Chemistry:Clozapine

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Short description: Atypical antipsychotic medication
Clozapine
Skeletal formula of clozapine
Stick-and-ball model of the clozapine molecule
Clinical data
Trade namesClozaril, Leponex, Versacloz, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa691001
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, intramuscular injection
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60 to 70%
MetabolismLiver, by several CYP isozymes
Elimination half-life4 to 26 hours (mean value 14.2 hours in steady state conditions)
Excretion80% in metabolized state: 30% biliary and 50% kidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC18H19ClN4
Molar mass326.83 g·mol−1
3D model (JSmol)
Melting point183 °C (361 °F)
Solubility in water0.1889[3]
  (verify)

Clozapine is the first atypical antipsychotic medication to have been discovered. It is usually used in tablet or liquid form 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. It is also used for the treatment of psychosis in Parkinson's disease. In the US it is also licensed for use in patients with recurrent suicidal behaviour associated with schizophrenia or schizoaffective disorder.[4] 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.[5][6][7][8][9][10][11] Compared to other antipsychotic drug treatments, initiating and maintaining clozapine is complex, expensive and time-consuming.[4][12][13] The role of clozapine in treatment-resistant schizophrenia was established by the 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.[14] There are a range of different adverse effects and compulsory blood monitoring is required in most developed countries.[15][16] Whilst there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response, and clozapine use is associated with multiple improved outcomes including all cause mortality, suicide and reduced hospitalisation.[17][18][19][20] In a network comparative meta-analysis of 15 antipsychotic drugs, clozapine was significantly more effective than all other drugs.[21] Surveys of patient satisfaction show preference over other antipsychotics.[22]

Compared to other antipsychotics there is an increased risk of agranulocytosis in the first 18 weeks of treatment; after one year this risk reduces to that found with most other antipsychotics and so its use is reserved for people who have not responded to two other antipsychotics and then only with stringent blood monitoring, although the exact frequency and blood count thresholds used vary by country.[23][4][15] Although it has been assumed that clozapine can also cause neutropenia this is not supported by the best available evidence.[24] The stringent risk monitoring and management systems that have been in place for several decades have resulted in deaths from these complications being extremely rare, in the order of 1 in 7700.[25] It remains the only treatment likely to be effective in treatment-resistant schizophrenia.[26]

Common adverse effects include:[27] agitation; amenorrhoea; arrhythmias; constipation; dizziness; drowsiness; dry mouth; erectile dysfunction; fatigue; galactorrhoea; gynaecomastia; hyperglycaemia; hyperprolactinaemia; hypersalivation; hypotension (dose-related); insomnia; leucopenia; movement disorders; muscle rigidity; neutropenia; parkinsonism; postural hypotension (dose-related); QT interval prolongation; rash; seizure; tremor; urinary retention; vomiting; and increased weight.[28] Uncommon side effects include: agranulocytosis; confusion; embolism and thrombosis; neuroleptic malignant syndrome.[28] Clozapine is not normally associated with tardive dyskinesia (TD)—although some case reports describe clozapine-induced TD—and is recommended as the drug of choice when this is present. Other serious risks include seizures, inflammation of the heart, high blood sugar levels, constipation resulting from clozapine-induced gastric hypomotility syndrome which can be severe and lead to bowel obstruction and death, and in older people with psychosis as a result of dementia, an increased risk of death. Clozapine's mechanism of action is not entirely clear.

It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.

History

Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine.[29][30] 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.[29] Further trials took place in 1972 when clozapine was released in Switzerland and Austria as Leponex.[29] Two years later it was released in West Germany and in Finland in 1975.[29] Early testing was performed in the United States around the same time.[29] 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.[31] 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.[32] 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.[33][34][35] 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 hospitalisation, especially in State Hospitals for those with treatment resistant schizophrenia might often be measured in years rather than days.[29] 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.[14] 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.[35][36]

In December 2002, clozapine was approved in the US for reducing the risk of suicide in people with schizophrenia or schizoaffective judged to be at chronic risk for suicidal behavior.[37] In 2005, the FDA approved criteria to allow reduced blood monitoring frequency.[38] In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared Patient Registry Called The Clozapine REMS Registry.[39] Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and do not include total white cell counts, international monitoring has not been standardised.[40][41][42]

Chemistry

Clozapine is a dibenzodiazepine 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).[3] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).[43]

Clinical uses

Schizophrenia

The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark multicenter double blind study[44] 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).[14] 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.[45][17][18] In a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs.[46] 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.[47] In a 2000 Canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness.[48][unreliable medical source?]

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. It is also used for the treatment of psychosis in Parkinson's Disease.[49][50] 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.[5][6][7][8][9][10][51][52] Whilst all current 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 drug.[53] Clozapine treatment has been demonstrated to produced 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.[17][18][19][20] Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics.[54] Very long term follow-up studies reveal multiple benefits in terms of reduced mortality,[45][55] 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.[56] Clozapine has a significant anti-aggressive effect.[57][58][59][60][61] 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.[62][63][64][65][66][67][68][69][70] 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.[71][72][57] 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.[63][73][65][74][75][76][67][77][66][78] Clozapine has also been used off-label to treat catatonia with success in over 80% of cases.[79]

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.[80][81][82][83] Bipolar disorder is an off-label indication for clozapine.[citation needed]

Severe personality disorders

Clozapine is also used in emotionally unstable personality disorder and a randomised controlled trial is currently underway.[84][85][86][87][72][88][89][71][90] The use of clozapine to treat personality disorder is uncommon and off-label.

