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Clozapine: dangerous orphan or neglected friend?

  • Saeed Farooq (a1) and Mark Taylor (a2)
Summary

Evidence concerning the superior efficacy and effectiveness of clozapine has not fully informed routine clinical practice. This is possibly because of the perception that clozapine is a dangerous therapeutic agent. Clozapine use may actually promote longevity, and earlier use of clozapine in adequate dosages represents a neglected therapeutic opportunity in this age of stagnated antipsychotic innovation.

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Copyright
Corresponding author
Mark Taylor, NHS Lothian, Ballenden House, Edinburgh EH8 9HL, UK. Email: marktaylor2@nhs.net
Footnotes
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Declaration of interest

S.F. has received fees as a speaker at a symposium organised by manufacturers of clozapine. No funding was received in relation to this editorial or research on this topic. M.T. has received hospitality or fees from various pharmaceutical firms, but not from the manufacturers of clozapine.

Footnotes
References
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2 Leucht, S, Komossa, K, Rummel-Kluge, C, Corves, C, Hunger, H, Schmid, F, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166: 152–63.
3 McEvoy, JP, Lieberman, JA, Stroup, TS, Davis, SM, Meltzer, H Y, Rosenheck, RA, et al. 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: 600–10.
4 Lewis, SW, Barnes, TRE, Davies, L, Murray, RM, Dunn, G, Hayhurst, KP, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32: 715–23.
5 Tiihonen, J, Wahlbeck, K, Lonnqvist, J, Klaukaa, T, Ioannidis, JPA, Volavka, J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of 2230 patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow up study. BMJ 2006; 333: 224.
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Clozapine: dangerous orphan or neglected friend?

  • Saeed Farooq (a1) and Mark Taylor (a2)
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eLetters

Re:Clozapine - dangerous orphan or neglected friend

Saeed Farooq
14 September 2011

Authors of two letters from India raise important points which are highly relevant for treatment of Schizophrenia in developing countries.

It is crucial that the management of Treatment Resistant Schizophrenia (TRS) is effective and prompt in developing countries. In most developing countries family is the sole carer for those suffering from Schizophrenia. The institutions and support workers such as social workers, community psychiatric nurses and rehabilitation facilities are almost non existent. Lack of response to treatment leads to vicious cycle of poverty, relapses and increasing treatment resistance (Large et al, 2009). Considering that the estimated population of those suffering from Schizophrenia and related disorders in developing countries is about 41 million (Patel et al , 2010), the prevalence of treatment resistant cases will be staggering. Reduction in suicide, disease burden and carer's burden from early and effective use of Clozapine can result in enormous public health benefits.

We agree that the use of Clozapine in developing countries is hampered by many factors, including long-distances from treatment centres,costs, misperceptions about the effects of drug, local beliefs in which giving blood is associated with negative connotations and problems associated with the monitoring. However, inadequate knowledge and non adherence to treatment guidelines amongst psychiatrists in these countriesare also important factors.Based on a survey of practising psychiatrists, Apiquian et al (2004) reported from Mexico that the majority considered risperidone as the first treatment choice for refractory schizophrenia. More importantly, less than half of the surveyed psychiatrists knew the recommended average doses of Clozapine. In many developing countries Clozapine is used in significantly lower doses. For example, Udomatn and Ng (2008) reported that the mean dosages received by patients in Thailand is 176mg/day, compared to the 450 milligrams recommended on the basis of systematic review of evidence. It is claimed that the use of such low doses is related to metabolic differences in different ethnic populations but this needs further investigation.

REFERENCESLarge M. Farooq S; Nielssen O. Duration of Untreated Psychosis in Low and Middle income economies: The relationship between GDP and DUP. British Journal of Psychiatry, 2008. 193; 272-278.

Patel V, Thornicroft G. Packages of Care for Mental, Neurological, and Substance Use Disorders in Low- and Middle-Income Countries. PLoS Med.2009;6:e1000160. doi: 10.1371/journal.pmed.1000160

Udomratn P, Ng CH. Outpatient prescribing practices in Asian Countries. In: Ng CH, Lin KM, Singh BS, Chui E, editors. Ethno-psychopharmacology: Advances in current practice. Cambridge: Cambridge University Press, 2008: 135-143

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Conflict of interest: None declared

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Lets Prevent secondary Treatment Resistant Schizophrenia and Reduce clozapine side effects

Hellme Najim, Consultant Psychiatrist
31 August 2011

Sir,I read with interest Farooq & Taylor's article (Clozapine:dangerous orphan or neglected friend?

