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Coroners warn health secretary of clozapine deaths

BMJ 2018; 363 doi: (Published 27 December 2018) Cite this as: BMJ 2018;363:k5421

Rapid Response:

The Art of Clozapine therapy and Clozaphobia

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,
Consultant Psychiatrist,
Northwest Boroughs Healthcare NHS Foundation Trust,
Hollins park Hospital, Warrington WA2 8WN, U. K.

Competing interests: No competing interests

06 January 2019
Consultant Psychiatrist
Hollins Park Hospital, Warrington WA2 8WN, United Kingdom