-14-102

©  Warnez and Alessi-Severini; licensee BioMed Central Ltd. 2014

  • Received: 5 November 2013
  • Accepted: 31 March 2014
  • Published:
Open Peer Review reports

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.

Keywords

  • Clozapine
  • Prescribing
  • Schizophrenia
  • Antipsychotic(s)
  • Utilization
  • Guidelines

Background

Clozapine efficacy as an “atypical” antipsychotic agent has been recognized since the early 1960s [1]. This agent became available on the European market for the treatment of schizophrenia with the promise of a better tolerability because of the absence of those extrapyramidal side effects that afflicted patients treated with other antipsychotic agents (e.g., chlorpromazine and haloperidol, now defined as “typical” or first- generation agents, FGAs) [1]. However, the release of alarming reports of agranulocytosis in Finnish patients created panic among prescribers; a total of 17 cases were confirmed among 100 patients treated with clozapine, 8 of those cases resulted in fatalities. Clozapine was immediately withdrawn from the market by Sandoz (1976) [1].

It was not until fourteen years after its withdrawal that the results of the pivotal US Clozaril Study were published and the important role of clozapine in clinical practice was discovered [2]. Clozapine demonstrated superiority to chlorpromazine in treatment-resistant patients in many outcomes including treatment response, with improvements in positive and negative symptoms of schizophrenia [2]. This led health agencies to grant clozapine access to the US and Canadian markets in 1990 and 1991, respectively.

The recognized risk for agranulocytosis, assessed at a prevalence of 1-2%, has been managed since then by mandatory monitoring systems administered by the manufacturers of the clozapine products (now generized in most countries) to assure that patients undergo routine blood testing before each dispensation. Current product monographs mandate that patients start therapy gradually and that normal WBC and absolute neutrophil counts (ANC) are maintained at safe levels (WBC count ≥3500/mm3 and ANC ≥2000/mm3) throughout treatment [3]. Thus, patients at risk of developing agranulocytosis can be identified before the condition becomes life-threatening. The implementation of registries for the monitoring of hematological toxicity has in fact significantly reduced mortality and morbidity in patients treated with clozapine [4].

The 1990s saw also the introduction of other new “atypical” antipsychotics (e.g., risperidone, olanzapine, quetiapine also identified as second-generation agents, SGAs). These agents, developed to obtain efficacious medications similar to clozapine without the hematological toxicity, generated hope for improved compliance and Quality of Life (QoL) in patients affected by schizophrenia. Early studies of SGAs demonstrated superiority over the FGAs, including a lower incidence of EPS, superior efficacy for positive, negative and mood symptoms, improved tolerability, as well as cognitive enhancing effects [5–8]. Despite higher costs, SGAs were widely adopted worldwide [9–12]. However, none of the newer SGAs could demonstrate superiority to clozapine and in the last decade many published clinical practice guidelines [13–20] have recommended that clozapine be prescribed to patients with treatment-resistant schizophrenia, which has been defined as not responsive to two trials of any other antipsychotic medication (either FGA or SGA). Despite such recommendations and the overwhelming evidence of clozapine effectiveness, prescribing of clozapine appears to be low, delayed and often preceded by attempts at polypharmacy treatment, which lacks clinical evidence of effectiveness [21–26].

Aim and scope

The main objectives of this article are to provide information on clozapine place in therapy and to discuss clozapine’s prescribing trends since the publication of the most recent schizophrenia clinical practice guidelines in North America and Europe.

Methods

Clinical practice guidelines, meta-analyses, and reports on clozapine prescribing trends have been identified from searches in PubMed, Psychinfo, EMBASE and Cochrane databases. The search was focused on publications in the last 10-year period (2004 and 2014). Articles selection was limited to those written in the English language. Individual clinical trials and older landmark studies have been cited where appropriate. Keywords used in the literature search included: clozapine, prescribing, schizophrenia, antipsychotic(s), utilization, guidelines.

Results

Clozapine vs. FGAs

Clozapine effectiveness was initially demonstrated against chlorpromazine, the prototype of the FGAs [2]. Evidence of clozapine advantage over FGAs has been well established and results of various trials, conducted mostly in the 1990s, have been included in meta-analyses [27–29]. The conclusions were that clozapine was more effective than FGAs in reducing symptoms of schizophrenia according to measurements of BPRS scores and SANS negative symptoms scores. Clozapine produced clinically meaningful improvements and postponed relapse [30–32].

