After 30 years, clozapine is still best for treatment-resistant patients

There is still “fear” among some clinicians about prescribing clozapine for patients with treatment-resistant schizophrenia. Jenny Bryan takes a look at the drug’s history

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Nearly half a century after it was introduced, the first atypical antipsychotic drug clozapine (Clozaril) has yet to reach its full potential. In the early 1970s, many psychiatrists questioned whether it could even be a neuroleptic agent because of its lack of extrapyramidal side effects[1].

But the subsequent development of a series of second-generation antipsychotic agents, still widely referred to as “atypical” because of their lack of associated movement problems, helped dispel the notion that antipsychotic and extrapyramidal effects must always go together. However, the risk of agranulocytosis with clozapine and the need for regular prophylactic blood monitoring continues to limit the drug’s true potential in treatment-resistant schizophrenia.

“The first generation antipsychotics didn’t work for everybody and, when they did work, there were significant problems with Parkinson’s-like movement disorders and longer term tardive dyskinesia, often affecting the tongue and mouth. This sometimes made people look different and could be stigmatising, so the relative absence of movement side effects with clozapine and the other second-generation drugs was very welcome,” explains Fiona Gaughran, lead consultant psychiatrist, National Psychosis Service, South London and Maudsley (SLAM) NHS Foundation Trust, London.

“The joy of clozapine was that you could use it to treat people who didn’t respond to anything else — and really make a difference,” she adds.

Not just a dopamine blocker?

Why clozapine is more effective for treatment-resistant schizophrenia than other antipsychotic agents remains uncertain. For many years, clinicians have linked schizophrenia to increased dopamine synthesis in striatal tissue, and the efficacy of antipsychotic agents — first and second generation — appears related to their ability to block dopamine (D2) receptors. However, brain scanning research has suggested that patients with treatment-resistant schizophrenia may not have abnormal dopamine synthesis, so clozapine could be working through other mechanisms, one of which may be glutamate dysfunction[2].

“We are at a new phase of research, acknowledging that schizophrenia may result from more than one disease process. Most patients respond to dopamine blockers, but clozapine probably does something on top because it helps those patients who don’t respond to other agents,” points out Dr Gaughran.

Launch, withdrawal, reintroduction

Clozapine was synthesised and characterised by Swiss pharmaceutical company Wander (now part of Novartis) in 1956 — only six years after the first-generation drug, chlorpromazine, was discovered in the laboratories of Rhône-Poulenc[3] (now part of Sanofi-Aventis).

In the mid-1960s, clozapine was one of three compounds that Wander offered to researchers in Berlin who were trying to establish the structural differences between tricyclic compounds that affected whether they were antidepressants or neuroleptics[1]. According to the theory of the German team, the orientation of the tricyclic rings of the three compounds should have made them antidepressants[1]. But clinical investigation showed that they had neuroleptic effects[1], and a new class of schizophrenia treatment was born.

After early clinical trials confirmed clozapine’s antipsychotic efficacy and lack of extrapyramidal side effects, the drug was gradually introduced across Europe during the early 1970s. However, when Finnish clinicians reported a cluster of cases of agranulocytosis in elderly and infirm patients treated with clozapine, resulting in seven deaths, the product was voluntarily withdrawn by Sandoz, which had merged with Wander in 1967[4].

Some psychiatrists did not want to lose clozapine because they had seen the benefits of treatment, particularly in those with tardive dyskinesia. Sandoz and the US Food and Drug Administration were therefore persuaded to set up a major comparative clinical trial of clozapine and chlorpromazine in patients who were refractory to at least three neuroleptic agents and had failed to respond to haloperidol = 60mg per day.

Of the 268 patients in the six-week study, 30 per cent of the clozapine-treated patients were categorised as responders compared with 4 per cent of chlorpromazine-treated patients[5]. The improvement with clozapine included “negative” as well as “positive” symptoms and there were no cases of agranulocytosis.

“The result was clearly in favour of clozapine, and led to the drug being brought back, but in a highly regulated way, with patients having baseline and weekly blood tests for the first 18 weeks, followed by fortnightly tests until week 52, and monthly tests after that,” says Dr Gaughran.

Clozapine was reintroduced in 1990, and it was soon followed by other second-generation agents, such as risperidone and olanzapine, which have not been linked to neutropenia and agranulocytosis.

Traffic lights for clozapine monitoring

Dr Gaughran explains that many patients with schizophrenia are treated successfully with clozapine over a number of years. A “traffic light” system is used to differentiate between patients with modest falls in neutrophils who require repeat tests (amber), and those with more serious reductions where immediate treatment cessation is needed (red).

Some people of black African heritage naturally have lower neutrophil counts than those of Caucasian origin. This is known as benign ethnic neutropenia (BEN). The clozapine traffic light system can be adapted to allow for the lower baseline neutrophil and white cell counts once a formal diagnosis of BEN is confirmed by a haematologist.

Psychiatrists have drawn attention to the importance of BEN, so that black patients are not mistakenly believed to be ineligible for clozapine use because of a low baseline neutrophil count[6].

