Clozapine

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Clozapine, sold under the brand name Clozaril among others, is a psychiatric medication and was the first atypical antipsychotic to be discovered.<ref>Template:Cite book</ref> It is used primarily to treat people with schizophrenia and schizoaffective disorder who have had an inadequate response to two other antipsychotics, or who have been unable to tolerate other drugs due to extrapyramidal side effects. In the US, clozapine is also approved for use in people with recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder.<ref name = "CDER">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is also used for the treatment of psychosis in Parkinson's disease.<ref name="medicines.org.uk" /><ref name="National Institute for Health and Care Excellence (Great Britain)" />

Clozapine is recommended by multiple international treatment guidelines, after resistance to two other antipsychotic medications, and is the only treatment likely to result in improvement if two (or one<ref name = "Kahn_2018" />) other antipsychotic has not had a satisfactory effect.<ref name="Hasan_2012" /><ref name="Buchanan_2010" /><ref name="Gaebel_2005" /><ref name="Kuipers_2014" /><ref name="Howes_2017" /><ref name="Galletly_2016" /><ref>Template:Cite journal</ref> Long term follow-up studies from Finland show significant improvements in terms of overall mortality including from suicide and all causes.<ref name="Taipale_2020"/> Clozapine is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> It is available as a generic medication.<ref name="AHFS2015" /> Common adverse effects include drowsiness, constipation, hypersalivation (increased saliva production), tachycardia, low blood pressure, blurred vision, significant weight gain, and dizziness.<ref name="AHFS2015" /> Clozapine is not normally associated with tardive dyskinesia (TD) and is recommended as the drug of choice when this is present, although some case reports describe clozapine-induced TD.<ref>Template:Cite journal</ref> Serious adverse effects include agranulocytosis, seizures, myocarditis (inflammation of the heart), and hyperglycemia (high blood glucose levels). The use of clozapine may result rarely in clozapine-induced, gastric hypomotility syndrome, which may lead to bowel obstruction and death.<ref name="Hart2012">Template:Cite journal</ref><ref name="FDA2020">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The mechanism of action is not clear.<ref name="AHFS2015" />

Medical uses

Schizophrenia

The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark multicenter double blind study<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> in which clozapine (up to 900 mg/d) showed marked benefits compared to chlorpromazine (up to 1800 mg/d) in a group of patients with protracted psychosis who had already shown an inadequate response to at least three previous antipsychotics including a prior single blind trial of haloperidol (mean 61+/− 14 mg/d for six weeks).<ref name="Kane_1988" /> While there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response. The use of clozapine is associated with multiple improved outcomes, including a reduced rate of all-cause mortality, suicide and hospitalization.<ref name="Taipale_2020" /><ref name="Masuda_2019" /><ref name="NIHR Evidence_2019">Template:Cite journal</ref> In a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs.<ref name="Lancet2013">Template:Cite journal</ref> In a 2021 UK study, the majority of patients (over 85% of respondents) who took clozapine preferred it to their previous therapies, felt better on it and wanted to keep taking it.<ref name="Taylor_2000" /> In a 2000 Canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness.<ref name="Waserman 666–668" />Template:Unreliable medical source UK studies into the perspectives of people taking clozapine and their families following treatment with and discontinuation of clozapine describe significant stress and fearfulness of clozapine being stopped.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Clozapine is usually used for people diagnosed with schizophrenia who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. The US FDA authorisation also includes clozapine for the treatment of people exhibiting suicidal behaviour who have schizophrenia or schizoaffective disorder.<ref name="CDER" /> It is also used for the treatment of psychosis in Parkinson's disease.<ref name="medicines.org.uk">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="National Institute for Health and Care Excellence (Great Britain)">Template:Cite book</ref> It is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, supported by systematic reviews and meta-analysis.<ref name="Hasan_2012">Template:Cite journal</ref><ref name="Buchanan_2010">Template:Cite journal</ref><ref name="Gaebel_2005">Template:Cite journal</ref><ref name="Kuipers_2014">Template:Cite journal</ref><ref name="Howes_2017">Template:Cite journal</ref><ref name="Galletly_2016">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> While the guidelines reserve clozapine for individuals in whom two other antipsychotics have already been tried, evidence indicates that clozapine might instead be used as a second-line medication.<ref name="Kahn_2018">Template:Cite journal</ref> Clozapine treatment has been demonstrated to produce improved outcomes in multiple domains including; a reduced risk of hospitalisation, a reduced risk of drug discontinuation, a reduction in overall symptoms and has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia.<ref name="Masuda_2019">Template:Cite journal</ref><ref name="NIHR Evidence_2019" /><ref name=":9">Template:Cite journal</ref><ref name=":10">Template:Cite journal</ref> Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics.<ref>Template:Cite journal</ref> Very long term follow-up studies reveal multiple benefits in terms of reduced mortality,<ref name="Taipale_2020">Template:Cite journal</ref><ref>Template:Cite journal</ref> with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of suicide or attempted suicide.<ref>Template:Cite journal</ref> Clozapine has a significant anti-aggressive effect.<ref name="Brown_2014" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Clozapine is widely used in secure and forensic mental health settings where improvements in aggression, shortened admission and reductions in restrictive practice such as seclusion have been found.<ref>Template:Cite journal</ref><ref name="Silva 231–239" /><ref name="Clozapine rechallenge and initiatio">Template:Cite journal</ref><ref name="Till_2019" /><ref name="FISHER 7–15" /><ref name="Kasinathan" /><ref>Template:Cite journal</ref><ref name="Silva 20451253211015070" /><ref>Template:Cite journal</ref> In secure hospitals and other settings clozapine has also been used in the treatment of borderline and antisocial personality disorder when this has been associated with violence or self-harm.<ref name="Swinton_2001" /><ref name="Haw_2011" /><ref name="Brown_2014">Template:Cite journal</ref> Although oral treatment is almost universal clozapine has on occasion been enforced using either nasogastric or a short acting injection although in almost 50% of the approximately 100 reported cases patients agreed to take oral medication prior to the use of a coercive intervention.<ref name="Silva 231–239">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Till_2019">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Kasinathan">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="FISHER 7–15">Template:Cite journal</ref><ref>Template:Cite journal</ref> Clozapine has also been used off-label to treat catatonia with success in over 80% of cases.<ref>Template:Cite journal</ref>