Clozapine vs. SGAs

The landmark study CUtLASS 2 found that in patients failing to respond to two or more antipsychotics, clozapine produced significant improvement in symptoms over 1 year [33]. The phase 2E CATIE study revealed that clozapine was significantly more effective than quetiapine and risperidone, and the authors concluded that in patients with an insufficient therapeutic response to a SGA, clozapine was more effective than switching to a different SGA [34–36].

More recent evidence has confirmed clozapine superiority to other SGAs and olanzapine [37, 38].

Clozapine effectiveness on mortality

Effects of clozapine treatment on patient mortality has been assessed and reviewed over the years in various populations. The evidence supports a clear advantage of clozapine therapy in terms of reduced mortality over other antipsychotic agents including FGAs, risperidone and quetiapine [39–42].

Clinical practice guidelines and algorithms

The evidence produced in the last 20 years, and summarized by published clinical practice guidelines and algorithms, has confirmed clozapine to be the gold standard for treatment-resistant schizophrenia. Please refer to Table 1 for a summary of recommendations.
Table 1

Summary of evidence-based recommendations for clozapine prescribing

Date

Source

Recommendation: clozapine to be prescribed or offered to patients

  
  

After failure of 2 adequate trials of 2 different AAs

With suicidal thoughts or behaviours

With persistent hostility and violent behaviours

2004

APA (US) [13]

X

  

2005

CPA (CAN) [14]

X

  

2007

TMAP (US) [15]

X (SGAs considered first-line)

  

2009

NICE (UK) [16]

X (at least one of the drugs should be a non-clozapine SGA)

  

2010

Schizophrenia PORT (US) [17]

X

X

X

2010

CADTH [18]

X

  

2011

BAP (UK) [19]

X

 

X

2013

PAP (US) [20]

X (SGA, risperidone and olanzapine) considered first-line)

X

X

Note: AA = antipsychotic agent, APA = American Psychiatric Association, BAP = British Association for Psychopharmacology, CADTH = Canadian Agency for Drugs and Technology in Health, CPA = Canadian Psychiatry Association, PAP = Psychopharmacology Algorithm Project, PORT = Patient Outcomes Research Team, TMPA = Texas Medication Algorithm Project.

Clozapine prescribing trends

Treatment-resistant schizophrenia has been established to affect 20-30% of all patients diagnosed with schizophrenia [21, 31]. Nevertheless, physicians’ prescribing practices reveal that only a small portion of patients with treatment-resistant schizophrenia are treated with clozapine [21]. In 1999, only 160,000 US patients of the 2.6 million diagnosed with schizophrenia were treated with clozapine (only 25% of treatment-resistant patients) [21]. Since the introduction of the newer SGAs, clozapine use decreased in the United States: in 1999, clozapine represented 11% out of the total SGAs prescribed, which steadily decreased to less than 5% in 2002 [21]. During phase 3 of the CATIE study, 51% of patients had previously discontinued medications due to ineffective therapeutic response, but only 11% of patients were offered clozapine during phase 3. Studies of clozapine utilization have shown that adherence to guidelines has been poor through the years with clozapine been consistently underutilized in the US, UK, Canada, New Zealand and Australia [9, 21–26, 42–46]. In a study of the Veterans Health Administration, only 2% of patients affected by schizophrenia were receiving clozapine [22].

Adherence to treatment guidelines in the UK was also very poor in terms of clozapine initiation as in more than 34% of patients’ polypharmacy and high dose treatments were used before commencing clozapine [23].

Recent Canadian statistics, based on physician drug recommendations from 2005 to 2009, show a 48% increase in clozapine recommendations over a 5-year period [10]; however, a more recent report determined that 68% of an outpatient population had tried 3 or more antipsychotics before switching to clozapine [26]. In contrast, clozapine utilization in Australia appears to be more appropriate with a percentage as high as 51% of clozapine use in treatment-resistance schizophrenia [46].

Discussion

Despite the long and still ongoing debate about the comparative safety and effectiveness of FGAs and SGAs [5, 6], during the last two decades, clozapine has maintained its place in therapy as the treatment of choice in refractory schizophrenia (third-line agent). It has also been suggested that earlier use (as a second line agent) can be recommended in individuals with persistent hostility/aggressive behaviour [47] and suicidalilty [39–42]. In fact the indication for recurrent suicidal behavior has been officially approved by the FDA [48]. Its role in first-episode and non-treatment-resistant patients has been investigated [49–53] and while further research in the area of early onset schizophrenia and time to treatment response is needed [54–57], clozapine value as a second line agent has been recently recognized in a first-episode schizophrenia population [58].