After someone has a red light on clozapine, there are significant risks associated with rechallenge, but this is sometimes possible. A systematic review showed that clozapine rechallenge was successful in 70 per cent of patients after neutropenia but only in 20 per cent if agranulocytosis had occurred[7]. Dr Gaughran points out that, because a second drop in neutrophils while on clozapine tends to be deeper and longer lasting than a first fall, careful clinical risk-benefit analyses are required. Rechallenge is not recommended following agranulocytosis.

Third-line treatment

Clozapine is the only antipsychotic agent licensed for treatment-resistant schizophrenia, and National Institute for Health and Care Excellence recommends that it should be offered to patients who have not responded sufficiently to sequential use of adequate doses of at least two different antipsychotic drugs. At least one of these should be a non-clozapine second-generation antipsychotic[8].

However, there is evidence of continuing delays in starting treatment-resistant patients on clozapine. A review of records of 149 patients started on clozapine at SLAM NHS Foundation Trust between 2006 and 2010 estimated a four-year delay in getting patients on the drug[9]. In about one-third of patients, there was evidence of polypharmacy or high-dose treatment before starting clozapine.

“Global rates of clozapine use in schizophrenia patients vary enormously from only about one in 20 in the US to around one-third in Finland. It’s clear that we aren’t yet treating everyone who could benefit from clozapine and much of this is due to concern about side effects and the practicalities of regular monitoring, especially during initiation,” says Dr Gaughran.

Balancing safety and efficacy

The risk of agranulocytosis, albeit low, is not the only reason why some clinicians are reluctant to prescribe clozapine to treatment-resistant patients with schizophrenia. Other side effects include weight gain, hypersalivation, constipation, tachycardia, dose-related reduction in seizure threshold, sedation and incontinence, although established management strategies are available for these potential side effects[10].

The impact of second-generation antipsychotic agents on risk factors for cardiovascular disease (CVD) such as obesity and diabetes has been a cause for concern. People with schizophrenia die 20–25 years earlier than the general population, and 60 per cent of the excess mortality is due to physical conditions, such CVD and pulmonary disease. However, research has shown that long-term use (7–11 years) of any antipsychotic treatment by people with schizophrenia is associated with lower mortality than no drug use and clozapine is associated with lower mortality than other commonly used first- and second-generation antipsychotic agents[11].

“People with schizophrenia, like the rest of us, need to be mentally well enough to manage their physical health. Effectively treating psychosis reduces disorganisation, allowing people to make choices regarding their lifestyle options and physical health,” says Dr Gaughran.

Neither she nor other psychiatrists advocate clozapine as first-line treatment for schizophrenia because there is no evidence of benefit over other antipsychotics in this group of patients. But Dr Gaughran suggests that, if people are resistant to two other antipsychotics, delays in moving onto clozapine can affect more than just their mental health. They can mean that patients become increasingly alienated and disenfranchised.

“We need to be less frightened of using clozapine where it’s indicated, and to get systems in place to monitor treatment initiation effectively. Treatment-resistant patients are much more likely to respond to clozapine than to another agent, and getting them onto something that works for them will help them get back into their social system and reduce the need for hospital admissions,” points out Dr Gaughran.

In south London, a home-treatment service for clozapine has been established that enables patients to have vital signs checked every day, along with their regular blood tests for neutropenia. The aim is to support patients through the early phase of treatment, pick up problems quickly, actively manage side effects and avoid the need for hospital admissions.

“We’ve spent 30 years looking for something better than clozapine for our treatment-resistant patients, but we still haven’t found anything to surpass it,” concludes Dr Gaughran. “We aren’t yet using it early enough in those who could benefit and we also need to work on individualising treatment. In that way, patients will get the lowest effective dose of clozapine, tolerate it better and will be happy to stay on it.”


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[2]Demjaha A, Murray RM, McGuire PK et al. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. American Journal of Psychiatry 2012;169:1203–10.

[3]Meltzer HY. Clozapine: balancing safety with superior antipsychotic efficacy. Clinical schizophrenia and related psychosis 2012;6:134–44.

[4]Idänpään-Heikkilä J, Alhava E, Olkinuora M et al. Clozapine and agranulocytosis. The Lancet 1975;2:611.

[5]Kane J, Honigfeld G, Singer J et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry 1988;45:789–96

[6]Whiskey E, Olofinjana O & Taylor D. The importance of the recognition of benign ethnic neutropenia in black patients during treatment with clozapine: case reports and database study. Journal of Psychopharmacology 2011;25:842–5.

[7]Manu P, Sarpal D, Muir O et al. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophrenia Research 2012;134:180–6.

[8]National Institute for Health and Care Excellence. Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. CG82, March 2009.

[9]Howes OD, Vergunst F, Gee S et al. Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. British Journal of Psychiatry 2012;201:481–5.

[10]Bleakley S & Taylor D. The clozapine handbook. London: Lloyd-Reinhold Communications LLP; 2013.

[11]Tiihonen J, Lönnqvist J, Wahlbeck K et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). The Lancet. 2009;374:620–7.

Last updated
The Pharmaceutical Journal, PJ, 18 January 2014, Vol 292, No 7793;292(7793):58:DOI:10.1211/PJ.2021.1.65553

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