Bipolar disorder

On the basis of systematic reviews clozapine is recommended in some treatment guidelines as a third or fourth line treatment for bipolar disorder.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> A long term follow-up study showed efficacy in terms of both psychiatric and somatic hospitialisation, but with bipolar disorder this effect was not as strong as with some other treatments (olanzapine long-acting injection (LAI) (aHR = 0.54, 95% CI 0.37–0.80), haloperidol LAI (aHR = 0.62, 0.47–0.81), zuclopenthixol LAI (aHR = 0.66, 95% CI 0.52–0.85), lithium (aHR = 0.74, 95% CI 0.71–0.76) and clozapine (aHR = 0.75, 95% CI 0.64–0.87)).<ref>Template:Cite journal</ref> Bipolar disorder is an off-label indication for clozapine.<ref name="CDER" />

Initiation

Whilst clozapine is usually initiated in hospital setting community initiation is also available.<ref>Template:Cite journal</ref><ref name="Beck_2014">Template:Cite journal</ref> Before clozapine can be initiated multiple assessments and baseline investigations are performed. In the UK and Ireland there must be an assessment that the patient satisfies the criteria for prescription; treatment resistant schizophrenia, intolerance due to extrapyramidal symptoms of other antipsychotics or psychosis in Parkinson's disease. Establishing a history of treatment resistance may include careful review of the medication history including the durations, doses and compliance of previous antipsychotic therapy and that these did not have an adequate clinical effect. A diagnostic review may also be performed. That could include review of antipsychotic plasma concentrations if available. The prescriber, patient, pharmacy and the laboratory performing blood counts are all registered with a specified clozapine provider who must be advised that there is no history of neutropenia from any cause. The clozapine providers collaborate by sharing information regarding patients who have had clozapine related neutropenia or agranulocytosis so that clozapine cannot be used again on license. Clozapine may only be dispensed after a satisfactory blood result has been received by the risk monitoring agency at which point an individual prescription may be released to an individual patient only.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Baseline tests usually also include; a physical examination including baseline weight, waist circumference and BMI, assessments of renal function and liver function, an ECG and other baseline bloods may also be taken to facilitate monitoring of possible myocarditis, these might include C reactive protein (CRP) and troponin. In Australia and New Zealand pre-clozapine echocardiograms are also commonly performed.<ref name="Taylor_2019">Template:Cite book</ref> A number of service protocols are available and there are variations in the extent of pre-clozapine work ups. Some might also include fasting lipids, HbA1c and prolactin. At the Maudsley Hospital in the UK the Treat service also routinely performs a wide variety of other investigations including multiple investigations for other causes of psychosis and comorbidities including; MRI brain imaging, thyroid function tests, B12, folate and serum calcium levels, infection screening for blood borne viruses including Hepatitis B and C, HIV and syphilis as well as screening for autoimmune psychosis by anti-NMDA, anti-VGKC and Anti-nuclear antibody screening. Investigations used to monitor the possibility of clozapine related side effects such as myocarditis are also performed including baseline troponin, CRP and BNP, and for neuroleptic malignant syndrome, a CK level may also be drawn.<ref name="Beck_2014" />

Other clozapine initiation schedules exist. In 2023 the Treatment Response and Resistance in Psychosis Working Group published consensus guidelines on clozapine optimisation including initiation.<ref>Template:Cite journal</ref> The Team Daniel (Dr Laitman's regimen) includes a much slower than usual titration (25 mg increments per week rather than per day) combined with the prescription of a variety of other medications to manage side effects such as nausea, hypersalivation, acid reflux, tachycardia, nocturnal enuresis, metformin and lamotrigine.