Initiation

Whilst clozapine is usually initiated in hospital setting community initiation is also available.[91][92] 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.[93]

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.[94] 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 CK.[92]

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.[94] In the UK the average clozapine dose is 450 mg/d.[95][96] But response is highly variable and some patients respond at much lower doses and vice versa.

Monitoring

During the initial dose titration phase the following are typically monitored, usually daily at first: pulse, blood pressure, and temperature. Since orthostatic hypotension can be problematic, blood pressure should be monitored both sitting and standing. If there is a significant drop then the rate of the dose increase may be slowed.[92]

Mandatory full blood counts are performed weekly for the first 18 weeks. In some services there will also be monitoring of markers that might indicate myocarditis, troponin, CRP and BNP, although the exact tests and frequency vary between services. Weight is usually measured weekly.

Thereon other investigations and monitoring will always include full blood counts (fortnightly for 1 year then monthly). Weight, waist circumference, lipids and glucose or HbA1c may also be monitored.

Clozapine response and treatment optimisation

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.[97][98] That said responses, especially those which are partial, can be delayed.[99] 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.[100][101] 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.

Optimising 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.[64]

Underuse of clozapine

Clozapine is widely recognised as being underused with wide variation in prescribing,[102][103][104][105][106][107][108][109] especially in patients with African heritage.[110][111][112][113][114]

Psychiatrists' prescribing practices have been found to be the most significant variable regarding variance in its use.[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.[115][116][117] In contrast to many psychiatrists' expectations most patients believe that the blood testing and other difficulties are worth the multiple benefits that they perceive.[47][48] Whilst psychiatrists fear the severe adverse effects such as agranulocytosis, patients are more concerned about hypersalivation.[118] Clozapine is no longer actively marketed and this may also be one of the explanations for its underuse.[119]

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.[47] A large study in England found that approximately 30% of those eligible for clozapine were being treated with it.[120] 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.[121] Treatments that have no evidence base or are regarded as actively harmful are used instead.[122]

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.[123][124][125][126] 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.[111][112][127] As well as being less likely to start clozapine black patients are more likely to stop clozapine, possibly on account of benign ethnic neutropenia.

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.[128] A difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations.[129] 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.[69][41][130] 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.[131]

Adverse effects

Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries five black box warnings, including (1) severe neutropenia (low levels of neutrophils), (2) orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting, (3) seizures, (4) myocarditis (inflammation of the heart), and (5) risk of death when used in elderly people with dementia-related psychosis.[2] Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.[132]

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.[132] Sexual problems, such as retrograde ejaculation, have been reported while taking clozapine.[2] Rare adverse effects include periorbital edema.[133] Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.[134]

Neutropenia and agranulocytosis

Clozapine Induced Neutropenia (CIN) occurs in approximately 3.8% of cases and Clozapine Induced Agranulocytosis (CIA) in 0.4%.[135] 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).[136] The exact schedules and blood count thresholds vary internationally[41] 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.[137] 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.[138] Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks.[135] 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.[138] 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.[135][138] 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. Rapid point-of-care tests may simplify the monitoring for agranulocytosis.[139]

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.[42] 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.[140][141]

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.[142] 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.[143] 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.[144] A large electronic health register study has revealed that nearly 90% of cases of suspected clozapine related myocarditis are false positives.[145] Rechallenge after clozapine induced myocarditis has been performed and a protocol for this specialist approach has been published.[146] A systematic review of rechallenge after myocarditis has shown success in over 60% of reported cases.[147]

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.[148] Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers.[149] Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis.[150] A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication.[151] 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.[152]

Hypersalivation

Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30–80%).[153] 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.[153] 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.[154] clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication.[153] 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,[155] diphenhydramine[153] and topical anticholinergic medications like ipratropium bromide.[156] Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.[156]

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.[157]

Urinary incontinence

Clozapine is linked to urinary incontinence,[158] though its appearance may be under-recognized.[159] This side-effect may be amendable to bethanechol.[160]

Withdrawal effects

Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation.[161] Abrupt withdrawal can also cause severe movement disorders, catatonia, and psychosis.[162] 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.[163][164]

Weight gain and diabetes

In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.[165] 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.[166] 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.[167]

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.[168] 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.[169][170]

Overdose

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.[171][172]

Drug interactions

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.[173]

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.[174][175] 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.[176]

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.[177] 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.[178]

Pharmacology

Pharmacodynamics

Clozapine and norclozapine binding[179][180]
Protein CZP Ki (nM) NDMC Ki (nM)
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
5-HT2C 9.44 11.9
5-HT3 241 272.2
5-HT5A 3,857 350.6
5-HT6 13.49 11.6
5-HT7 17.95 60.1
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 >10,000 >10,000
H4 665 1,028
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
SERT 1,624 316.6
NET 3,168 493.9
DAT >10,000 >10,000

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.[181] It acts as an antagonist at both receptors.

Clozapine is an antagonist at the 5-HT2A subtype of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.[182][183]

A direct interaction of clozapine with the GABAB receptor has also been shown.[184] GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.[185] GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.[186]

Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,[187] 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.[188]

Pharmacokinetics

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.[189] The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).

