Coroners warn health secretary of clozapine deathsBMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k5421 (Published 27 December 2018) Cite this as: BMJ 2018;363:k5421
All rapid responses
It is astonishing and appalling that some staff giving clozapine to psychiatric patients are still not familiar with the side effect profile.
The unjustified aura of atypical anti-psychotics as 'miracle drugs' has never been properly deconstructed.
Clozapine is, of course, the prime prototype of the modern atypical.It remains the last resort for refractory schizophrenia.
Clozapine was first produced in 1958. It was marketed from 1970. It began killing patients. After multiple deaths in Finland, it was banned there, and then across Europe. The major problem was 'agranulocytosis'. The BMJ feature mentions agranulocytosis among other side effects, without emphasizing agranulocytosis as the prime key danger.
Research on clozapine stopped in 1976.
The recent sad deaths of Julia MacPherson and Tom Jackson are part of the Clozapine pattern.
Clozapine reemerged in 1988. Unlike the 'typical' anti-psychotics, it does not appear to cause Tardive Dyskinesia, and it does not seem to raise Prolactin.
A long-term risk of Clozapine - and other anti-psychotics - is the Metabolic Syndrome - from weight gain to diabetes to cardiovascular damage to premature death (1).
The Maudsley Guidelines carry a huge section (pages 62 to 77) on Clozapine side effects (2) - about which a portion of psychiatric nurses seem not to be aware.
An author of the Maudsley Guidelines is David Taylor, who with others in a Rapid Response to this article puts a case for Clozapine. Indeed, as I skim through these Rapid Responses, I witness the seemingly common complacency of health professionals about Clozapine, and anti-psychotics in general. These drugs are a means to suppress rather than a means to cure. They are the ultimate tools of stigmatization.
Psychiatry, perhaps more than any other part of medicine, cannot work without caution - and criticism.
(1) Stahl's Essential Psychopharmacology. S.M.Stahl. Cambridge. 2008.
(2) The Maudsley Guidelines. David Taylor, Carol Paton and Shitij Kapur. Tenth Edition. Informa Healthcare. 2009.
Competing interests: No competing interests
We read with sadness of the experiences of the patients and their families described in your article 'Coroners warn health secretary of clozapine deaths'. We are however, concerned that the author does not acknowledge the experiences of the countless people who have been able to rebuild their lives through the stability that clozapine can provide.
People with schizophrenia suffer profoundly disabling and distressing psychotic symptoms, such as tormenting voices and paranoid thoughts, and face increased risks of death by suicide and through poor physical health. For many thousands of people, clozapine is the only effective drug; it alone provides relief from symptoms. Clozapine has been proven, in several large scale studies, to reduce overall mortality, compared to other antipsychotics, and compared to no treatment at all. Clozapine not only reduces the risk of suicide and self-harm, but also enables patients to better care for their physical health, and to live independent, fulfilled lives in the community. It is a serious treatment for a serious illness.
The cases described by the BMJ highlight the vital importance of careful monitoring of patients taking clozapine, and it is essential that doctors are properly trained in its safe prescription. With the appropriate care and monitoring, clozapine can be a safe and effective treatment for patients for whom all other treatment options have been exhausted.
Competing interests: No competing interests
The reporting and excellent responses to these tragic events highlight ongoing concerns about the quality of patient monitoring, rather than the quality of prescribing. In acute mental health care [1-3] and other settings , we have shown that the introduction of thorough, structured checks by nurses and care staff can identify antipsychotic-related problems and prompt preventative action. An intervention developed in our research [5,6] to facilitate nurse-led review of patients with serious mental illness pre-empted serious adverse reactions, including chest pain and pancreatitis . Monitoring takes 10-20 minutes per patient, including checks of vital signs, and causes no harm [1,4]. Although this does take the time of front-line staff (nurses and carers), recording of constipation, hypersalivation, behaviour change, weight gain and other problems on a single sheet shared with prescribers and pharmacists can bring real benefits by preventing escalation.