The dose of clozapine is initially low and gradually increased over a number of weeks. Initial doses may range from 6.5 to 12.5 mg/d, increasing stepwise typically, to doses in the range of 250–350 mg per day, at which point an assessment of response will be performed.<ref name="Taylor_2019" /> In the UK, the average clozapine dose is 450 mg/d.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> But response is highly variable and some patients respond at much lower doses, and vice versa. A genome wide association study from the MRC Centre for Neuropsychiatric Genetics and Genomics in Cardiff, UK has shown significant interethnic variation in clozapine metabolism due to variation in the frequency of CYP alleles involved in clozapine metabolism such as UGT1A and CYP1A1/1A2. This found faster average clozapine metabolism in people of sub-Saharan African ancestry than in those of European ancestry and that individuals with east Asian or southwest Asian ancestry were more likely to be slow clozapine metabolisers than those with European ancestry.<ref>Template:Cite journal</ref>

Clozapine response and treatment optimization

As with other antipsychotics, and in contrast to received wisdom, responses to clozapine are typically seen soon after initiation and often within the first week.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> That said responses, especially those which are partial, can be delayed.<ref>Template:Cite book</ref> Quite what an adequate trial of clozapine is, is uncertain, but a recommendation is that this should be for at least 8 weeks on a plasma trough level above 350-400 micro g/L.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> There is considerable inter-individual variation. A significant number of patients respond at lower and also much higher plasma concentrations and some patients, especially young male smokers may never achieve these plasma levels even at doses of 900 mg/day. Options then include either increasing the dose above the licensed maximum or the addition of a drug that inhibits clozapine metabolism. Avoiding unnecessary polypharmacy is a general principle in drug treatment. However, what constitutes "unnecessary" is important, because antipsychotics are associated with metabolic syndrome and a corresponding increased risk of type 2 diabetes and atherosclerotic cardiovascular disease, especially with long-term treatment. Polypharmacy with metformin, along with statins and ACE inhibitors, have the potential to significantly attenuate this risk.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> However, statins may increase blood glucose levels themselves, therefore necessitating polypharmacy with metformin whenever a statin is initiated. Together, this combination may have the potential to negate the negative metabolic and cardiovascular effects associated with antipsychotics, but further research is needed.<ref>Template:Cite journal</ref>

Optimizing blood sampling

The neutrophil cut off for clozapine have shown an exceptional ability to mitigate the risk of neutropenia and agranulocytosis. There is a significant margin of safety. Some patients may have marginal neutrophil counts before and after initiation and they are at risk of premature clozapine discontinuation. A knowledge of neutrophil biology allows blood sampling optimisation. Neutrophils show a diurnal variation in response to the natural cycle of G-CSF production, they are increased in the afternoons, they are also mobilised into the circulation after exercise and smoking. Simply shifting blood sampling has been shown to avoid unnecessary discontinuations, especially in black populations. However this is a disruption to usual hospital practice. Other practical steps are to ensure that blood results become available in hours and when senior staff are available.<ref name="Clozapine rechallenge and initiatio" />

Benign ethnic neutropenia

Benign reductions in neutrophils are observed in individuals of all ethnic backgrounds. Ethnic neutropenia (BEN), neutropenia without immune dysfunction or increased liability to infection, is not due to abnormal neutrophil production; although, the exact aetiology of the reduction in circulating cells remains unknown. BEN is associated with several ethnic groups, but in particular those with Black African and West African ancestry.<ref>Template:Cite journal</ref> A difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations.<ref>Template:Cite journal</ref> For significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use, as the thresholds did not take BEN into account. Since 2002, clozapine monitoring services in the UK have used reference ranges 0.5 × 10⁹/l lower for patients with haematologically confirmed BEN and similar adjustments are available in the current US criteria, although with lower permissible minima.<ref name="Silva 20451253211015070">Template:Cite journal</ref><ref name="Nielsen_2016">Template:Cite journal</ref><ref>Template:Cite journal</ref> But even then significant numbers of black patients will not be eligible even though the low neutrophil counts do not in their case reflect disease. The Duffy–Null polymorphism, which protects against some types of malaria, is predictive of BEN.<ref>Template:Cite journal</ref><ref name="tandfonline.com">Template:Cite journal</ref> In the UK the Royal College of Psychiatrists recommends consideration of Duffy typing when using or considering clozapine for people with Black or Middle Eastern ancestry, in the UK this can be requested from the International Blood Group Reference laboratory based in Bristol.<ref name="tandfonline.com"/>

Adverse effects

Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries boxed warnings, including severe neutropenia (low levels of neutrophils); orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting; seizures; myocarditis (inflammation of the heart); and risk of death when used in elderly people with dementia-related psychosis.<ref name="Clozaril FDA label" /> Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.<ref name="MCQ" />

Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, high blood sugar, and weight gain. The risk of developing extrapyramidal symptoms, such as tardive dyskinesia, is below that of typical antipsychotics; this may be due to clozapine's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine.<ref name="MCQ">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Sexual problems, such as retrograde ejaculation and priapism, have been reported while taking clozapine.<ref name="Clozaril FDA label" /> Rare adverse effects include periorbital edema and hematological malignancy.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.<ref>Template:Cite journal</ref>

Mortality

The overall all cause mortality for people with serious psychotic illnesses such as schizophrenia who are prescribed clozapine is lower than those who take other treatments and much lower than those who take no drug treatments at all. Reductions are particularly marked for death by suicide but also from all natural causes. This is demonstrated by studies which have used whole-population databases, such as those completed in Sweden, Finland, Denmark and Taiwan and following systematic review and meta-analysis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Neutropenia and agranulocytosis

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Clozapine use has been associated with neutropenia, and as a result clozapine therapy is typically done with stringent blood monitoring.<ref name="medicines.org.uk" /> However, meta-analysis of controlled trial data fails to show that clozapine has a stronger association with neutropenia than other antipsychotic medications, or to find a difference in rates of agranulocytosis before and after 1990 (at which point mandatory monitoring was introduced).<ref>Template:Cite journal</ref><ref name="A meta-analysis of controlled studi">Template:Cite journal</ref> Overall, despite the concerns relating to blood and other side effects, clozapine use is associated with a reduced mortality, especially from suicide which is a major cause of premature death in people with schizophrenia.<ref>Template:Cite journal</ref> The risk of clozapine related agranulocytosis and neutropenia warranted the mandatory use of stringent risk monitoring and management systems, which have reduced the risk of death from these adverse events to around 1 in 7,700.<ref name="Li_2020" /> The association between clozapine use and specific blood dyscrasias was first noted in the 1970s when eight deaths from agranulocytosis were noted in Finland.<ref name="Griffith_1975" /> At the time it was not clear if this exceeded the established rate of this side effect which is also found in other antipsychotics and although the drug was not completely withdrawn, its use became limited.<ref name="Crilly_2007" />

Clozapine Induced Neutropenia (CIN) occurs in approximately 3.8% of cases and Clozapine Induced Agranulocytosis (CIA) in 0.4%.<ref name="Myles_2018" /> These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory absolute neutrophil count (ANC) monitoring (neutrophils are the most abundant of the granulocytes); for example, in the United States, the Risk Evaluation and Mitigation Strategy (REMS).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The exact schedules and blood count thresholds vary internationally<ref name="Nielsen_2016" /> and the thresholds at which clozapine can be used in the U.S. has been lower than those currently used in the U.K. and Australasia for some time.<ref>Template:Cite journal</ref> The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7700 patients treated.<ref name="Li_2020" /> Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks.<ref name="Myles_2018" /> After one year of treatment these risks reduce markedly to that seen in other antipsychotic drugs 0.01% or about 1 in 10,000 and the risk of death is markedly lower still.<ref name="Li_2020" /> When reductions in neutrophil levels are noted on regular blood monitoring then, depending on the value, monitoring may be increased or, if the neutrophil count is sufficiently low, then clozapine is stopped immediately and can then no longer be used within the medicinal licence. Stopping clozapine almost always results in resolution of the neutrophil reduction.<ref name="Myles_2018">Template:Cite journal</ref><ref name="Li_2020">Template:Cite journal</ref> However severe agranulocytosis can result in spontaneous infection and death, is a severe decrease in the amount of a specific kind of white blood cell called granulocytes. Clozapine carries a black box warning for drug-induced agranulocytosis, although meta-analysis of controlled studies comparing the association between clozapine and other antipsychotic medications and the development of neutropenia fails to show a specific clozapine related risk, which is contrary to the previously accepted beliefs.<ref name="A meta-analysis of controlled studi"/> Rapid point-of-care tests may simplify the monitoring for agranulocytosis.<ref name="pmid31692521">Template:Cite journal</ref>

Pharmacogenetics and Mechanism of Clozapine Related Blood Dyscrasias

CIA is a type B idiosyncratic adverse drug reaction (ADR). It is unrelated to the mode of therapeutic action, and there is no evidence that it is dose dependent and is one of many non-chemotherapy drugs with the potential to induce an idiosyncratic drug-induced agranulocytosis (IDIN). The mechanisms of CIA have not been fully elucidated but are thought to involve a combination of toxic, immunological and genetic factors, combined with oxidised drug metabolites and HLA-activating T helper cells, which induce B cells to produce drug-dependent neutrophil antibodies.<ref name="Non-chemotherapy drug-induced neutr">Template:Cite journal</ref> Severe life-threatening CIA has a distinctive pattern, with a continuous and rapid fall to zero or near-zero ANC within 2–15 days, followed by a prolonged nadir of a similar duration.<ref name="Distinctive pattern of neutrophil c">Template:Cite journal</ref> Genetic linkage studies have identified specific HLA types and transporter genes as conferring increased risk, but the pharmacogenetics has not yet progressed so as to make testing sufficiently predictive to be used clinically, and the identified genetic risk factors are not generalisable across ethnic groups.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Overall, IDINs now have a mortality estimated at 5%; this is a marked improvement compared with previous levels, owing to early recognition and the introduction of hematopoietic growth factors such as G-CSF (granulocyte colony stimulating factor).