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.[190]

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.[191] 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.[190]

List of trade names for clozapine[1]
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

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.[192][193][194] Clozapine is available as a generic medication.[195]

References

  1. ↑ 1.0 1.1 "Clozapine International Brands". Drugs.com. https://www.drugs.com/international/clozapine.html. 
  2. ↑ 2.0 2.1 2.2 "Clozaril- clozapine tablet". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=90876802-0e3a-44c9-9ff7-1754dfbe736a. 
  3. ↑ 3.0 3.1 "Findings of the challenge to predict aqueous solubility". Journal of Chemical Information and Modeling 49 (1): 1–5. January 2009. doi:10.1021/ci800436c. PMID 19117422. 
  4. ↑ 4.0 4.1 4.2 Research, Center for Drug Evaluation and (2023-09-22). "Information on Clozapine" (in en). FDA. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-clozapine. 
  5. ↑ 5.0 5.1 "World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance". The World Journal of Biological Psychiatry 13 (5): 318–378. July 2012. doi:10.3109/15622975.2012.696143. PMID 22834451. 
  6. ↑ 6.0 6.1 "The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements". Schizophrenia Bulletin 36 (1): 71–93. January 2010. doi:10.1093/schbul/sbp116. PMID 19955390. 
  7. ↑ 7.0 7.1 "Schizophrenia practice guidelines: international survey and comparison". The British Journal of Psychiatry 187 (3): 248–255. September 2005. doi:10.1192/bjp.187.3.248. PMID 16135862. 
  8. ↑ 8.0 8.1 "Management of psychosis and schizophrenia in adults: summary of updated NICE guidance". BMJ 348: g1173. February 2014. doi:10.1136/bmj.g1173. PMID 24523363. http://www.bmj.com/cgi/content/short/348/mar19_4/g2234. 
  9. ↑ 9.0 9.1 "Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology". The American Journal of Psychiatry 174 (3): 216–229. March 2017. doi:10.1176/appi.ajp.2016.16050503. PMID 27919182. 
  10. ↑ 10.0 10.1 "Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders". The Australian and New Zealand Journal of Psychiatry 50 (5): 410–472. May 2016. doi:10.1177/0004867416641195. PMID 27106681. 
  11. ↑ "Guidelines for the Pharmacotherapy of Schizophrenia in Adults". Canadian Journal of Psychiatry 62 (9): 604–616. September 2017. doi:10.1177/0706743717720448. PMID 28703015. 
  12. ↑ Zhang, Mingliang; Owen, R. R.; Pope, S. K.; Smith, G. R. (1996). "Cost-effectiveness of Clozapine Monitoring After the First 6 Months". Archives of General Psychiatry 53 (10): 954–958. doi:10.1001/archpsyc.1996.01830100104013. PMID 8857873. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/497664. Retrieved 2023-12-08. 
  13. ↑ Girardin, François R; Poncet, Antoine; Blondon, Marc; Rollason, Victoria; Vernaz, Nathalie; Chalandon, Yves; Dayer, Pierre; Combescure, Christophe (June 2014). "Monitoring white blood cell count in adult patients with schizophrenia who are taking clozapine: a cost-effectiveness analysis". The Lancet Psychiatry 1 (1): 55–62. doi:10.1016/s2215-0366(14)70245-7. ISSN 2215-0366. PMID 26360402. https://doi.org/10.1016/s2215-0366(14)70245-7. 
  14. ↑ 14.0 14.1 14.2 "Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine". Archives of General Psychiatry 45 (9): 789–796. September 1988. doi:10.1001/archpsyc.1988.01800330013001. PMID 3046553. 
  15. ↑ 15.0 15.1 Oloyede, Ebenezer; Taylor, David; MacCabe, James (2023-06-01). "International Variation in Clozapine Hematologic Monitoring—A Call for Action" (in en). JAMA Psychiatry 80 (6): 535–536. doi:10.1001/jamapsychiatry.2023.0376. ISSN 2168-622X. PMID 37017962. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2803139. 
  16. ↑ "High risk medicines: clozapine - Care Quality Commission". https://www.cqc.org.uk/guidance-providers/adult-social-care/high-risk-medicines-clozapine. 
  17. ↑ 17.0 17.1 17.2 "Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics: A Systematic Review and Meta-analysis of Cohort Studies". JAMA Psychiatry 76 (10): 1052–1062. October 2019. doi:10.1001/jamapsychiatry.2019.1702. PMID 31365048. 
  18. ↑ 18.0 18.1 18.2 "'Last resort' antipsychotic remains the gold standard for treatment-resistant schizophrenia". NIHR Evidence. 2019-10-02. doi:10.3310/signal-000826. https://evidence.nihr.ac.uk/alert/last-resort-antipsychotic-remains-the-gold-standard-for-treatment-resistant-schizophrenia. 
  19. ↑ 19.0 19.1 "Effectiveness of clozapine use in delaying hospitalization in routine clinical practice: a 2 year observational study". Psychopharmacology Bulletin 43 (2): 67–81. 2010. PMID 21052043. 
  20. ↑ 20.0 20.1 "The impact of clozapine initiation and cessation on psychiatric hospital admissions and bed days: a mirror image cohort study". Psychopharmacology 236 (6): 1931–1935. June 2019. doi:10.1007/s00213-019-5179-6. PMID 30715572. https://kclpure.kcl.ac.uk/portal/en/publications/the-impact-of-clozapine-initiation-and-cessation-on-psychiatric-hospital-admissions-and-bed-days(f8558f24-c0c7-4187-a9ca-fce9592341de).html. 
