Despite the fact that schizophrenia is one of the most common psychotic disorders, its diagnosis is so complex that it requires specialist input from secondary care in order to determine whether a patient is suffering from schizophrenia (1). In order to aid the diagnostic process, the National Institute of Health and Care Excellence (NICE) recommend the use of the diagnostic criteria outlined in ICD-10, which is a document published by the World Health Organisation and contains the various classifications of a wide variety of medical diseases (2). Treatment of schizophrenia is often divided into two broad categories: non-pharmacological and pharmacological therapy. Non-pharmacological interventions typically consist of cognitive behavioural therapy (CBT), family interventions which are structured programs in which the patient’s own family members play an active role in therapy and arts therapy, which is an emerging strategy which involves allowing patients to express themselves in a controlled environment  through the medium of art (3,4, 5). Pharmacological treatment of schizophrenia involves the use of antipsychotic medication such as olanzapine and amisulpride, however, the wide variety between antipsychotics in terms of their adverse effects and pharmacokinetics often means that choice of the therapeutic agent is guided by a complex interaction between presenting symptoms, patient co-morbidities and patient preferences (5,6). Despite the wide variety of antipsychotic drugs available for the treatment of schizophrenia, there is evidence to suggest that even the newer, so-called atypical antipsychotics are not as effective against negative symptoms as previously thought (7,8). Therefore, guidelines now recommend the use of a combination of non-pharmacological and pharmacological interventions in order to achieve optimal outcomes for patients due to an emerging body of evidence suggesting that this combination provides greater outcomes compared to just using one method (5,8). However, despite these evidence-based recommendations, up to a third of patients will not respond to initial therapy, and is often associated with poorer outcomes such as higher suicide rates, increased morbidity and higher treatment costs(9). This is known as treatment-resistant schizophrenia. Options are often limited in the treatment of this form of schizophrenia, creating a considerable problem for both prescribers and patients, however, there is one drug which has a strong evidence portfolio for its use in such circumstances.

Clozapine: a possible saviour for treatment resistance?

Clozapine is an atypical antipsychotic discovered in the late 1950s, by scientists working on the properties of tricyclic antidepressants. Its antipsychotic properties were then investigated in a series of trials throughout the 1960s, before finally being marketed in 1972 in Switzerland (10). Pharmacologically, clozapine exerts its antipsychotic effect by binding to serotonin, muscarinic and dopamine receptors within the brain, and acting as an antagonist. Crucially, it does not bind strongly to the D2 subtype of dopamine receptors, found in the striatum of the brain which is the area of the brain responsible for co-ordinating motor movement. Therefore, clozapine does not induce extra-pyramidal side effects (EPSEs) seen with other antipsychotics since it does not have a considerable impact on normal neuronal transmission within the striatum, whereas other antipsychotics tend to have a stronger inhibitory effect on the D2 receptors in this area of the brain, leading to EPSEs (11).

The evidence base for the efficacy of clozapine, particularly in treatment-resistant schizophrenia is considerable. Research has shown that up to 40% of patients classified as having treatment-resistant schizophrenia will respond to clozapine, compared to other antipsychotics to which the majority of such patients do not respond (12,13) As such, it is now recommended as the antipsychotic of choice when patients fail to respond to trials of at least two antipsychotics (one of which must be an atypical antipsychotic) (5). As a result, clozapine is, therefore, an asset in the treatment of resistant schizophrenia. Despite this, as well as the fact that clozapine is the oldest atypical antipsychotic, prescribing patterns worldwide suggest that it is still underutilised. In America, only 10-25% of patients classed as treatment-resistant are prescribed clozapine, with almost 32% of treatment-resistant patients not being prescribed clozapine in the UK, despite having no significant contra-indications or co-morbidities which would make clozapine unsuitable (14,15). So why are prescribers reluctant to prescribe a drug which could provide a solution to a massive problem? The answer may lie in the drug’s safety profile.

Is clozapine safe?

Despite its proven efficacy for treating treatment-resistant schizophrenia and the fact that it causes no EPSEs, clozapine has a considerable side-effect profile, which has restricted its prescribing to specialists. The main safety issue relating to clozapine therapy is the side effect of agranulocytosis (14). The risk of developing agranulocytosis is highest in the first 3 months of therapy; however, this risk tends to decrease with time (16). Agranulocytosis is such a concern with clozapine therapy, that there are strict requirements for its use in the United Kingdom (UK). Firstly, there are three brands of clozapine available in the UK; Clozaril (Mylan), Denzapine (Britannia) and Zaponex (Leyden Delta). Each brand has its own unique patient monitoring system, and patients must register with the monitoring system associated with the brand that they are taking. Additionally, prescribers and pharmacists must also register with the respective monitoring system if they wish to prescribe or dispense the brand to a particular patient (17,18,19). Once registered, patients then undergo blood tests to measure white blood cell (WBC) levels which are then uploaded to the respective monitoring service. Results follow a traffic light system (amber, green or red) and can be checked online. Amber results mean that leucocyte levels are normal, and a supply can be given, but the patient requires more frequent blood tests until a green or red result is obtained. A green result means that a supply can be given, whereas a red result means clozapine should be stopped immediately, and the monitoring system should be contacted for further advice (20).

