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Clozapine Rechallenge After Major Adverse Effects: Clinical Guidelines Based on 259 Cases

Manu, Peter, MD1,2; Lapitskaya, Yevgeniya, MD3,*; Shaikh, Atef, DO3; Nielsen, Jimmi, MD, PhD4

doi: 10.1097/MJT.0000000000000715
Systematic Review and Clinical Guidelines

Background: Clozapine is widely prescribed for treatment-refractory schizophrenia, but its use is limited by many potentially life-threatening adverse effects. The risk of rechallenge after these complications has never been comprehensively assessed in controlled studies. Thus, clinical guidelines must rely on the published case reports. The number of such reports is likely to increase over time, and updated analyses of larger samples are needed, as they may lead to changes in clinical guidelines.

Study Questions: How safe is the clozapine rechallenge after life-threatening adverse effects?

Study Design: The published case reports of clozapine rechallenge were identified in a MEDLINE search. We added 121 cases reported from 2012 through 2017 to the 138 cases reported from 1972 through 2011 analyzed by us in a previous publication. The 95% confidence intervals (CIs) of the successful rechallenge rate were calculated for each adverse effect with at least 5 published case reports. The rechallenge was considered a valid clinical option when the lower end of the CI range was at least 50%.

Results: A successful outcome was documented in 128/203 patients rechallenged after neutropenia (63.0%, CI, 56.0%–69.6%), 3/17 after agranulocytosis (17.7%, CI, 4.7%–44.2%), 11/17 after myocarditis (64.7%, CI, 38.6%–84.7%), and 7/7 after neuroleptic malignant syndrome (100%, CI, 56.1%–100%). Among the 15 patients with other clozapine-induced adverse effects, the rechallenge was successful in those with eosinophilia, cardiac complications other than myocarditis (QTc prolongation, pericarditis, cardiomyopathy, and atrial flutter), and gastrointestinal hypomotility. The rechallenge failed in patients who had developed pancreatitis or renal insufficiency.

Conclusion: Clozapine rechallenge is a reasonable clinical option after return to baseline for patients who had developed neutropenia and neuroleptic malignant syndrome, but not after agranulocytosis or myocarditis. Data are insufficient to formulate rechallenge guidelines for any other clozapine-related adverse effects.

1Hofstra Northwell School of Medicine, Hempstead, NY;

2Northwell Health, South Oaks Hospital, Amityville, NY;

3Department of Psychiatry, Northwell Health, Zucker Hillside Hospital, Glen Oaks, NY; and

4Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark.

Address for correspondence: Department of Psychiatry, Zucker Hillside Hospital, 75-59 263rd St, Glen Oaks, NY 11004. E-mail:

The authors have no conflicts of interest to declare.

Treatment-resistant schizophrenia constitutes a significant challenge for clinicians, patients, and their families. It is associated with major impairment in social, occupational, and vocational spheres.1 The challenge is even higher in present times, after the evolution of medical act from paternalistic approach to the concept of shared decision, patient–physician therapeutic alliance, and informed consent.2,3 Although the definition of treatment-resistant schizophrenia varies, the main features are psychotic symptoms that failed to respond to 2–3 conventional antipsychotics, preferably from 2 different classes, at appropriate doses that are equivalent or higher to chlorpromazine 600 mg daily and used for a minimum of 4–6 weeks.4 Response is typically defined as at least 20% symptom reduction as measured by rating scales such as Brief Psychiatric Rating Scale (BPRS) or Positive and Negative Syndrome Scale (PANSS).5–7 It is important to note that to meet the criteria for treatment resistance, adequate adherence is implied. Given the absence of precise definition, the prevalence of treatment-resistant schizophrenia is difficult to estimate. However, different sources cite prevalence as being between 5% and 60%.8,9

Clozapine is a second-generation antipsychotic that carries a unique indication for treatment-refractory schizophrenia. Its efficacy and superiority to first-generation antipsychotics was first studied and demonstrated in the late 1980s10 and has been reproduced by others in later studies.11 In addition, clozapine has been shown to reduce suicidality in patients with schizophrenia12 and, up until this year, has been the only drug with an effect on tardive dyskinesia.13 However, patients and clinicians alike are hesitant to initiate the drug secondary to the perceived burden of frequent blood monitoring and fears of potential serious, and even life-threatening, adverse effects, such as agranulocytosis and severe neutropenia, myocarditis and cardiomyopathy, gastrointestinal hypomotility leading to bowel infarction, pancreatitis, and renal insufficiency. As a result of reluctance to start the drug, by the time many patients started taking clozapine, they have failed in numerous other drugs and combination of drugs.