Clozapine-induced neutropenia (CIN) and CIA are often regarded as synonymous, with the belief that CIN is a precursor to the more serious dyscrasia. However, there is little if any evidence to support this idea. Instead, it seems that the two are distinct, with most cases of CIN being incidental findings and artefacts of increased blood monitoring.<ref name="Understanding clozapine-related blo">Template:Cite journal</ref>

International Variation and Cost effectiveness of Monitoring

There is very significant international variation in the frequency of full blood count (for neutrophil counts) monitoring including both the thresholds for increased monitoring and for clozapine withdrawal as well as the duration and frequency of blood testing. The most extreme variation is between Iceland, where clozapine is given without full blood monitoring, and with no demonstrable increase in risk and Japan, where the thresholds and frequency is highest. Likewise there are differences between the US thresholds and those in the UK. The US and UK thresholds for clozapine monitoring were identical until 2015, at which point the US Food and Drug Administration (FDA) approved a reduction of 0.5 × 10⁻⁹/L for each ANC range and removed the requirement for white blood cell, eosinophil and platelet monitoring completely. The frequency used in many parts of mainland Europe and the reduced US thresholds and alternate, extended intervals in monitoring used in the Netherlands have had no demonstrable increase in risk.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Understanding clozapine-related blo"/> The rationale for monitoring after the first 18 weeks of treatment is questionable, given that monthly blood sampling is highly unlikely to detect the sudden and profound falls in ANC that accompany agranulocytosis<ref name="Distinctive pattern of neutrophil c"/> and the economic analysis of the cost effectiveness of the current clozapine monitoring schedules shows that these are of highly questionable utility.<ref>Template:Cite journal</ref> Similarly several other drugs, for example carbimazole, which is commonly used in medical practice and with very similar risks of agranulocytosis is used without mandatory FBC monitoring.<ref name="Non-chemotherapy drug-induced neutr"/><ref>Template:Cite journal</ref>

Clozapine rechallenge

A clozapine "rechallenge" is when someone that experienced agranulocytosis while taking clozapine starts taking the medication again. In countries in which the neutrophil thresholds are higher than those used in the US a simple approach is, if the lowest ANC had been above the US cut off, to reintroduce clozapine but with the US monitoring regime. This has been demonstrated in a large cohort of patients in a hospital in London in which it was found that of 115 patients who had had clozapine stopped according to the US criteria only 7 would have had clozapine stopped if the US cut offs had been used. Of these 62 were rechallenged, 59 continued to use clozapine without difficulty and only 1 had a fall in neutrophils below the US cut off.<ref name="There Is Life After the UK Clozapin" /> Other approaches have included the use of other drugs to support neutrophil counts including lithium or granulocyte colony-stimulating factor (G-CSF). However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited.<ref name="Myles">Template:Cite journal</ref><ref name="LallyJ">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Cardiac toxicity

Clozapine can rarely cause myocarditis and cardiomyopathy. A large meta-analysis of clozapine exposure to over 250,000 people revealed that these occurred in approximately 7 in 1000 patients treated and resulted in death in 3 and 4 in 10,000 patients exposed respectively and although myocarditis occurred almost exclusively within the first 8 weeks of treatment, cardiomyopathy can occur much later on.<ref>Template:Cite journal</ref> First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever, and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness.<ref>Template:Cite journal</ref> Signs of heart failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate.<ref>Template:Cite journal</ref> A large electronic health register study has revealed that nearly 90% of cases of suspected clozapine related myocarditis are false positives.<ref>Template:Cite journal</ref> Rechallenge after clozapine induced myocarditis has been performed and a protocol for this specialist approach has been published.<ref>Template:Cite journal</ref> A systematic review of rechallenge after myocarditis has shown success in over 60% of reported cases.<ref>Template:Cite journal</ref>

Gastrointestinal hypomotility

Another underrecognized and potentially life-threatening effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.<ref>Template:Cite journal</ref> Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers.<ref>Template:Cite journal</ref> Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis.<ref>Template:Cite journal</ref> A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication.<ref>Template:Cite journal</ref> Monitoring bowel function and the preemptive use of laxatives for all clozapine-treated people has been shown to improve colonic transit times and reduce serious sequelae.<ref>Template:Cite journal</ref>