  21. ↑ Leucht, Stefan; Cipriani, Andrea; Spineli, Loukia; Mavridis, Dimitris; Örey, Deniz; Richter, Franziska; Samara, Myrto; Barbui, Corrado et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". The Lancet 382 (9896): 951–962. doi:10.1016/s0140-6736(13)60733-3. ISSN 0140-6736. PMID 23810019. https://doi.org/10.1016/S0140-6736(13)60733-3. 
  22. ↑ Taylor, D.; Shapland, L.; Laverick, G.; Bond, J.; Munro, J. (December 2000). "Clozapine – a survey of patient perceptions" (in en). Psychiatric Bulletin 24 (12): 450–452. doi:10.1192/pb.24.12.450. ISSN 0955-6036. 
  23. ↑ "Clozaril 25 mg Tablets - Summary of Product Characteristics (SmPC) - (emc)". https://www.medicines.org.uk/emc/product/4411/smpc. 
  24. ↑ Myles, N.; Myles, H.; Xia, S.; Large, M.; Kisely, S.; Galletly, C.; Bird, R.; Siskind, D. (2018-05-21). "Meta-analysis examining the epidemiology of clozapine-associated neutropenia". Acta Psychiatrica Scandinavica 138 (2): 101–109. doi:10.1111/acps.12898. ISSN 0001-690X. PMID 29786829. http://dx.doi.org/10.1111/acps.12898. 
  25. ↑ Li, Xiao-Hong; Zhong, Xiao-Mei; Lu, Li; Zheng, Wei; Wang, Shi-bin; Rao, Wen-wang; Wang, Shuai; Ng, Chee H. et al. (March 2020). "The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies" (in en). Psychological Medicine 50 (4): 583–594. doi:10.1017/S0033291719000369. ISSN 0033-2917. PMID 30857568. https://www.cambridge.org/core/journals/psychological-medicine/article/abs/prevalence-of-agranulocytosis-and-related-death-in-clozapinetreated-patients-a-comprehensive-metaanalysis-of-observational-studies/1E2A9A53E6C2D6A3C2D5867332E2E03B. 
  26. ↑ Luykx, Jurjen J.; Stam, Noraly; Tanskanen, Antti; Tiihonen, Jari; Taipale, Heidi (September 2020). "In the aftermath of clozapine discontinuation: comparative effectiveness and safety of antipsychotics in patients with schizophrenia who discontinue clozapine" (in en). The British Journal of Psychiatry 217 (3): 498–505. doi:10.1192/bjp.2019.267. ISSN 0007-1250. PMID 31910911. 
  27. ↑ "Clozaril 25 mg Tablets - Summary of Product Characteristics (SmPC) - (emc)". https://www.medicines.org.uk/emc/product/4411/smpc#gref. 
  28. ↑ 28.0 28.1 "BNF is only available in the UK". https://www.nice.org.uk/bnf-uk-only. 
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 "The history of clozapine and its emergence in the US market: a review and analysis". History of Psychiatry 18 (1): 39–60. March 2007. doi:10.1177/0957154X07070335. PMID 17580753. 
  30. ↑ Atypical Antipsychotics. Birkhäuser. 6 December 2012. ISBN 9783034884488. https://books.google.com/books?id=08kGCAAAQBAJ&pg=PA144. 
  31. ↑ "Letter: Clozapine and agranulocytosis". Lancet 2 (7935): 611. September 1975. doi:10.1016/s0140-6736(75)90206-8. PMID 51442. 
  32. ↑ "Agranulocytosis in patients treated with clozapine. A study of the Finnish epidemic". Acta Psychiatrica Scandinavica 56 (4): 241–248. October 1977. doi:10.1111/j.1600-0447.1977.tb00224.x. PMID 920225. 
  33. ↑ "Letter: Clozapine and agranulocytosis". Lancet 2 (7936): 657. October 1975. doi:10.1016/S0140-6736(75)90135-X. PMID 52022. 
  34. ↑ "Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective". Pharmacogenomics 20 (4): 279–290. March 2019. doi:10.2217/pgs-2018-0188. PMID 30767710. 
  35. ↑ 35.0 35.1 "More than 25 years of genetic studies of clozapine-induced agranulocytosis". The Pharmacogenomics Journal 17 (4): 304–311. July 2017. doi:10.1038/tpj.2017.6. PMID 28418011. 
  36. ↑ The Psychopharmacologists. CRC Press. 8 May 2018. doi:10.1201/9780203736159. ISBN 9780203736159. 
  37. ↑ "Supplemental NDA Approval Letter for Clozaril, NDA 19-758 / S-047". United States Food and Drug Administration. 18 December 2002. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/19758se1-047ltr.pdf. 
  38. ↑ "Letter to Novartis Pharmaceuticals Corporation". http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019758s054ltr.pdf. 
  39. ↑ "FDA Modifies REMS Program for Clozapine". www.raps.org. https://www.raps.org/news-and-articles/news-articles/2019/1/fda-modifies-rems-program-for-clozapine. 
  40. ↑ "Evaluating the Effect of the Changes in FDA Guidelines for Clozapine Monitoring". The Journal of Clinical Psychiatry 78 (8): e933–e939. 2017-10-25. doi:10.4088/jcp.16m11152. PMID 28742291. 
  41. ↑ 41.0 41.1 41.2 "Worldwide Differences in Regulations of Clozapine Use". CNS Drugs 30 (2): 149–161. February 2016. doi:10.1007/s40263-016-0311-1. PMID 26884144. 
  42. ↑ 42.0 42.1 "There Is Life After the UK Clozapine Central Non-Rechallenge Database". Schizophrenia Bulletin 47 (4): 1088–1098. July 2021. doi:10.1093/schbul/sbab006. PMID 33543755. 
  43. ↑ Novartis Pharmaceuticals (April 2006). "Prescribing Information" (PDF). Novartis Pharmaceuticals. pp. 36. http://www.rxlist.com/clozaril-drug.htm. 