Clinically, complex situations arise when patients survive major adverse effects of clozapine to clozapine during treatment with clozapine but have severe psychotic symptoms that do not respond to any other pharmacological intervention. Therefore, it is important to know if and when it is safe to proceed to a clozapine rechallenge, but these issues have never been assessed in randomized controlled trials, controlled studies without randomization, quasi-experimental studies, in comparative, correlational, and case–control studies, or expert committee reports, that is, acceptable levels of evidence for developing clinical guidelines.14 All we have are individual case reports, which contain clinical narratives that cannot be generalized, may be prone to publication bias through selection of positive experiences by authors and journal editors, and may reflect the memory recall inherent in retrospective and unplanned work.15 Nonetheless, we believe that by systematically searching and assembling issue-specific case reports, clinicians may derive knowledge helpful for informing decisions when sources with higher levels of evidence are not available.

In 2012, we evaluated the 138 case reports of clozapine rechallenge after life-threatening adverse effects16 and concluded that the intervention was reasonable in patients who had returned to baseline after neutropenia (ie, absolute neutrophil count 500/cubic millimeter or greater) and neuroleptic malignant syndrome (NMS) but was not recommended for agranulocytosis (ie, absolute neutrophil count less than 500/cubic millimeter) and myocarditis. For this updated evaluation of the safety of clozapine rechallenge, we expanded the database with the case reports published in the past 5 years.

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We used PubMed site to search the published literature for all reports of cases and studies of patients who were rechallenged after developing adverse reactions to clozapine from January 1972 through June 2017. The search was performed using the search terms “clozapine,” “rechallenge,” and “retrial.” Successful rechallenge was defined as a case when a patient did not redevelop the complication of interest or any other serious adverse effect during an interval time of follow-up as determined by the authors of the report. We calculated confidence intervals (CIs) for adverse effects that had at least 5 reported patients. The outcome of rechallenge after a particular adverse effect was considered favorable if the proportion of patients able to continue clozapine treatment after rechallenge had a lower bound of the continuity-corrected 95% CI of greater than 50%.

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Our search identified a total of 259 published case reports of clozapine rechallenge after major adverse effects, of which 138 had been published by July 2011 and analyzed in a previous publication16 and 121 published from August 2011 through June 2017. Of the 259 cases, 222 reported rechallenge after hematological adverse effects, 21 after cardiac events, 7 after NMS, and 6 after gastrointestinal tract disorders (Table 1). The 95% CI was calculated for the 4 adverse effects with at least 5 case reports, that is, neutropenia, agranulocytosis, myocarditis, and NMS.

Table 1

Table 1

The outcome of rechallenge was favorable in 128/203 patients after neutropenia (63.0%, 95% CI, 56.0%–69.6%), 3/17 after agranulocytosis (17.7%, 95% CI, 4.7%–44.2%), 11/17 after myocarditis (64.7%, 95% CI, 38.6%–84.7%), and 7/7 after NMS (100%, 95% CI, 56.1%–100%). No fatal outcomes were reported in any of the cases.

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Based on the 259 case reports of clozapine rechallenge after adverse effects with life-threatening potential, our analysis suggests that starting clozapine after return to baseline is a reasonable clinical option for patients who had developed neutropenia or NMS, but not after agranulocytosis or myocarditis. The addition of the 121 cases published in the past 5 years did not change the conclusion reached by us16 after looking at the 138 cases reported from 1972 through 2011. The new data set indicates that most reports continue to describe cases of neutropenia and that there is increased interest in reporting rechallenge after myocarditis. There may be a selection bias among the authors of case reports as to which rechallenge outcomes get written up and published. Furthermore, there have been only 2 new rechallenge cases after agranulocytosis potentially signifying that clinicians do not anticipate a successful rechallenge based on previously reported data. On the contrary, there has been an increase in the number of rechallenge cases reported after the development of myocarditis.