Hypersalivation

Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30–80%).<ref name="Syed Cochrane 2008" /> The saliva production is especially bothersome at night and first thing in the morning, as the immobility of sleep precludes the normal clearance of saliva by swallowing that occurs throughout the day.<ref name="Syed Cochrane 2008" /> While clozapine is a muscarinic antagonist at the M₁, M₂, M₃, and M₅ receptors, clozapine is a full agonist at the M₄ subset. Because M₄ is highly expressed in the salivary gland, its M₄ agonist activity is thought to be responsible for hypersalivation.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication.<ref name="Syed Cochrane 2008" /> Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically absorbed anticholinergic medications such as hyoscine,<ref>Template:Cite journal</ref> diphenhydramine<ref name="Syed Cochrane 2008">Template:Cite journal</ref> and topical anticholinergic medications like ipratropium bromide.<ref name="Bird et al 2011 Review" /> Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.<ref name="Bird et al 2011 Review">Template:Cite journal</ref>

Central nervous system

CNS side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. Rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paresthesia, status epilepticus, and obsessive compulsive symptoms. Similar to other antipsychotics, clozapine rarely has been known to cause neuroleptic malignant syndrome.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Urinary incontinence

Clozapine is linked to urinary incontinence,<ref name="Raja">Template:Cite journal</ref> though its appearance may be under-recognized.<ref>Template:Cite journal</ref> This side-effect may be amendable to bethanechol.<ref>Dadlani N, Austin M. Bethanechol and Aripiprazole for the management of refractory urinary incontinence in a patient on Clozapine. Aust N Z J Psychiatry. 2016 Feb;50(2):182. doi: 10.1177/0004867415583878. Epub 2015 Apr 28. PMID 25922356.</ref>

Withdrawal effects

Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation.<ref>Template:Cite journal</ref> Abrupt withdrawal can also cause severe movement disorders, catatonia, and psychosis.<ref>Template:Cite journal</ref> Doctors have recommended that patients, families, and caregivers be made aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.<ref name="Ahmed-1998">Template:Cite journal</ref><ref name="Szafrański-">Template:Cite journal</ref>

Weight gain and diabetes

In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.<ref>Template:Cite journal</ref> Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.<ref name="pmid17848919">Template:Cite journal</ref> For people who gain weight because of clozapine, taking metformin may reportedly improve three of the five components of the metabolic syndrome: waist circumference, fasting glucose, and fasting triglycerides.<ref>Template:Cite journal</ref>

Pneumonia

International adverse drug effect databases indicate that clozapine use is associated with a significantly increased incidence of and death from pneumonia and this may be one of the most significant adverse events.<ref>Template:Cite journal</ref> The mechanisms for this are unknown although it has been speculated that it may be related to hypersalivation or the immune effects of clozapine's effects on the resolution of inflammation.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Overdose

Template:Expand section Symptoms of overdose can be variable, but often include; sedation, confusion, tachycardia, seizures and ataxia. Fatalities have been reported due to clozapine overdose, though overdoses of greater than 5000 mg have been survived.<ref name="Keck et al">Template:Cite journal</ref><ref name="pmid9754851">Template:Cite journal</ref>

Drug interactions

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.<ref>Template:Cite journal</ref>

When carbamazepine is concurrently used with clozapine, it has been shown to decrease plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Patients should be monitored for "decreased therapeutic effects of clozapine if carbamazepine" is started or increased. If carbamazepine is discontinued or the dose of carbamazepine is decreased, therapeutic effects of clozapine should be monitored. The study recommends carbamazepine to not be used concurrently with clozapine due to increased risk of agranulocytosis.<ref>Template:Cite journal</ref>

Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate. Randomized study reported elevation in clozapine concentration in subjects concurrently taking ciprofloxacin.<ref>Template:Cite journal</ref> Thus, the prescribing information for clozapine recommends "reducing the dose of clozapine by one-third of original dose" when ciprofloxacin and other CYP1A2 inhibitors are added to therapy, but once ciprofloxacin is removed from therapy, it is recommended to return clozapine to original dose.<ref>Prescribing information. Clozaril (clozapine). East Hanover, NJ: Novartis Pharmaceuticals Corporation, September 2014.</ref>

Smoking induces CYP1A2 enzyme activity, which accelerates the metabolism of clozapine and reduces its plasma concentrations. Smoking on average reduced the concentration by 30%, but some people may see as much as a 50% reduction.<ref>Template:Cite journal</ref>

The FDA warns that caution should be used when combining clozapine with drugs that depress the central nervous system (alcohol, benzodiazepines, and opioids)<ref name=":0">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> As using these drugs together can lead to a potentially life threatening complication known as Respiratory depression.