I think it is important to try to treat to primary treatment resistant schizophrenia(TRS)and prevent secondary TRS. Meltzer et al (1)had traced back patients with TRS and found that 56% of them have neverresponded to any antipsychotic before clozapine. This leaves 44% who developed TRS through the course of treatment. There is also evidence thatinterrupted and incomplete treatment of schizophrenia lead to poorer outcome(2). These issues makes prompt and early treatment of patient mandatory in order to improve outcome.

The other important issue, I would like to raise, is the valid question about outcome with clozapine. About one to two thirds of patientsdon't respond to clozapine monotherapy, or if they respond with adequate dose, they suffer from side effects. Reinstein et al (3) put 65 patients on clozapine and quatiepine and followed up for 10 months, after 6 months of clozapine alone. All patients lost weight (0.22-10.5kg), 20% of the patients who developed diabetes in the initial phase showed significant improvement in their diabetes. It indicates that there is a place for combination of antipsychotics either if there is no response or to reduce side effects.

Kindest regardsHellme NajimConsultant Psychiatrist

South Essex University Foundation Trust

References:

1.Meltzer H.The evolution of treatment resistance:biologic implication. J Clin

Psychopharmacology.1998;18(2Suppl 1): 5S-11S.

2.Schooler, N.R., Keith, S.J., Severe, J.B., et al. Relapse and rehospitalization during maintenance treatment of schizophrenia: the effects of dose reduction and family management. Arch Gen Psychiatry 1997; 54:453-463 3.Reinstein M, Sirotovskaya LA, Jones LE, Mohan S & Chsanov MA. Effect of Clozapine-Quetiepine combination therapy on weight and Glycaemiccontrol. Clin Drug Invest 1999; 18(2):99-104.

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Conflict of interest: None declared

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Clozapine - dangerous orphan or neglected friend

Manjeet S. Bhatia, Professor
08 June 2011

Dr. Saeed Farooq and Mark Taylor are correct in highlighting the plight of clozapine. There are many factors responsible for making it an orphan drug. The important ones are discomfort among psychiatrists (fearing agranulocytosis though its prevalence is much less than most of the popularly used medical drugs); marketing - orphan (pharmaceuticals promoting olanzapine and other profitable second generation antipsychotics(SGAs over clozapine));US FDA approval for only treatment resistant schizphrenia; fancy of psychiatrists for newer drugs (in India prescription frequency of olanzapine may be as high as over 25% among SGAsin comparison to less than 0.5% for clozapine); unwarranted conclusions oftrials (many have used sub therapeutic dosages or for inadequate periods);and problem in definition of treatment resistance(definition includes adequate dose, which is undefined as equivalent doses of most SGAs are unknown; definition does not include maximal doses). One of the important reason of low prescription of clozapine in developing countries had been its inclusion in Schedule -X, to be written on three prescriptions; availability in select outlets leading to discomfort and negative attitude in prescription and its purchase. The prescribing of clozapine (versus olanzapine)similar to sildenafil (versus dapoxetine) and methylphenidate (versus atomoxetine)had become unpopular. Many generationsof new residents had no experience of prescribing clozapine. ... More

Conflict of interest: None Declared

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Clozapine use, agranulocytosis and blood monitoring: Perspectives from the developing world

Raman D Pattanayak, Senior Research Associate (CSIR)
12 April 2011

We welcome the editorial (1) raising a pertinent issue. Four decades later, and nearly 20 years after its re-introduction, time is ripe to discuss the clinical use and experience of clozapine. We agree that clozapine is used uncommonly in the initial years of the illness for its approved indication, that is failure to respond to two anti-psychotic trials. Apart from the effectiveness in suicidality, aggression and substance use, we wish to add a mention of patients with tardive dyskinesia, which had been omitted. Though we need more research on barriers to use clozapine in developing countries, it is quite likely thatthe agranulocytosis risk and difficulty in frequent blood monitoring do contribute to decision against or delay in the use of clozapine and these issues need to be adequately highlighted.