The study identified agranulocytosis, myocarditis, pancreatitis, renal failure, and clozapine-induced lupus erythematosus as nonrechallengeable adverse effects. Only 3 reported patients have been successfully rechallenged after agranulocytosis, making up only 18% of patients. Historically, agranulocytosis has been the most feared adverse effect of clozapine. It led to the drug's withdrawal from the market after reports of fatalities among patients who developed agranulocytosis. Currently, prescribers are required to monitor patients' blood work including complete blood cell count once weekly for the first 6 months after the initiation of the drug, then every 2 weeks for the next 6 months, and every 4 weeks thereafter.77 If the patient's absolute neutrophil count drops below 500, clozapine has to be discontinued. According to the Clozapine Remote Electronic Monitoring System guide for health care providers,77 clozapine should not be restarted unless “prescriber determines benefits outweigh risks.” Based on our findings, the likelihood of successful rechallenge is very low. It may benefit the patient to consider other treatments, including nonpharmacological interventions such as electroconvulsive therapy.78 By contrast, neutropenia is a rechallengeable condition, as 63% of the reported cases were able to resume clozapine treatment. This difference is likely related to a higher incidence of neutropenia as an adverse effect and clinicians' acceptance of rechallenge as an appropriate strategy. The risks are minimized by the increased frequency of blood monitoring and the availability of filgrastim or another granulocyte colony-stimulating factor preparations.79,80 These drugs stimulate the proliferation and differentiation of myeloid precursor cells in the bone marrow and enhance mature neutrophil function.80 They can be used to shorten the recovery time after agranulocytosis and neutropenia. However, currently, there are no guidelines that would formally describe indications and treatment with granulocyte colony-stimulating factor preparations in patients undergoing clozapine rechallenge. In addition, lithium has been used during clozapine rechallenge. It enhances the release of reserve granulocytes from bone marrow, upregulates granulopoiesis-stimulating factors, and redistributes marginated neutrophils.80 Finally, clinicians should be aware of benign ethnic neutropenia. It is most commonly observed in patients of African descent but does occur in other races as well.81 These patients have lower baseline neutrophil counts and, hence, have different thresholds for neutropenia.82

Since 2011, we have seen an increase in the number of reported cases of clozapine rechallenge after myocarditis. It was successfully challenged in 11 of 17 patients or 64.7%. The proportion is similar to that calculated for rechallenge after neutropenia but failed to meet the lower bound of 95% CI set at 50%. Assuming that the current success rate remains stable, we will need at least 50 cases before recommending rechallenge for clozapine-induced myocarditis. Almost all these cases have occurred in Australia or New Zealand,47,51,53,55 a geographical difference that is possibly explained by the clinicians' lower threshold for diagnosing the condition and monitoring, and by the widespread use of laboratory monitoring of troponin and C-reactive protein during clozapine titration.83,84 Patients with absent or mild left ventricular dysfunction at the time of diagnosis seem to have a better chance of avoiding a new deterioration during rechallenge.53

The outcome after NMS continues to be excellent. All 7 patients or 100% were successfully rechallenged. However, NMS can be controversial during treatment with clozapine, as it can mimic other conditions, such as clozapine-induced benign fever. Slower titration of clozapine is the only strategy that has been used.65,66