  44. ↑ "clozapine (CHEBI:3766)". https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3766. 
  45. ↑ 45.0 45.1 "20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20)". World Psychiatry 19 (1): 61–68. February 2020. doi:10.1002/wps.20699. PMID 31922669. 
  46. ↑ "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–962. September 2013. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
  47. ↑ 47.0 47.1 47.2 "Clozapine – a survey of patient perceptions" (in en). Psychiatric Bulletin 24 (12): 450–452. December 2000. doi:10.1192/pb.24.12.450. ISSN 0955-6036. 
  48. ↑ 48.0 48.1 "Subjective experiences of clozapine treatment by patients with chronic schizophrenia". Psychiatric Services 51 (5): 666–668. May 2000. doi:10.1176/appi.ps.51.5.666. PMID 10783189. 
  49. ↑ "Clozaril 25 mg Tablets - Summary of Product Characteristics (SmPC)". https://www.medicines.org.uk/emc/product/4411/smpc. 
  50. ↑ National Institute for Health and Care Excellence (Great Britain). Parkinson's disease in adults : diagnosis and management : full guideline. OCLC 1105250833. 
  51. ↑ "Clozapine versus typical neuroleptic medication for schizophrenia". The Cochrane Database of Systematic Reviews 2009 (1): CD000059. January 2009. doi:10.1002/14651858.CD000059.pub2. PMID 19160174. 
  52. ↑ "Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis". The British Journal of Psychiatry 209 (5): 385–392. November 2016. doi:10.1192/bjp.bp.115.177261. PMID 27388573. 
  53. ↑ "Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study". The Lancet. Psychiatry 5 (10): 797–807. October 2018. doi:10.1016/S2215-0366(18)30252-9. PMID 30115598. https://kclpure.kcl.ac.uk/portal/en/publications/amisulpride-and-olanzapine-followed-by-openlabel-treatment-with-clozapine-in-firstepisode-schizophrenia-and-schizophreniform-disorder-optimise(e2ac95c9-d392-41b5-9392-6c9bbdfac360).html. 
  54. ↑ "Clozapine maintenance therapy in schizophrenia". Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (3): 465–469. May 2004. doi:10.1016/j.pnpbp.2003.11.011. PMID 15093952. 
  55. ↑ "11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study)". Lancet 374 (9690): 620–627. August 2009. doi:10.1016/S0140-6736(09)60742-X. PMID 19595447. 
  56. ↑ "Comparative Effectiveness of Antipsychotics for Risk of Attempted or Completed Suicide Among Persons With Schizophrenia". Schizophrenia Bulletin 47 (1): 23–30. January 2021. doi:10.1093/schbul/sbaa111. PMID 33428766. 
  57. ↑ 57.0 57.1 "Clozapine: an effective treatment for seriously violent and psychopathic men with antisocial personality disorder in a UK high-security hospital". CNS Spectrums 19 (5): 391–402. October 2014. doi:10.1017/S1092852914000157. PMID 24698103. 
  58. ↑ "Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder". Archives of General Psychiatry 63 (6): 622–629. June 2006. doi:10.1001/archpsyc.63.6.622. PMID 16754835. 
  59. ↑ "Clozapine treatment of long-standing schizophrenia and serious violence: a two-year follow-up study of the first 50 patients treated with clozapine in Rampton high security hospital" (in en). Criminal Behaviour and Mental Health 9 (2): 168–178. June 1999. doi:10.1002/cbm.304. 
  60. ↑ "The pharmacological management of violence in schizophrenia: a structured review". Expert Review of Neurotherapeutics 11 (1): 53–63. January 2011. doi:10.1586/ern.10.180. PMID 21158555. 
  61. ↑ "A systematic review of the evidence of clozapine's anti-aggressive effects". The International Journal of Neuropsychopharmacology 15 (9): 1351–1371. October 2012. doi:10.1017/S146114571100201X. PMID 22339930. 
  62. ↑ "Management of schizophrenia in conditions of high security". Advances in Psychiatric Treatment 6 (4): 252–260. July 2000. doi:10.1192/apt.6.4.252. ISSN 1355-5146. 
  63. ↑ 63.0 63.1 "Ethical dilemmas in psychiatry: When teams disagree". BJPsych Advances 23 (4): 231–239. July 2017. doi:10.1192/apt.bp.116.016147. 
  64. ↑ 64.0 64.1 "Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide". BMC Psychiatry 20 (1): 279. June 2020. doi:10.1186/s12888-020-02592-2. PMID 32503471. 
  65. ↑ 65.0 65.1 "The assertive approach to clozapine: nasogastric administration". BJPsych Bulletin 43 (1): 21–26. February 2019. doi:10.1192/bjb.2018.61. PMID 30223913. 
  66. ↑ 66.0 66.1 "Elements of successful restraint and seclusion reduction programs and their application in a large, urban, state psychiatric hospital". Journal of Psychiatric Practice 9 (1): 7–15. January 2003. doi:10.1097/00131746-200301000-00003. PMID 15985912. 
  67. ↑ 67.0 67.1 "Evaluating the use of enforced clozapine in an Australian forensic psychiatric setting: two cases". BMC Psychiatry 7 (S1): P13. December 2007. doi:10.1186/1471-244x-7-s1-p13. ISSN 1471-244X. 
  68. ↑ "Clozapine in Special Hospital: a retrospective case-control study". The Journal of Forensic Psychiatry 11 (3): 587–596. January 2000. doi:10.1080/09585180010006205. ISSN 0958-5184. 