Failure to recognise adverse drug reactions (ADRs) is often due to their complexity and diversity. ADRs to prescribed medicines often develop after the prescriber has left, and a mechanism is needed to transfer information from patient to prescriber, across geographical and social distance. Comprehensive, nurse-led monitoring with supporting information has potential to bridge this gap in communication and care. ADRs may be contributing to the 5-8% of unplanned hospital admissions [7,8]. Adopting structured ADR monitoring instruments , for example in monthly haematological monitoring clinics, has potential to prevent recurrence of the tragic cases described here.
1. Jones R, Moyle C, Jordan S. Nurse-led medicines monitoring: a study examining the effects of the West Wales Adverse Drug Reaction Profile. Nurs Stand 2016;31:42-53. doi: 10.7748/ns.2016.e10447 [published Online First: 2016/12/03]
2. Jordan S. Managing adverse drug reactions: an orphan task. J Adv Nurs 2002;38:437-48.
3. Jordan S, Tunnicliffe C, Sykes A. Minimizing side-effects: the clinical impact of nurse-administered 'side-effect' checklists. J Adv Nurs 2002;37:155-65.
4. Jordan S, Gabe-Walters ME, Watkins A, et al. Nurse-Led Medicines' Monitoring for Patients with Dementia in Care Homes: A Pragmatic Cohort Stepped Wedge Cluster Randomised Trial. PLoS One 2015;10:e0140203. doi: 10.1371/journal.pone.0140203 [published Online First: 2015/10/16]
5. ADRE – THE ADVERSE DRUG REACTION PROFILE: HELPING TO MONITOR MEDICINES http://www.swansea.ac.uk/adre/ (accessed 7 January 2019)
6. Jordan S, Logan PA, Panes G, Vaismoradi M, Hughes D. Adverse Drug Reactions, Power, Harm Reduction, Regulation and the ADRe Profiles. Pharmacy (Basel). 2018 Sep 18;6(3). pii: E102. doi: 10.3390/pharmacy6030102. PubMed PMID: 30231573. http://www.mdpi.com/2226-4787/6/3/102/pdf
7. Jordan S, Banner T, Gabe-Walters M the Medicines Management Group, et al Nurse-led medicines’ monitoring in care homes study protocol: a process evaluation of the impact and sustainability of the adverse drug reaction (ADRe) profile for mental health medicines BMJ Open 2018;8:e023377. doi: 10.1136/bmjopen-2018-023377
8. NICE Medicines and Prescribing Centre. Medicines optimisation:the safe and effective use of medicines to enable the best possible outcomes. NICE guideline 5 London: NICE; 2015. Available from: https://www.nice.org.uk/guidance/ng5/resources/medicines-optimisation-th... (accessed 7 January 2019).
Competing interests: There is no commercial interest. We are the authors of the instrument described. This is free to those wishing to use it for patient benefit. http://www.swansea.ac.uk/adre/
Although clozapine reduces overall mortality in schizophrenia (1), a growing body of evidence links its use with elevated rates of pneumonia-related admission (2-4) and mortality (5-8). Various mechanisms for the increase in pneumonia have been suggested, including sedation, sialorrhoea and aspiration, agranulocytosis, and smoking (9, 10). Following the introduction of calculated globulin screening in Wales (11), we have recently reported a novel and striking association between use of the antipsychotic clozapine and antibody deficiency (12). Whilst clozapine-treated patients follow an intensive regimen of blood testing for the rare risk of agranulocytosis (with cumulative incidence of <1% cases), antibody testing is not included in existing clozapine monitoring programmes. We urge consideration of this potential mechanistic explanation as a modifiable risk factor for the increased rates of pneumonia and sepsis-related mortality previously reported in this vulnerable cohort.
1. Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). The Lancet 2009;374(9690):620-627.