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1. Muesser KT, McGurk SR. Schizophrenia. Lancet. 2004;363:2063–2072.
2. Purcaru D, Preda A, Popa D, et al. Informed consent: how much awareness is there? PLoS One. 2014;9:e110139. eCollection 2014.
3. Dima L, Repanovici A, Purcaru D, et al. Informed consent and E-communication in medicine. Revista Română de Bioetică. 2014;12:37–46.
4. Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biol Psychiatry. 2001;50:898–911.
5. Suzuki T, Remington G, Mulsant BH, et al. Defining treatment –resistant schizophrenia and response to antipsychotics: a review and recommendation. Psychiatry Res. 2012;197:1–6.
6. Overall JE, Gorham DR. The Brief psychiatric rating scale. Psychol Rep. 1962;10:799–812.
7. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bull. 1987;13:261–276.
8. Meltzer H, Kostakoglu A. Treatment Resistant Schizophrenia in Comprehensive Care of Schizophrenia—A Textbook of Clinical Management. In: Lieberman L, Murray R, eds. London, United Kingdom: Martin Dunitz; 2001:181–203.
9. Dammak M. Treatment-resistant schizophrenia: prevalence and risk factors. In: Mental Disorders—Theoretical and Emperical Perspectives. Rijeka, Croatia: InTech; 2013:1–25.
10. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic, A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–796.
11. McEvoy JP, Lieberman JA, Stroup TS, et al. CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600–610.
12. Duggan A, Warner J, Knapp M, et al. Modelling the impact of clozapine on suicide in patients with treatment-resistant schizophrenia in the UK. Br J Psychiatry. 2003;182:505–508.
13. Bassitt DP, Louza Neto MR. Clozapine efficacy in tardive dyskinesia in schizophrenic patients. Eur Arch Psychiatry Clin Neurosci. 1998;248:209–211.
14. Shekelle P, Woolf S, Eccles M, et al. Developing clinical guidelines. West J Med. 1999;170:348–351.
15. Nissen T, Wynn R. The clinical case report: a review of its merits and limitations. BMC Res Notes. 2014;7:264.
16. Manu P, Sarpal D, Muir O, et al. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systemic review of the published literature. Schizophrenia Res. 2012;134:180–186.
17. Grohmann R, Schmidt LG, Spiess-Kiefer C, et al. Agranulocytosis and significant leucopenia with neuroleptic drugs: results from the AMUP program. Psychopharmacol (Berl). 1989;99(suppl S):109–112.
18. Frankenburg FR, Stormberg D, Gerson SL. Unsuccessful reexposure to clozapine. J Clin Psychopharmacol. 1994;14:428–429.
19. Sperner-Unterweger B, Czeipek I, Gaggl S, et al. Treatment of severe clozapine-induced neutropenia with granulocyte colony-stimulating factor (G-CSF). Remission despite continuous treatment with clozapine. Br J Psychiatry. 1998;172:82–84.
20. Silvestrini C, Arcangeli T, Biondi M, et al. A second trial of clozapine in a case of granulocytopenia. Hum Psychopharmacol. 2000;15:275–279.
21. Gerbino-Rosen G, Roofeh D, Tompkins DA, et al. Hematological adverse events in clozapine-treated children and adolescents. J Am Acad Child Adolesc Psychiatry. 2005;44:1024–1031.
22. Dunk LR, Annan LJ, Andrews CD. Rechallenge with clozapine following leucopenia or neutropenia during previous therapy. Br J Psychiatry. 2006;188:255–263.
23. Kanaan RA, Kerwin RW. Lithium and clozapine rechallenge: a retrospective case analysis. J Clin Psychiatry. 2006;67:756–760.
24. Mathewson KA, Lindenmayer JP. Clozapine and granulocyte colony-stimulating factor: potential for long-term combination treatment for clozapine-induced neutropenia. J Clin Psychopharmacol. 2007;27:714–715.
25. Bray A. Ethnic neutropenia and clozapine. Aust N Z J Psychiatry. 2008;42:342–345.
26. Ghaznavi S, Nakic M, Rao P, et al. Rechallenging with clozapine following neutropenia: treatment options for refractory schizophrenia. Am J Psychiatry. 2008;165:813–818.
27. Wu SY, Liu CC, Hsieh MH. Successful re-exposure to clozapine following uneventful rechallenge with olanzapine in a patient with neutropenia related to both agents. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1089–1090.
28. Joffe G, Eskelinen S, Sailas E. Add-on filgrastim during clozapine rechallenge in patients with a history of clozapine-related granulocytopenia/agranulocytosis. Am J Psychiatry. 2009;166:236.
29. Eseonu C, Carlson J. Clozapine rechallenge in refractory schizophrenia. Am J Psychiatry. 2010;167:602–603.
30. Lertxundi U, Sanchez P, Hernandez R, et al. A case of agranulocytosis secondary to re-challenge with clozapine following severe neutropenia during previous therapy. J Clin Psychiatry. 2011;72:1659.