  69. ↑ 69.0 69.1 "Clozapine re-challenge and initiation following neutropenia: a review and case series of 14 patients in a high-secure forensic hospital". Therapeutic Advances in Psychopharmacology 11: 20451253211015070. 2021-01-01. doi:10.1177/20451253211015070. PMID 34221348. 
  70. ↑ "Schizophrenia, Violence, Clozapine and Risperidone: a Review". British Journal of Psychiatry 169 (S31): 21–30. December 1996. doi:10.1192/s0007125000298589. ISSN 0007-1250. 
  71. ↑ 71.0 71.1 "Clozapine in severe borderline personality disorder" (in en). The Journal of Forensic Psychiatry 12 (3): 580–591. January 2001. doi:10.1080/09585180110091994. ISSN 0958-5184. 
  72. ↑ 72.0 72.1 "Medication for borderline personality disorder: a survey at a secure hospital". International Journal of Psychiatry in Clinical Practice 15 (4): 280–285. November 2011. doi:10.3109/13651501.2011.590211. PMID 22122000. 
  73. ↑ "Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series". BJPsych Bulletin 44 (6): 239–243. December 2020. doi:10.1192/bjb.2020.6. PMID 32081110. 
  74. ↑ "A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis". The British Journal of Psychiatry 217 (3): 506–513. September 2020. doi:10.1192/bjp.2020.115. PMID 32605667. https://orca.cardiff.ac.uk/134637/3/Manuscript%2Brevised3_no-highlight.pdf. 
  75. ↑ "Parenteral clozapine: five years of experience". Journal of Clinical Psychopharmacology 19 (5): 479–480. October 1999. doi:10.1097/00004714-199910000-00018. PMID 10505595. 
  76. ↑ "Compulsory treatment with clozapine: a retrospective long-term cohort study". International Journal of Law and Psychiatry 30 (6): 539–545. November 2007. doi:10.1016/j.ijlp.2007.09.003. PMID 17928054. 
  77. ↑ "Parenteral Clozapine (Clozaril)" (in en). Australasian Psychiatry 9 (4): 371. 2001-12-01. doi:10.1046/j.1440-1665.2001.0367a.x. ISSN 1039-8562. 
  78. ↑ "Conventional and atypical antipsychotics and the evolving standard of care". Psychiatric Services 51 (12): 1528–1535. December 2000. doi:10.1176/appi.ps.51.12.1528. PMID 11097649. 
  79. ↑ "Indications for electroconvulsive treatment in schizophrenia: a systematic review". Schizophrenia Research 146 (1–3): 1–9. May 2013. doi:10.1016/j.schres.2022.09.021. PMID 23499244. 
  80. ↑ "Clozapine for treatment-resistant bipolar disorder: a systematic review". Bipolar Disorders 17 (3): 235–247. May 2015. doi:10.1111/bdi.12272. PMID 25346322. https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1027&context=psychiatry_facpub. 
  81. ↑ "Evidence-based guidelines for treating bipolar disorder: revised second edition--recommendations from the British Association for Psychopharmacology". Journal of Psychopharmacology 23 (4): 346–388. June 2009. doi:10.1177/0269881109102919. PMID 19329543. 
  82. ↑ "NICE guidance: why not clozapine for treatment-refractory bipolar disorder?". The Lancet. Psychiatry 3 (6): 502–503. June 2016. doi:10.1016/s2215-0366(16)30081-5. PMID 27262046. 
  83. ↑ "Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder". Bipolar Disorders 20 (2): 97–170. March 2018. doi:10.1111/bdi.12609. PMID 29536616. 
  84. ↑ "Pharmacological Treatments for Borderline Personality Disorder: A Systematic Review and Meta-Analysis". CNS Drugs 35 (10): 1053–1067. October 2021. doi:10.26226/morressier.59d4913bd462b8029238a351. PMID 34495494. 
  85. ↑ "Clozapine in borderline personality disorder: a review of the evidence". Annals of Clinical Psychiatry 26 (2): 139–144. May 2014. PMID 24812651. 
  86. ↑ "A case series of clozapine for borderline personality disorder". Annals of Clinical Psychiatry 25 (2): 125–134. May 2013. PMID 23638443. 
  87. ↑ "Experiences of women in secure care who have been prescribed clozapine for borderline personality disorder". Borderline Personality Disorder and Emotion Dysregulation 3 (1): 12. 2016-10-07. doi:10.1186/s40479-016-0049-x. PMID 27761261. 
  88. ↑ "Real-World Effectiveness of Clozapine for Borderline Personality Disorder: Results From a 2-Year Mirror-Image Study". Journal of Personality Disorders 32 (6): 823–837. December 2018. doi:10.1521/pedi_2017_31_328. PMID 29120277. 
  89. ↑ "Pharmacotherapy for Borderline Personality Disorder: an Update of Published, Unpublished and Ongoing Studies". Current Psychiatry Reports 22 (8): 37. June 2020. doi:10.1007/s11920-020-01164-1. PMID 32504127. 
  90. ↑ "NIHR Funding and Awards Search Website". https://fundingawards.nihr.ac.uk/award/16/157/02. 
  91. ↑ "Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals". British Medical Bulletin 135 (1): 73–89. October 2020. doi:10.1093/bmb/ldaa024. PMID 32885238. 
  92. ↑ 92.0 92.1 92.2 "The practical management of refractory schizophrenia--the Maudsley Treatment REview and Assessment Team service approach". Acta Psychiatrica Scandinavica 130 (6): 427–438. December 2014. doi:10.1111/acps.12327. PMID 25201058. 
  93. ↑ "Clozaril 25 mg Tablets - Summary of Product Characteristics (SmPC) - (emc)". https://www.medicines.org.uk/emc/product/4411/smpc#gref. 