Result WBC count (x109/L) Neutrophil count (x109/L)
Green >3.5 >2.0
Amber 3.0-3.5 1.5-2.0
Red <3.0 <1.5

Table 1: The traffic light system for clozapine blood results and their respective thresholds

The frequency of blood tests often follows a usual pattern. For the first 18 weeks of treatment, blood tests must be monitored weekly, followed by fortnightly blood tests between weeks 18 and 52. If WBCs remain stable, then blood test frequency can be every 4 weeks after week 52 (17,18,19, 21). However, despite the fact that the issue of agranulocytosis with clozapine therapy requires consistent monitoring, it affects less than 1% of patients who take clozapine (16). Consequently, the issue of agranulocytosis should not be the sole concern when dealing with clozapine therapy.

In addition to agranulocytosis, clozapine is associated with a wide range of side effects, which can be associated with significant mortality and morbidity. Among these, one of the most notorious adverse effects is gastrointestinal hypomotility. This often presents as constipation, which is a very common side effect associated with clozapine therapy (22). However, if left untreated it can lead to fatal consequences. Untreated constipation in patients on clozapine can lead to complications such as bowel obstruction, severe bowel distension and even paralytic ileus, which can be fatal (23). Furthermore, there is also the potential for such complications to be easily overlooked when patients present with constipation, suggesting that the prevalence of such complications may actually be underestimated, meaning that the issue of gastrointestinal hypomotility is far more significant than previously thought (23). However, the progression of constipation to more serious outcomes can be minimised through recommending that patients follow a high fluid and high fibre diet along with maintaining an active lifestyle, as well as promoting the effective use of laxatives at the earliest presentation of constipation (24).

Clozapine therapy has also been associated with cardiac toxicity, which usually presents as myocarditis or cardiomyopathy (25). Symptoms are often varied, ranging from symptoms similar to that of a chest infection to shortness of breath, tachycardia and congestive heart failure (25,26). Prevalence of cardiac toxicity has been reported to be around 1-3%, however, it has become such a concern that it is now recommended that prescribers take a full cardiac history from patients, as well as assessing a patient’s physical health before commencing clozapine. Counselling patients on reporting symptoms is also recommended to allow early detection and treatment of any cardiac complications arising from clozapine therapy (21.

Hypersalivation is another common side effect arising from clozapine therapy and is normally managed through the use of anticholinergics such as hyoscine or atropine. However, this has to be balanced against the risk of augmenting the issue of gastric hypomotility (21).

As well as side effects, the risk of drug interactions must be borne in mind with clozapine therapy. Clozapine is primarily metabolised by the cytochrome P450 family of enzymes, specifically, it is metabolised by the enzymes CYP1A2 and CYP3A4 (27). Since a wide variety of drugs can act as both inducers and inhibitors of the cytochrome P450 family, clozapine, therefore, has the potential to be affected by the actions of other drugs. One of the main drug interactions to be aware of is through fluvoxamine’s action as an inhibitor of CYP1A2, which blocks one of the main routes of clozapine metabolism. This may cause an increase in plasma levels of clozapine, leading to toxicity. As a result, a dose reduction of clozapine is advised if fluvoxamine is started at any time throughout therapy. Clozapine levels are also affected by drugs such as carbamazepine, rifampicin and phenytoin, which all act as enzyme inducers, which may lead to lower plasma clozapine levels and subsequently, reduced efficacy. Furthermore, the combination of carbamazepine, chloramphenicol or co-trimoxazole with clozapine should be avoided, due to potentially augmenting the risk of bone marrow suppression (17,18,19, 27). As well as drugs, lifestyle factors can also affect clozapine therapy. Smoking acts as an enzyme inhibitor of the CYP450 system, and so sudden cessation of smoking can lead to increased clozapine levels, and subsequent toxicity. Also, caffeine acts as a CYP1A2 inhibitor, mimicking fluvoxamine’s effects on plasma clozapine levels. Therefore, any sudden or major changes in smoking habits or caffeine intake can have an adverse effect on clozapine levels and may require a review of clozapine dosages (27)

Despite the risks associated with clozapine therapy with regards to interactions, side effects and monitoring requirements, there are clear benefits to be gained from the use of clozapine in patients with treatment-resistant schizophrenia. Furthermore, these risks are further negated by the fact that the most severe side effect of agranulocytosis is relatively rare and the other potentially dangerous side effects of clozapine can be minimised through appropriate measures. Those with treatment-resistant schizophrenia often have limited options with regards to pharmacotherapy. Clozapine has the potential to be an invaluable asset for extending and improving the quality of life of patients suffering from resistant forms of schizophrenia.

Author: Raj Dhaliwal MPharm


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