Pharmacology

Pharmacodynamics

Template:Nowrap<ref name="PDSP" /><ref name="PDSP-2" />

Site	Template:Abbr Ki (Template:Abbr)	Template:Abbrlink Ki
5-HT1A	123.7	13.9
5-HT1B	519	406.8
5-HT1D	1,356	476.2
5-HT2A	5.35	10.9
5-HT2B	8.37	2.8
5HT4	9.44	11.9
α1A	1.62	104.8
α1B	7	85.2
α2A	37	137.6
α2B	26.5	95.1
α2C	6	117.7
β1	5,000	6,239
β2	1,650	4,725
D1	266.25	14.3
D2	157	101.4
D3	269.08	193.5
D4	26.36	63.94
D5	255.33	283.6
H1	1.13	3.4
H2	153	345.1
H3	1	1
H4	6	1
M1	6.17	67.6
M2	36.67	414.5
M3	19.25	95.7
M4	15.33	169.9
M5	15.5	35.4
Template:Abbrlink	1624	316.6
Template:Abbrlink	3168	493.9
Template:Abbrlink	>10000	>10000
The smaller the value, the more strongly the drug binds to the site. All data are for cloned human proteins.<ref name="PDSP">{{#invoke:citation/CS1|citation			CitationClass=web }}</ref><ref name="PDSP-2">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.<ref name="Nahgre01">Template:Cite journal</ref> It acts as an antagonist at both receptors.

Clozapine is an inverse agonist at the 5-HT_2A subtype of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A direct interaction of clozapine with the GABA_B receptor has also been shown.<ref name="WUY">Template:Cite journal</ref> GABA_B receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.<ref name="VCM">Template:Cite journal</ref> GABA_B receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.<ref name="WJM">Template:Cite journal</ref>

Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,<ref name="TAS">Template:Cite journal</ref> and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.<ref name="XID">Template:Cite journal</ref>

Pharmacokinetics

File:Desmethylclozapine.svg

N-desmethylclozapine (norclozapine), clozapine's major active metabolite.

The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. However, it was shown that co-administration of food decreases the rate of absorption.<ref>Template:Cite journal</ref> The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).Template:Medical citation needed

Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and feces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g., cigarette smoke) or inhibit (e.g., theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.<ref name="ReferenceA" />

Clozapine and norclozapine (desmethyl-clozapine) plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age.<ref>Template:Cite journal</ref> Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimisation.<ref name="ReferenceA">Template:Cite journal</ref>

Chemistry

Clozapine is a dibenzodiazepine<ref name="Nahgre01" /><ref>Template:Cite journal</ref> that is structurally very similar to loxapine (originally deemed a typical antipsychotic). It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C).<ref name="Hopfinger" /> Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

History

Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine.<ref name="Crilly_2007" /><ref name="Ellenbroek2012">Template:Cite book</ref> The first test in humans in 1962 was considered a failure. Trials in Germany in 1965 and 1966 as well as a trial in Vienna in 1966 were successful. In 1967, Wander AG was acquired by Sandoz.<ref name="Crilly_2007" /> Further trials took place in 1972 when clozapine was released in Switzerland and Austria as Leponex.<ref name="Crilly_2007" /> Two years later, it was released in West Germany and in Finland in 1975.<ref name="Crilly_2007" /> Early testing was performed in the United States around the same time.<ref name="Crilly_2007" /> In 1975, 16 cases of agranulocytosis leading to 8 deaths in clozapine-treated patients, reported from 6 hospitals mostly in southwestern Finland, led to concern.<ref>Template:Cite journal</ref> Analysis of the Finnish cases revealed that all the agranulocytosis cases had occurred within the first 18 weeks of treatment and the authors proposed blood monitoring during this period.<ref>Template:Cite journal</ref> The rate of agranulocytosis in Finland appeared to be 20 times higher than in the rest of the world and there was speculation that this may have been due a unique genetic variant in the region.<ref name="Griffith_1975">Template:Cite journal</ref><ref name="Legge2019">Template:Cite journal</ref><ref name="deWith2017">Template:Cite journal</ref> Whilst the drug continued to be manufactured by Sandoz, and remained available in Europe, development in the U.S. halted.

Interest in clozapine continued in an investigational capacity in the United States because, even in the 1980s, the duration of hospitalization, especially in state hospitals for those with treatment resistant schizophrenia, might often be measured in years rather than days.<ref name="Crilly_2007">Template:Cite journal</ref> The role of clozapine in treatment-resistant schizophrenia was established by the landmark Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. This involved both stringent blood monitoring and a double-blind design with the power to demonstrate superiority over standard antipsychotic treatment. The inclusion criteria were patients who had failed to respond to at least three previous antipsychotics and had then not responded to a single blind treatment with haloperidol (mean dose 61 mg +/− 14 mg/d). Two hundred and sixty-eight were randomised were to double blind trials of clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d). 30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas.<ref name="Kane_1988">Template:Cite journal</ref> Following this study, the US Food and Drug Administration (FDA) approved its use in 1990. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.<ref name="deWith2017" /><ref>Template:Cite book</ref>