  94. ↑ 94.0 94.1 The Maudsley prescribing guidelines in psychiatry (13th ed.). Hoboken, NJ. 2019. ISBN 978-1-119-44260-8. OCLC 1029071684. 
  95. ↑ "A prescription survey of the use of atypical antipsychotics for hospital inpatients in the United Kingdom". International Journal of Psychiatry in Clinical Practice 4 (1): 41–46. January 2000. doi:10.1080/13651500052048749. PMID 24927311. 
  96. ↑ "Maintenance doses for clozapine: past and present". BJPsych Bulletin 42 (5): 217. October 2018. doi:10.1192/bjb.2018.64. PMID 30345070. 
  97. ↑ "Time course of improvement with antipsychotic medication in treatment-resistant schizophrenia". The British Journal of Psychiatry 199 (4): 275–280. October 2011. doi:10.1192/bjp.bp.110.083907. PMID 22187729. 
  98. ↑ "Evidence for onset of antipsychotic effects within the first 24 hours of treatment". The American Journal of Psychiatry 162 (5): 939–946. May 2005. doi:10.1176/appi.ajp.162.5.939. PMID 15863796. 
  99. ↑ "Augmenting Clozapine Response in Treatment-Resistant Schizophreni a". Therapy-Resistant Schizophrenia. Advances in Biological Psychiatry. 26. Basel: KARGER. 2010. pp. 129–151. doi:10.1159/000319813. ISBN 978-3-8055-9511-7. 
  100. ↑ "What is an adequate trial with clozapine?: therapeutic drug monitoring and time to response in treatment-refractory schizophrenia". Clinical Pharmacokinetics 42 (7): 607–618. 2003. doi:10.2165/00003088-200342070-00001. PMID 12844323. 
  101. ↑ "Time to clozapine response in a standardized trial". The American Journal of Psychiatry 154 (9): 1243–1247. September 1997. doi:10.1176/ajp.154.9.1243. PMID 9286183. 
  102. ↑ "Underuse of clozapine in treatment-resistant schizophrenia". Advances in Psychiatric Treatment 17 (4): 250–255. July 2011. doi:10.1192/apt.bp.110.008128. ISSN 1355-5146. 
  103. ↑ "Geographic and clinical variation in clozapine use in the United States". Psychiatric Services 65 (2): 186–192. February 2014. doi:10.1176/appi.ps.201300180. PMID 24233347. 
  104. ↑ "Clozapine: national review of postcode prescribing" (in en). Psychiatric Bulletin 31 (10): 384–387. October 2007. doi:10.1192/pb.bp.106.013144. ISSN 0955-6036. 
  105. ↑ "Postcode prescribing in psychiatry". Psychiatric Bulletin 24 (11): 420–422. November 2000. doi:10.1192/pb.24.11.420. ISSN 0955-6036. 
  106. ↑ "Postcode prescribing for schizophrenia". The British Journal of Psychiatry 182 (4): 281–283. April 2003. doi:10.1192/bjp.182.4.281. PMID 12668398. 
  107. ↑ "Geographical and temporal variations in clozapine prescription for schizophrenia". European Neuropsychopharmacology 22 (11): 818–824. November 2012. doi:10.1016/j.euroneuro.2012.03.003. PMID 22503785. 
  108. ↑ "Underprescribing of clozapine and unexplained variation in use across hospitals and regions in the Canadian province of Québec". Clinical Schizophrenia & Related Psychoses 7 (1): 33–41. April 2013. doi:10.3371/csrp.lawy.012513. PMID 23367500. 
  109. ↑ "An evaluation of the variation and underuse of clozapine in the United Kingdom". Acta Psychiatrica Scandinavica 143 (4): 339–347. April 2021. doi:10.2139/ssrn.3716864. PMID 33501659. https://kar.kent.ac.uk/96371/1/Acta%20Psychiatr%20Scand%20-%202021%20-%20Whiskey%20-%20An%20evaluation%20of%20the%20variation%20and%20underuse%20of%20clozapine%20in%20the%20United%20Kingdom.pdf. 
  110. ↑ "Clozapine underutilization and discontinuation in African Americans due to leucopenia". Schizophrenia Bulletin 33 (5): 1221–1224. September 2007. doi:10.1093/schbul/sbl068. PMID 17170061. 
  111. ↑ 111.0 111.1 "Racial disparities in the use of second-generation antipsychotics for the treatment of schizophrenia". Psychiatric Services 57 (1): 133–136. January 2006. doi:10.1176/appi.ps.57.1.133. PMID 16399976. 
  112. ↑ 112.0 112.1 "Racial disparity in the use of atypical antipsychotic medications among veterans". The American Journal of Psychiatry 160 (10): 1817–1822. October 2003. doi:10.1176/appi.ajp.160.10.1817. PMID 14514496. 
  113. ↑ "Clozapine utilization and outcomes by race in a public mental health system: 1994-2000". The Journal of Clinical Psychiatry 67 (9): 1404–1411. September 2006. doi:10.4088/jcp.v67n0911. PMID 17017827. 
  114. ↑ "The importance of the recognition of benign ethnic neutropenia in black patients during treatment with clozapine: case reports and database study". Journal of Psychopharmacology 25 (6): 842–845. June 2011. doi:10.1177/0269881110364267. PMID 20305043. 
  115. ↑ "Clozapine prescribing in adolescent psychiatry: survey of prescribing practice in in-patient units". Psychiatric Bulletin 29 (10): 377–380. October 2005. doi:10.1192/pb.29.10.377. 
  116. ↑ "Psychiatrists' attitude towards and knowledge of clozapine treatment". Journal of Psychopharmacology 24 (7): 965–971. July 2010. doi:10.1177/0269881108100320. PMID 19164499. 