2. Leung J, Hasassri M, Barreto J, Nelson S, Morgan Rr. Characterization of Admission Types in Medically Hospitalized Patients Prescribed Clozapine. Psychosomatics 2017;58(2):164-172.
3. Stoecker ZR, George WT, O’Brien JB, Jancik J, Colon E, Rasimas JJ. Clozapine usage increases the incidence of pneumonia compared with risperidone and the general population: a retrospective comparison of clozapine, risperidone, and the general population in a single hospital over 25 months. International Clinical Psychopharmacology 2017;32(3):155-160.
4. Kuo CJ YS, Liao YT, Chen WJ, Lee WC, Shau WY, Chang YT, Tsai SY, Chen CC. Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophrenia bulletin 2013;39(3):648-657.
5. Rohde C, Polcwiartek C, Kragholm K, Ebdrup BH, Siskind D, Nielsen J. Adverse cardiac events in out-patients initiating clozapine treatment: a nationwide register-based study. Acta Psychiatrica Scandinavica 2018;137(1):47-53.
6. Taylor DM D-HP, Olofinjana B, Whiskey E, Thomas A. Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-acting injection. The British Journal of Psychiatry 2009;194(2):165-167.
7. Mustafa F, Burke J, Abukmeil S, Scanlon J, Cox M. “Schizophrenia past Clozapine”: Reasons for Clozapine Discontinuation, Mortality, and Alternative Antipsychotic Prescribing. Pharmacopsychiatry 2015;48(01):11-14.
8. Dyer C. Coroners warn health secretary of clozapine deaths. BMJ 2018;363:k5421.
9. Abdelmawla N, Ahmed MI. Clozapine and risk of pneumonia. British Journal of Psychiatry 2009;194(5):468-469.
10. Bello S, Menéndez R, Antoni T, Reyes S, Zalacain R, Capelastegui A, et al. Tobacco Smoking Increases the Risk for Death From Pneumococcal Pneumonia. CHEST 2014;146(4):1029-1037.
11. Jolles S, Borrell R, Zouwail S, Heaps A, Sharp H, Moody M, et al. Calculated globulin (CG) as a screening test for antibody deficiency. Clinical and experimental immunology 2014;177(3):671-678.
12. Ponsford M, Castle D, Tahir T, Robinson R, Wade W, Steven R, et al. Clozapine is associated with secondary antibody deficiency. The British Journal of Psychiatry 2018:1-7.
Competing interests: S.J. has received support from CSL Behring, Shire, LFB, Biotest, Binding Site, Sanofi, GSK, UCB Pharma, Grifols, BPL SOBI, Weatherden, Zarodex and Octapharma for projects, advisory boards, meetings, studies, speaker and clinical trials.
Causes for death with Clozapine
Antipsychotic drug Clozapine can be associated with Myocarditis Cardiomyopathy Venous thrombosis Pulmonary embolism and Gsterointestinal motility disorders. All these can leads to sudden death in clozapine users. Myocarditis with in two to three weeks may be due to IgE immune mediated one . Venous thrombosis around three months can be due to hypercoagulabe state on venous side. Constipation may be due to slow peristaltic movement of the intestines.
Competing interests: No competing interests
The article in BMJ (Coroners warn of clozapine deaths,15th January,2019) seems to increase the “clozaphobia,” the phobia of professionals for prescribing clozapine 1 which is potentially a transformative drug for schizophrenia sufferers. Since 1975, many clinicians have had reservations about its use because of the rare incidence of agranulocytosis. In fact, the risk of developing granulocycytopenia and agranulocytosis during clozapine therapy is around 1.0%. 2 Most of the cases happen during the first six weeks or first six months and can be prevented by strictly adhering to mandatory blood monitoring.