31. McKnight C, Guirgis H, Votolato N. Clozapine rechallenge after excluding the high-risk clozapine-induced agranulocytosis genotype of HLA-DQB1 6672G>C. Am J Psychiatry. 2011;168:1120.
32. Toni-Uebari T, Rees J. Successful re-challenge with clozapine following “red alert”. BMJ Case Rep. 2013;2013.
    33. Gopalakrishnan R, Subhalakshmi TP, Kuruvilla A, et al. Clozapine re-challenge under the cover of Filgrastim. J Postgrad Med. 2013;59:54–55.
    34. Huguet G, Lillo-Le Louet A, Darnige L, et al. Clozapine re-challenge in resistant schizophrenia disorder affecting “super sensitive” patients, after neutropenia under clozapine: a case report. L'Encéphale. 2013;39(suppl 1):42–48.
      35. Bavle A, Vidhyavathi M. Case report of clozapine induced neutropenia and rechallenge. J Neuropsychiatry Clin Neurosci. 2015;27:e61.
      36. Meyer N, Gee S, Whiskey E, et al. Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis. J Clin Psychiatry. 2015;76:e1410–e1416.
      37. Prokopez CR, Armesto AR, Gil Aguer MF, et al. Clozapine rechallenge after neutropenia or leucopenia. J Clin Psychopharmacol. 2016;36:377–380.
      38. Yamaki N, Hishimoto A, Otsuka I, et al. Optimizing outcomes in clozapine rechallenge following neutropenia using human leukocyte antigen typing: a case report. Psychiatry Clin Neurosci. 2017;71:289–290.
      39. Juul Povlsen U, Noring U, Fog R, et al. Tolerability and therapeutic effect of clozapine. A retrospective investigation of 216 patients treated with clozapine for up to 12 years. Acta Psychiatr Scand. 1985;71:176–185.
      40. Safferman AZ, Lieberman JA, Alvir JM. Rechallenge in clozapine-induced agranulocytosis. Lancet. 1992;339:1296–1297.
      41. Safferman AZ, Lieberman JA, Zeman D, et al. Unrelated agranulocytosis in a patient taking clozapine. J Clin Psychopharmacol. 1993;13:218–219.
      42. Small JG, Weber MC, Klapper MH, et al. Rechallenge of late-onset neutropenia with clozapine. J Clin Psychopharmacol. 2005;25:185–186.
      43. Tourian L, Margolese HC. Late-onset agranulocytosis in a patient treated with clozapine and lamotrigine. J Clin Psychopharmacol. 2011;31:665–667.
      44. Hazewinkel AW, Bogers JP, Giltay EJ. Add-on filgrastim during clozapine re-challenge unsuccessful in preventing agranulocytosis. Gen Hosp Psychiatry. 2013;35:576.e11–576.e12.
      45. Roberts CE, Mortenson LY, Merrill DB, et al. Successful re-challenge with clozapine after eosinophilia. Am J Psychiatry. 2011;168:1147–1151.
      46. McArdle PA, Siskind DJ, Kolur U, et al. Successful rechallenge with clozapine after treatment associated eosinophilia. Australas Psychiatry. 2016;24:365–367.
      47. Reid P. Clozapine re-challenge after myocarditis. Aust N Z J Psychiatry. 2001;35:249.
      48. Reinders J, Parsonage W, Lange D, et al. Clozapine-related myocarditis and cardiomyopathy in an Australian metropolitan psychiatric service. Aust N Z J Psychiatry. 2004;38:915–922.
      49. Jayathilake I, Singh AK. Clozapine re-challenge after myocarditis. Australas Psychiatry. 2009;17:421–422.
      50. Rosenfeld AJ, Gibbs T, Ivie R, et al. Successful clozapine retrial after suspected myocarditis. Am J Psychiatry. 2010;167:350–351.
      51. Bray A, Reid R. Successful clozapine re-challenge after acute myocarditis. Aust N Z J Psychiatry. 2011;45:90.
      52. Hassan I, Brennan A, Carroll A, et al. Monitoring in clozapine rechallenge after myocarditis. Australasia Psychiatry. 2011;19:370–371.
        53. Ronaldson KJ, Fitzgerald PB, Taylor AJ, et al. Observations from 8 cases of clozapine re-challenge after development of myocarditis. J Clin Psychiatry. 2012;73:252–254.
        54. Ittasakul P, Archer A, Kezmn J, et al. Rapid re-challenge with clozapine following pronounced myocarditis in a treatment-resistance schizophrenia patient. Clin Schizophr Relat Psychoses. 2013:1–11.
          55. Chow V, Feijo I, Trieu J, et al. Kritharides Successful re-challenge of clozapine therapy following previous clozapine-induced myocarditis confirmed on cardiac MRI. J Child Adolesc Psychopharmacol. 2014;24:99–101.
          56. Davey P, Gee S, Shergill SS. Inflammatory response to clozapine in the absence of myocarditis: case report. Br J Psychiatry Open. 2016;2:244–246.
            57. Crews MP, Dhillon GS, MacCabe JH. Clozapine rechallenge following clozapine-induced pericarditis. J Clin Psychiatry. 2010;71:959–961.
            58. Perdue M, Botello T. Development of atrial flutter after initiation of clozapine and successful rechallenge without recurrence. J Clin Psychopharmacol. 2017;37:475–477.