In December 2002, clozapine was approved in the US for people with schizophrenia or schizoaffective disorder judged to be at chronic risk for suicidal behavior.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2005, the FDA approved criteria to allow reduced blood monitoring frequency.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared patient registry called The Clozapine Risk Evaluation and Mitigation Strategy (REMS) Registry.<ref>Template:Cite news</ref> As of 24 February 2025, the FDA no longer requires participation in the Clozapine REMS, but blood monitoring is still recommended.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:Dead linkTemplate:Cbignore</ref> Despite the demonstrated safety of the 2005 FDA monitoring requirements, which have lower neutrophil levels and do not include total white cell counts, international monitoring has not been standardized.<ref>Template:Cite journal</ref><ref name="Nielsen_2016" /><ref name="There Is Life After the UK Clozapin">Template:Cite journal</ref>

Society and culture

Underuse of clozapine

Clozapine is widely recognised as being underused with wide variation in prescribing,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> especially in patients with African heritage.<ref>Template:Cite journal</ref><ref name="Racial disparities in the use of se">Template:Cite journal</ref><ref name="Racial disparity in the use of atyp">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Psychiatrists' prescribing practices have been found to be the most significant variable regarding variance in its use.Template:Citation needed Surveys of psychiatrists' attitudes to clozapine have found that many had little experience in its use, overestimated the incidence of side effects, and did not appreciate that many patients prefer to take clozapine over other antipsychotics.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In contrast to many psychiatrists' expectations most patients believe that the blood testing and other difficulties are worth the multiple benefits that they perceive.<ref name="Taylor_2000">Template:Cite journal</ref><ref name="Waserman 666–668">Template:Cite journal</ref> Whilst psychiatrists fear the severe adverse effects such as agranulocytosis, patients are more concerned about hypersalivation.<ref>Template:Cite journal</ref> Clozapine is no longer actively marketed and this may also be one of the explanations for its underuse.Template:Cn

Despite the strong evidence and universal endorsement by national and international treatment guidelines and the experiences of patients themselves, most people eligible for clozapine are not treated with it.<ref name="Taylor_2000" /> A large study in England found that approximately 30% of those eligible for clozapine were being treated with it.<ref>Template:Cite journal</ref> Those patients that do start clozapine usually face prolonged delay, multiple episodes of psychosis and treatments such as high dose antipsychotics or polypharmacy. Instead of two previous antipsychotics many will have been exposed to ten or more drugs which were not effective. A study of 120 patients conducted in four hospitals in South-East London found a mean of 9.2 episodes of antipsychotic prescription before clozapine was initiated and the mean delay in using clozapine was 5 years.<ref>Template:Cite journal</ref> Treatments that have no evidence base or are regarded as actively harmful are used instead.<ref>Template:Cite journal</ref>

As well as variation within counties there is massive variation in the use of clozapine internationally. An international study of 17 counties found greatest use in Finland (189/100,000 persons) and New Zealand (116/100,000), and least in the Japanese cohort (0.6/100,000) and in the privately insured US cohort (14/100,000).<ref>Template:Cite journal</ref>

Racial disparity in the use of clozapine

A general finding in healthcare provision is that minority groups receive inferior treatment; this is a particular finding in the US.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite book</ref><ref>Template:Cite journal</ref> In the US a general finding is that compared to their white peers African American people are less likely to be prescribed the second generation antipsychotics, which are more expensive than alternatives and this was even apparent and especially so for clozapine when comparison was made in the Veterans Affairs medical system and when differences regarding socioeconomic factors were taken into account.<ref name="Racial disparities in the use of se" /><ref name="Racial disparity in the use of atyp" /><ref>Template:Cite journal</ref> As well as being less likely to start clozapine black patients are more likely to stop clozapine, possibly on account of benign ethnic neutropenia.

Economics

Despite the expense of the risk monitoring and management systems required, clozapine use is highly cost effective, with a number of studies suggesting savings of tens of thousands of dollars per patient per year compared to other antipsychotics, as well as advantages regarding improvements in quality of life.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Clozapine is available as a generic medication.<ref name="AHFS2015">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Brand names

List of brand names for clozapine<ref name=brands>{{#invoke:citation/CS1|citation

CitationClass=web }}</ref>
A	Alemoxan, Azaleptine, Azaleptol
C	Cloment, Clonex, Clopin, Clopine, Clopsine, Cloril, Clorilex, Clozamed, Clozapex, Clozapin, Clozapina, Clozapinum, Clozapyl, Clozarem, Clozaril
D	Denzapine, Dicomex
E	Elcrit, Excloza
F	FazaClo, Froidir
I	Ihope
K	Klozapol
L	Lanolept, Lapenax, Leponex, Lodux, Lozapine, Lozatric, Luften
M	Medazepine, Mezapin
N	Nemea, Nirva
O	Ozadep, Ozapim
R	Refract, Refraxol
S	Sanosen, Schizonex, Sensipin, Sequax, Sicozapina, Sizoril, Syclop, Syzopin
T	Tanyl
U	Uspen
V	Versacloz
X	Xenopal
Z	Zaclo, Zapenia, Zapine, Zaponex, Zaporil, Ziproc, Zopin

Research

Severe personality disorders

Clozapine is also used in borderline personality disorder and a randomized controlled trial is underway.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Haw_2011">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Swinton_2001">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Further reading

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