The introduction of Clozapine met with a lot of pessimism because of the unfortunate initial fatalities in Finland and the causes of those deaths were not well established. Clozapine was discovered in Switzerland in 1956 a few years after the discovery of chlorpromazine. A cluster of elderly and frail patients in Finland were thought to have developed agranulocytosis, leading to eight deaths in a small geographic area.
Since the Finland occurrence, no such clustering of deaths has been reported anywhere else. Investigation into that incident excluded the conclusion that clozapine was the cause of these deaths, at least through an agranulocytosis mechanism.3 Being effective for treating tardive dyskinesia and the only antipsychotic effective enough to control psychotic symptoms of patients suffering from tardive dyskinesia and the drug that has minimal risk of causing tardive dyskinesia, clozapine was later reintroduced with restrictions.4 The mandatory hematological monitoring is closely followed in developed countries and mortality due to agranulocytosis has been reduced. The drug has always been vulnerable to criticisms because of its gloomy start and more so now because it is generic and defenseless without a caretaker!
The BMJ report does not state what exactly led to the fatality of the patients. The major side effects of clozapine are a) agranulocytosis; b) metabolic side effects; c) myocarditis; d) seizures; e) severe constipation with gastrointestinal complications such as intestinal obstruction, bowel perforation, paralytic ileus and toxic megacolon; f) sialorrhea Clozapine is thought to be an immunosuppressant and could make patients more susceptible to infections. Sialorrhea can lead to aspiration pneumonia. These side effects can be detected and minimized. Two epidemiological studies have shown that clozapine has the lowest mortality rate among other antipsychotic drugs. It is primarily recommended for treatment-resistant schizophrenia or schizoaffective disorder presenting with florid psychotic symptoms despite two or more clinical trials with other antipsychotic drugs. It is also advocated in patients with schizophrenia or schizoaffective disorder who are at high risk for suicide. Its highest usage is in Scandinavian countries and China.
Clozapine is a lifesaving drug, but without extra care, it can also shorten the life span of patients. To asses what dose of clozapine has the maximum effect with least side effects is a challenge and an art. It may be variable with individual patients. Finding the right combination of antipsychotics or augmenting agent when the clinician is helpless and torn between monotherapy and polypharmacy is yet another task. Clinical judgment combined with patient preference must take over when treatment algorithms fall short.
Once clozapine is initiated successfully, patients will have to maintain “clozapine life style” that includes dietary control, regular exercises and abstinence from substance misuse to avoid some of the disabling side effects and stay well; clinical team has the duty to offer intense psycho-education with this effect. Clozapine is a drug patient must earn and it should be safe in the hands of the mental health professionals.
Clozapine can be effective at lower doses and becomes more effective as time goes by, but many clinicians do not wait to give the drug a longer trial at lower doses because of various clinical pressures. For belligerent, agitated in-patients with florid positive symptoms and potential for self-harm and harm to others, rapid titration may be required. For other patients, such rapid and high dose titration can be avoided to study the individual variations of side effects and prescribe accordingly so as to avoid fatalities.
Subramanian et al analysed various clozapine studies pertaining to the varying doses of prescription of clozapine. They describe up to 150 mg/day as very low dose, 150 mg/day to 300 mg/day as low dose and standard dose as 300 mg/day to 600 mg/day.5
Above these doses, there are high and very high doses. Unfortunately, there are no studies relating to the efficacy of clozapine comparing the effects of clozapine at higher than the standard dose. Weight gain is greater in those receiving the standard dose compared to those receiving the low dose. The incidence of unpleasant side effects which also include feeling lethargic, hypersalivation, dizziness is less at low dose compared to standard dose. Most of the side effects except agranulocytosis become evident at a higher dose. Clozapine is a popular antipsychotic in India and an Indian study found satisfactory response to very low dose of clozapine as maintenance therapy.6 Low dose prescription of clozapine to diminish allied side effects is currently getting buttressed from clozapine studies.