While clinical practice guidelines have strongly endorsed clozapine as the gold standard of therapy, its use has been lower that recommended. Reasons for physicians’ reluctance to prescribe clozapine have been evaluated and the relatively high incidence of agranulocytosis has certainly had great influence; however, the careful monitoring of WBC counts and ANC has almost completely abolished the risk of fatal agranulocytosis; frequency of blood tests has recently been simplified and once WBC counts and ANCs have been maintained within normal levels for one year, blood tests are now only required once every 4 weeks [27, 47]. It is also of importance to note that in some European countries a more flexible monitoring schedule, which can be reduced to quarterly blood testing in individuals not at risk, has been proposed [59, 60].

Concerns over other adverse effects, which include weight gain, hyperglycemia, seizures, tachycardia, myocarditis and neuromalignant syndrome [61], can affect the decision making process and even less severe side effects (sedation, constipation, nocturnal hypersalivation) might result in patients’ resistance to try this medication [42, 62]. Clozapine has shown, however, a definite advantage in reversing tardive dyskinesia [13, 17, 34, 58]. Suggestions on how to balance safety and effectiveness of clozapine have been given [63]. Other issues can be seen in the added costs associated with blood monitoring and health care system contacts due to the need for gradual titration of clozapine therapy, however, clozapine cost-effectiveness has been consistently shown over other agents [64, 65]. Recent reports have highlighted the need to inform health professionals about the benefits of treating patients with clozapine [24, 66–69] and have voiced concern that clozapine is still under utilized especially in patients at risk of suicide [66]. Interprofessional practice models that see pharmacists being more involved in patient care have been advocated to improve and optimize prescribing of clozapine [70].

Summary

  • Published clinical evidence has supported clozapine as the gold standard in the treatment of refractory schizophrenia as it is reflected in the recommendations of many clinical practice guidelines.

  • Clinical practice guidelines, however, do not appear to have been followed by prescribers and clozapine remains an underutilized medication in patients with treatment-resistant schizophrenia.

  • Efforts are needed to encourage and optimize clozapine utilization.

Notes

Abbreviations

AA: 

Antipsychotic agent

ANC: 

Absolute neutrophil count

APA: 

American Psychiatric Association

BAP: 

British Association for Psychopharmacology

BPRS: 

Brief Psychiatric Rating Scale

CADTH: 

Canadian Agency for Drugs and Technologies in Health

CPA: 

Canadian Psychiatry Association

CATIE: 

Clinical Antipsychotic Trials of Intervention Effectiveness

CUtLASS: 

Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study

EPS: 

Extrapyramidal Symptoms

FDA: 

Food and Drug Administration

FGAs: 

First Generation Antipsychotics

NICE: 

National Institute of Health and Clinical Excellence

PAP: 

Psychopharmacology Algorithm Project

PORT: 

Patient Outcomes Research Team

QoL: 

Quality of Life

SANS: 

Scale for the Assessment of Negative Symptoms

SGAs: 

Second Generation Antipsychotics

TD: 

Tardive dyskinesia

TMAP: 

Texas Medication Algorithm Project

WBC: 

White blood cells.

Declarations

Acknowledgments

No financial support was sought for this project.