There are many factors unique to the developing world which may discourage clinicians from using it. Some cultural concerns for frequent blood sampling has been reported in asian countries e.g. blood is perceived as a ‘precious commodity’ (one hundred rice grains make a drop of blood), leading to considerable time and effort on part of clinicians to assure the patients (2). Illiteracy, poverty and unawareness add to thehindrances in regular blood monitoring. Often, there is no well defined geographical catchment area and people travel several hundred kilometers to seek psychiatric consultation. Unlike in west, it is not possible to always repeat a prescription contingent on availability of a weekly blood report. In many parts of low and middle income countries, the resources tomanage agranulocytosis may be inadequate in the event it happens.

We, now, steer to a related issue of need for risk-benefit evaluationin context of developing countries. Since its re-introduction, the risk for agranulocytosis has been reported from several western patient databases, with a prevalence of 0.08% in UK and Ireland (n=6316, 4.5 years, Neutropenia: 2.9%), mostly in initial months of treatment (3). Similarly, the clozaril national registry data for 67,000 patients of which 66 developed agranulocytosis led FDA to reduce frequency of blood monitoring to 2-weekly after the initial 6 months of use and to 4-weekly after one year. Schultze (4) compared the literature on blood dyscrasias with clozapine (1966-2005 medline literature search and data from Novartis) to risks from other medications and life in general. The chance for agranulocytosis in the second 6 months of treatment was 0.70/1000 patient-years and, after the first year, 0.39/1000 patient-years, with a case mortality rate of 4.2-16% of agranulocytosis cases. It concluded thatafter at least 6 months' treatment with clozapine, the mortality is about the same as the mortality associated with other medications, such as mianserin or phenylbutazone, and with life in general (traffic or occupational accident). Treatment with clozapine was found to reduce overall mortality, probably because it reduced suicidality.

What do the developing countries make of this clozapine debate? Thereis some merit in initiating such debate within developing countries havinglarge absolute numbers of ‘treatment resistant cases’. Is there a merit inutilizing clozapine to its full potential in the approved indications, despite the difficulties in blood monitoring described above? Of all countries, Chinese psychiatrists appear to be using clozapine to a greatest degree (25-60% of all patients with schizophrenia). As reported in a recent review of Chinese-language literature (5), the incidence (not prevalence) of agranulocytosis was reportedly 0.21% (leucopenia:3.9%). Without going into their details, some preliminary reports from Asian countries have found no agranulocytosis, but we must mention that their sample was limited to few hundred only.Patient monitoring from UK (2,6) has reported increased likelihood of agranulocytosis in patients of Asian origin (2.4 times) and in patients of African and Afro-caribean descent (2times). Research on ethnic aspects of clozapine psychopharmacology is likely to resolve the contrasting results and inform our decisions better.

What are the net public health benefits from reduction in suicide andresistant illness versus the risk estimations for agranulocytosis and other adverse effects? To initiate such a public health debate in a non-western context, we need further safety and efficacy data from non-westernsettings.

Commenting on the title if clozapine is a ‘dangerous orphan’ or ‘neglected friend’, we think it has been a friend in need, but so far we like to keep an eye on it. We have to know more about it, and make an effort to do so, especially from the developing world.

References: (1)Farooq S, Taylor M. Clozapine: dangerous orphan or neglected friend? British J Psychiatry 2011;198: 247–249(2)Chong SA, Chua L.Clozapine, Chinese and blood. British J Psychiatry 1997; 171: 89-90(3)Atkin K, Kendall F, Gould D, Freeman H, Liberman J, D O'Sullivan. Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. British J Psychiatry 1996; 169: 483-88(4)Schulte PFJ. Risk of Clozapine-Associated Agranulocytosis and Mandatory White Blood Cell Monitoring . Ann Pharmacother 2006;40: 683-88(5)Tang YL, Mao PX, Jiang F, Chen Q, Wang CY, Cai ZJ, Mitchell PB.Clozapine in China. Pharmacopsychiatry. 2008;41:1-9(6)Munro J, O'Sullivan D, Andrews C, Arana A, Mortimer A, Kerwin R. Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Beyond pharmacovigilance. British J Psychiatry 1999; 175: 576-580Declaration of interest: None
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