Herbert Y Meltzer 4 maintains that the following advantages are well established: a) superiority for positive symptoms in treatment-resistant patients; b) lower risk for suicide; c) lower risk for tardive dyskinesia and suppression of established tardive dyskinesia; d) improvement in cognition contributing to better work and social function; e) higher quality of life and longer time to discontinuation; and, f) decreased relapse. More studies are needed to report on outcomes such as relapse, remission, social functioning, service utilization, cost-effectiveness, satisfaction with care, and quality of life. Over twenty years have passed by since Clozapine was reintroduced and there is no evidence to submit that the mortality among clozapine patients are on the increase. A derivate of clozapine without the major side effects including agranulocytosis could be a game changer in schizophrenia research.
1.Cetin Mesut. Clozaphobia: Fear of Prescribers of Clozapine for Treatment of SchizophreniaKlinik Psikofarmakoloji Bülteni, Cilt: 24, Sayı: 4, 2014 / Bulletin of Clinical Psychopharmacology,2014; 24 (4) :295-301.
2.Alvir JMJ, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis. New England Journal of Medicine 1993; 329:162-167.
3.Amsler HA, Teerenhovi L, Barth E, Harjula K, Vuopio P. Agranulocytosis in patients treated with clozapine. A study of the Finnish epidemic. Acta Psychiatr Scand 1977;56(4):241-248.
4.Meltzer Herbert Y. Clozapine: Balancing Safety with Superior Antipsychotic Efficacy. Clinical Schizophrenia & Related Psychoses 2012,6(3):134-144 DOI:10.3371/CSRP.6.3.5
5.Subramanian S, Völlm BA, Huband N. Clozapine dose for schizophrenia. Cochrane Database of Systematic Reviews 2017, Issue 6. Art. No.: CD009555. DOI: 10.1002/14651858.CD009555.pub2
6. Shrivastava A, Shah N. Prescribing practices of clozapine in India: Results of an opinion survey of psychiatrists. Indian J Psychiatry. 2009;51(3):225-6.
Dr James Paul Pandarakalam,
Northwest Boroughs Healthcare NHS Foundation Trust,
Hollins park Hospital, Warrington WA2 8WN, U. K.
Competing interests: No competing interests
Official concerns about clozapine’s distinctive toxicity are nothing new; they surface from time to time in various countries, typically in response to preventable deaths. Resulting calls for improved monitoring (1) are justified but have had only limited impact, in part due to the fact that fatal agranulocytosis is very rare and already largely prevented by the requirement for regular blood counts. On the other hand, clozapine-induced severe constipation is not at all rare (2), despite assertions to the contrary (1); it is also more difficult to monitor in practice, and leads to a disproportionate share of preventable deaths.
Crucial to factor into any discussion of its harms is clozapine’s superior efficacy (3) and its association with reduced mortality overall: despite its range of serious toxicities, and in contrast to other antipsychotics, clozapine treatment reduces mortality from both natural and unnatural causes (4), including suicide (5). Based on this evidence, calls have been made for clozapine to be used sooner in the treatment of severe psychotic illness, rather than third-line or as a last resort (4).
1. Dyer C. Coroners warn health secretary of clozapine deaths. BMJ 2018;363:k5421.
2. Every-Palmer S, Inns SJ, Grant E, Ellis PM. Effects of clozapine on the gut: Cross-sectional study of delayed gastric emptying and small and large intestinal dysmotility. CNS Drugs (epub ahead of print, 19 November 2018) doi:10.1007/s40263-018-0587-4.
3. Stroup TS, Gerhard T, Crystal S, Huang C, Olfson M. Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. American Journal of Psychiatry 2016;173:166-73.
4. Hayes RD, Downs J, Chang CK, Jackson RG, Shetty H, Broadbent M, et al. The effect of clozapine on premature mortality: an assessment of clinical monitoring and other potential confounders. Schizophrenia Bulletin 2015;41:644-55.
5. Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophrenia Research 2005;73:139-45.
Competing interests: No competing interests