Authors’ Affiliations

(1)
Faculty of Pharmacy, University of Manitoba, Winnipeg, MB, Canada

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. 10.1177/0957154X07070335.View ArticlePubMedGoogle Scholar
  2. 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. 10.1001/archpsyc.1988.01800330013001.View ArticlePubMedGoogle Scholar
  3. Clozaril: Product Monograph. Health Canada http://webprod5.hc-sc.gc.ca/dpd-bdpp/info.do?code=11421&lang=eng Accessed on January 30, 2014
  4. 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.PubMedGoogle Scholar
  5. 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. 10.7326/0003-4819-157-7-201210020-00525.View ArticlePubMedGoogle Scholar
  6. 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. 10.1016/S0140-6736(13)60733-3.View ArticlePubMedGoogle Scholar
  7. 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. 10.1016/S0920-9964(98)00105-4.View ArticleGoogle Scholar
  8. 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. 10.1176/appi.ajp.161.3.414.View ArticlePubMedGoogle Scholar
  9. 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. 10.1176/appi.ps.59.5.547.View ArticlePubMedGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 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. 10.1080/10401230591002084.View ArticlePubMedGoogle Scholar
  12. 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. 10.1007/s00228-004-0868-3.View ArticlePubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.Google Scholar
  15. 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. 10.4088/JCP.v68n1115.View ArticlePubMedGoogle Scholar
  16. National Institute of Health and Clinical Excellence: Core intervention in the treatment and management of schizophrenia in primary and secondary care (CG82). 2009, http://publications.nice.org.uk/schizophrenia-cg82 Accessed January 30, 2014
  17. 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. 10.1093/schbul/sbp116.View ArticlePubMedGoogle Scholar
  18. Clozapine Treatment of Hospitalized Patients: A Review of Clinical Practice Guidelines and Safety. Report December 20, 2010 Accessed on August 10, 2012 http://www.cadth.ca/en/search?q=Clozapine+treatment+in+hospitalized
  19. 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. 10.1177/0269881110391123.View ArticlePubMedGoogle Scholar
  20. 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. 10.1097/HRP.0b013e31827fd915.View ArticlePubMedGoogle Scholar
  21. Moore TA, Covell NH, Essock SM, Miller AL: Real-world antipsychotic treatment practices. Psychiatr Clin North Am. 2007, 30 (3): 401-416. 10.1016/j.psc.2007.04.008.View ArticlePubMedGoogle Scholar
  22. 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. 10.4088/JCP.v64n0107.View ArticlePubMedGoogle Scholar
  23. Wheeler AJ: Treatment pathway and patterns of clozapine prescribing for schizophrenia in New Zealand. Ann Pharmacother. 2008, 42: 852-860. 10.1345/aph.1K662.View ArticlePubMedGoogle Scholar
  24. Joober R, Boksa P: Clozapine: a distinct, poorly understood and underused molecule. J Psychiatry Neurosci. 2010, 35 (3): 147-159. 10.1503/jpn.100055.View ArticlePubMedPubMed CentralGoogle Scholar
  25. 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. 10.1192/bjp.bp.111.105833.View ArticleGoogle Scholar
  26. Alessi-Severini S, LeDorze JA, Nguyen D, Honcharik P, Eleff M: Clozapine prescribing in a Canadian outpatient population. Plos One. 2013, 8 (12): e83539-10.1371/journal.pone.0083539.View ArticlePubMedPubMed CentralGoogle Scholar
  27. Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A, Carpenter WT: Effect of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry. 1994, 151: 20-26.View ArticlePubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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. 10.1056/NEJM199709183371202.View ArticlePubMedGoogle Scholar
  30. 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. 10.1176/appi.ajp.158.4.518.View ArticlePubMedGoogle Scholar
  31. 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. 10.1016/S0140-6736(08)61764-X.View ArticlePubMedGoogle Scholar
  32. Essali A, Al-Haj HN, Li C, Rathbone J: Clozapine versus typical neuroleptic medications for schizophrenia. Cochrane Database Syst Rev. 2010, 20 (1): CD000059-pub2Google Scholar
  33. 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.View ArticlePubMedPubMed CentralGoogle Scholar
  34. 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. 10.1056/NEJMoa051688.View ArticlePubMedGoogle Scholar
  35. 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. 10.1016/j.schres.2008.10.011.View ArticlePubMedGoogle Scholar
  36. 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. 10.1176/appi.ajp.163.4.600.View ArticlePubMedGoogle Scholar
  37. 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, CD006633-11Google Scholar
  38. 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. 10.1017/S1092852912000806.View ArticlePubMedGoogle Scholar
  39. 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. 10.1192/bjp.182.6.505.View ArticleGoogle Scholar
  40. 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. 10.1016/S0140-6736(09)60742-X.View ArticlePubMedGoogle Scholar