            59. Floreani J, Bastiampillai T. Successful re-challenge with clozapine following development of clozapine-induced cardiomyopathy. Aust N Z J Psychiatry. 2008;42:747–748.
            60. Law D, Mohan T, Bastiampillai T, et al. Clozapine re-challenge following QTc prolongation. Aust N Z J Psychiatry. 2014;48:198–139.
            61. Anderson ES, Powers PS. Neuroleptic malignant syndrome associated with clozapine use. J Clin Psychiatry. 1991;52:102–104.
            62. Goates MG, Escobar JI. An apparent neuroleptic malignant syndrome without extrapyramidal symptoms upon initiation of clozapine therapy: report of a case and results of a clozapine rechallenge. J Clin Psychopharmacol. 1992;12:139–140.
            63. Tsai G, Crisostomo G, Rosenblatt ML, et al. Neuroleptic malignant syndrome associated with clozapine treatment. Ann Clin Psychiatry. 1995;7:91–95.
            64. Chatterton R, Cardy S, Schramm TM. Neuroleptic malignant syndrome and clozapine monotherapy. Aust N Z J Psychiatry. 1996;30:692–693.
            65. Huang TL. Neuroleptic malignant syndrome associated with long-term clozapine treatment: report of a case and results of a clozapine rechallenge. Chang Gung Med J. 2001;24:522–525.
            66. Anbalagan E, Ithman M, Lauriello J. Rechallenging clozapine after neuroleptic malignant syndrome. Psychiatry Quaterly. 2014;85:345–348.
            67. Ramasamy RS, Bronson B, Lerman M. Systemic inflammatory response syndrome associated with clozapine and successful rechallenge: a case report. J Clin Psychopharmacol. 2016;36:93–95.
            68. Rondla S, Crane S. A case of clozapine-induced paralytic ileus. Emerg Med J. 2007;24:e12.
            69. McKinnon N, Azad A, Waters BM, et al. Clozapine-induced bowel infarction: a case report. Psychiatry (Edgmont). 2009;6:30–35.
              70. Ikai S, Suzuki T, Uchida H, et al. Reintroduction of clozapine after perforation of the large intestine—a case report and review of the literature. Ann Pharmacother. 2013;47:e31.
              71. Frankenburg FR, Kando J. Eosinophilia, clozapine and pancreatitis. Lancet. 1992;340:251.
              72. Roy Chengappa KN, Pelucio M, Baker RW, et al. Recurrent pancreatitis on clozapine rechallenge. J Psychopharmacol. 1995;9:381–382.
              73. Huang YJ, Lane HY, Liao CH, et al. Recurrent pancreatitis without eosinophilia on clozapine rechallenge. Prog Neuro-Psychopharmacology Biol Psychiatry. 2009;33:1561–1562.
                74. Fraser D, Jibani M. An unexpected and serious complication of treatment with the atypical antipsychotic drug clozapine. Clin Nephrol. 2000;54:78–80.
                75. Hunter R, Gaughan T, Queirazza F, et al. Clozapine-induced interstitial nephritis—a rare but important complication: a case report. J Med Case Rep. 2009;3:8574.
                  76. Rami AF, Barkan D, Mevorach D, et al. Clozapine-induced systemic lupus erythematosus. Ann Pharmacother. 2006;40:983–985.
                  77. Clozapine and risk of neutropenia: a guide for healthcare providers. Available at: Accessed July 1, 2017.
                  78. Chanpattana W, Sackeim HA. Electroconvulsive therapy in treatment-resistant schizophrenia: prediction of response and the nature of symptomatic improvement. J ECT. 2010;26:289–298.
                  79. Myles N, Myles H, Clark SR, et al. Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: a systematic review of the literature and clinical recommendations. Aust N Z J Psychiatry. 2017;51:980–989.
                  80. Esposito D, Rouillon F, Limosin F. Continuing clozapine treatment despite neutropenia. Eur J Clin Pharmacol. 2005;60:759–764.
                  81. Denic S, Showqi S, Klein C, et al. Prevalence, phenotype and inheritance of benign neutropenia in Arabs. BMC Blood Disord. 2009;9:3.
                  82. Manu P, Sarvaiya N, Rogozea LM, et al. Benign ethnic neutropenia and clozapine use: a systematic review of the evidence and treatment recommendations. J Clin Psychiatry. 2016;77:e909–e916.
                  83. Ronaldson KJ, Fitzgerald PB, Taylor AJ, et al. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N Z J Psychiatry. 2011;45:458–465.
                  84. Clozapine-induced myocarditis—monitoring protocol. 2012. Available at: Accessed July 1, 2017.
                  85. Roge R, Moller BK, Andersen CR, et al. Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far? Schizophrenia Res. 2012;140:204–213.

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