  41. Kasckow J, Felmet K, Zisook S: Managing suicide risk in patients with schizophrenia. CNS Drugs. 2011, 25 (2): 129-143. 10.2165/11586450-000000000-00000.View ArticlePubMedPubMed CentralGoogle Scholar
  42. 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. 10.1016/j.eurpsy.2011.06.003.View ArticlePubMedGoogle Scholar
  43. Conley RB, Kelly DL, Lambert TJ, Love RC: Comparison of clozapine use in Maryland and in Victoria, Australia. Psychiatr Serv. 2005, 56: 320-323. 10.1176/appi.ps.56.3.320.View ArticlePubMedGoogle Scholar
  44. 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. 10.1176/appi.ps.002022012.View ArticlePubMedGoogle Scholar
  45. 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. 10.3371/CSRP.LAWY.012513.View ArticlePubMedGoogle Scholar
  46. Malalagama G, Bastiampillai T, Dhillon R: Clozapine use in Australia. Australas Psychiatry. 2011, 19 (2): 175-View ArticlePubMedGoogle Scholar
  47. 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. 10.1017/S146114571100201X.View ArticlePubMedGoogle Scholar
  48. “Clozaril” Prescribing information http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019758s069s071lbl.pdf Accessed January 30, 2014
  49. 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. 10.1176/appi.ajp.160.8.1514.View ArticlePubMedGoogle Scholar
  50. 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.PubMedGoogle Scholar
  51. 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. 10.1097/jcp.0b013e3180d0a6d4.View ArticlePubMedGoogle Scholar
  52. 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. 10.1176/appi.ajp.164.3.428.View ArticlePubMedGoogle Scholar
  53. 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. 10.1016/j.psychres.2010.02.018.View ArticlePubMedGoogle Scholar
  54. 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. 10.1093/schbul/sbm134.View ArticlePubMedGoogle Scholar
  55. Chang YC, Lane HY, Yang KH, Huang CL: Optimizing early prediction for antipsychotic response in schizophrenia. J Clin Psychopharmacol. 2006, 26 (6): 554-559. 10.1097/01.jcp.0000246211.95905.8c.View ArticlePubMedGoogle Scholar
  56. 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. 10.1176/appi.ajp.160.11.2063. Erratum in: Am J Psychiatry 2005, 162(9):1774View ArticlePubMedGoogle Scholar
  57. 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. 10.4088/JCP.10m06349.View ArticlePubMedPubMed CentralGoogle Scholar
  58. 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. 10.4088/JCP.09m05785yel.View ArticlePubMedGoogle Scholar
  59. Netherlands Clozapine Collaboration Group: Guideline for the use of clozapine [English version]. 2009, [Cited 14 July 2010] http://clozapinepluswerkgroep.nl/pdf/SKMBT_C45110040808460.pdf Google Scholar
  60. 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.PubMedGoogle Scholar
  61. Van-Kammen DP, Marder SR: Serotonin/dopamine antagonists. Comprehensive Textbook of Psychiatry. Edited by: Kaplan HI, Sadock BJ. 2000, Baltimore, Md: Lippincott Williams & Wilkins, 2455-2473. 7Google Scholar
  62. Hermes E, Resenheck : Choice of randomization to clozapine versus other second-generation antipsycotics in the CATIE schizophrenia trial. J Psychopharmacol. 2012, 26: 1194-1200. 10.1177/0269881112443744.View ArticlePubMedPubMed CentralGoogle Scholar
  63. Meltzer HY: Clozapine: balancing safety with superior antipsychotic efficacy. Clin Schizophr Relat Psychoses. 2012, 6 (3): 134-144. 10.3371/CSRP.6.3.5.View ArticlePubMedGoogle Scholar
  64. Phanthunane P, Vos T, Whitefors H, Bertram M: Cost-effectiveness of pharmacological and psychosocial interventions for schizophrenia. Cost Eff Resour Alloc. 2011, 9: 6-10.1186/1478-7547-9-6. doi:10.1186/1478-7547-9-6View ArticlePubMedPubMed CentralGoogle Scholar
  65. Attard A, Taylor DM: Comparative Effectiveness of Atypical Antipsychotics in Schizophrenia. CNS Drugs. 2012, 26 (6): 491-508. 10.2165/11632020-000000000-00000.View ArticlePubMedGoogle Scholar
  66. Sinyor M, Remington G: Is psychiatry ignoring suicide?. J Clin Psychopharmacol. 2012, 32 (3): 307-308. 10.1097/JCP.0b013e31825501fb.View ArticlePubMedGoogle Scholar
  67. Hill M, Freudenreich O: Clozapine: key discussion points for prescribers. Clin Schizophr Relat Psychoses. 2013, 6 (4): 177-185. 10.3371/CSRP.HIFR.01062013.View ArticlePubMedGoogle Scholar
  68. Damkier NJ, Taylor LH: Optimizing clozapine treatment. Acta Psychiatric Scand. 2011, 123: 411-422. 10.1111/j.1600-0447.2011.01710.x.View ArticleGoogle Scholar
  69. Beck K, Howes O: Optimising treatment of refractory schizophrenia. Psychopharmacology. 2013, 227: 373-374. 10.1007/s00213-013-3076-y.View ArticlePubMedGoogle Scholar
  70. Williams T, Purvis TL: Development of an outpatient pharmacist-managed clozapine clinic. Am J Health-Syst Pharm. 2012, 69: 1192-1195. 10.2146/ajhp110461.View ArticlePubMedGoogle Scholar

    71. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/14/102/prepub

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© Warnez and Alessi-Severini; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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