  117. ↑ "Side-effects and treatment with clozapine: a comparison between the views of consumers and their clinicians". International Journal of Mental Health Nursing 17 (1): 2–8. February 2008. doi:10.1111/j.1447-0349.2007.00506.x. PMID 18211398. 
  118. ↑ "Patients' and relatives' assessment of clozapine treatment". Psychological Medicine 31 (3): 509–517. April 2001. doi:10.1017/S0033291701003749. PMID 11305859. https://qmro.qmul.ac.uk/xmlui/handle/123456789/289. 
  119. ↑ "Why Not Clozapine?". Clinical Schizophrenia & Related Psychoses 1 (1): 92–95. April 2007. doi:10.3371/csrp.1.1.8. 
  120. ↑ "Clozapine: national review of postcode prescribing". Psychiatric Bulletin 31 (10): 384–387. October 2007. doi:10.1192/pb.bp.106.013144. ISSN 0955-6036. 
  121. ↑ "Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review". The Journal of Clinical Psychiatry 64 (1): 30–34. January 2003. doi:10.4088/jcp.v64n0107. PMID 12590620. 
  122. ↑ "Psychopharmacology: underuse of evidence-based treatments in psychiatry". Psychiatric Services 54 (11): 1453–4, 1456. November 2003. doi:10.1176/appi.ps.54.11.1453. PMID 14600298. 
  123. ↑ "Why Health Care Is Different If You're Black, Latino Or Poor" (in en). https://www.forbes.com/sites/robertpearl/2015/03/05/healthcare-black-latino-poor/. 
  124. ↑ "Racism in healthcare: Statistics and examples" (in en). 2020-09-17. https://www.medicalnewstoday.com/articles/racism-in-healthcare. 
  125. ↑ (in en) Stress. National Academies Press (US). 2004. https://www.ncbi.nlm.nih.gov/books/NBK24685/. 
  126. ↑ "Dissecting racial bias in an algorithm used to manage the health of populations". Science 366 (6464): 447–453. October 2019. doi:10.1126/science.aax2342. PMID 31649194. Bibcode: 2019Sci...366..447O. https://escholarship.org/uc/item/6h92v832. 
  127. ↑ "Clozapine utilization and outcomes by race in a public mental health system: 1994-2000". The Journal of Clinical Psychiatry 67 (9): 1404–1411. September 2006. doi:10.4088/JCP.v67n0911. PMID 17017827. 
  128. ↑ "Benign ethnic neutropenia". Blood Reviews 37: 100586. September 2019. doi:10.1016/j.blre.2019.06.003. PMID 31255364. 
  129. ↑ "Benign ethnic neutropenia: what is a normal absolute neutrophil count?". The Journal of Laboratory and Clinical Medicine 133 (1): 15–22. January 1999. doi:10.1053/lc.1999.v133.a94931. PMID 10385477. 
  130. ↑ "Clozapine, agranulocytosis, and benign ethnic neutropenia". Postgraduate Medical Journal 81 (959): 545–546. September 2005. doi:10.1136/pgmj.2004.031161. PMID 16143678. 
  131. ↑ "Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene". PLOS Genetics 5 (1): e1000360. January 2009. doi:10.1371/journal.pgen.1000360. PMID 19180233. 
  132. ↑ 132.0 132.1 "Clozapine". Pharmacology: MCQs. https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril. 
  133. ↑ "Clozapine Associated Periorbital Edema in First Episode Psychosis: A Case Report of a Rare Adverse Effect in Treatment-Resistant Schizophrenia". Journal of Clinical Psychopharmacology 42 (6): 594–596. September 2022. doi:10.1097/JCP.0000000000001600. PMID 36066404. 
  134. ↑ "Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided?". The Journal of Clinical Psychiatry 74 (6): 603–13; quiz 613. June 2013. doi:10.4088/JCP.12r08064. PMID 23842012. 
  135. ↑ 135.0 135.1 135.2 "Meta-analysis examining the epidemiology of clozapine-associated neutropenia". Acta Psychiatrica Scandinavica 138 (2): 101–109. August 2018. doi:10.1111/acps.12898. PMID 29786829. 
  136. ↑ "A Guide for Patients and Caregivers: What You Need to Know About Clozapine and Neutropenia". Clozapine REMS Program. https://www.clozapinerems.com/CpmgClozapineUI/rems/pdf/resources/Clozapine_REMS_Guide_Patients_Caregivers.pdf. 
  137. ↑ "Need to bleed? Clozapine haematological monitoring approaches a time for change". International Clinical Psychopharmacology 34 (5): 264–268. September 2019. doi:10.1097/yic.0000000000000258. PMID 30882426. https://kclpure.kcl.ac.uk/portal/en/publications/need-to-bleed(f1dea2eb-0cc6-452b-acab-84e047cb6554).html. 
  138. ↑ 138.0 138.1 138.2 "The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies". Psychological Medicine 50 (4): 583–594. March 2020. doi:10.1017/S0033291719000369. PMID 30857568. 
  139. ↑ "Development of point-of-care testing devices to improve clozapine prescribing habits and patient outcomes". Neuropsychiatric Disease and Treatment 15: 2365–2370. 2019. doi:10.2147/NDT.S216803. PMID 31692521. 
  140. ↑ "Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations". The Australian and New Zealand Journal of Psychiatry 51 (10): 980–989. October 2017. doi:10.1177/0004867417720516. PMID 28747065. 
  141. ↑ "The Use of Granulocyte Colony-Stimulating Factor in Clozapine Rechallenge: A Systematic Review". Journal of Clinical Psychopharmacology 37 (5): 600–604. October 2017. doi:10.1097/JCP.0000000000000767. PMID 28817489. https://kclpure.kcl.ac.uk/portal/en/publications/the-use-of-granulocyte-colonystimulating-factor-in-clozapine-rechallenge(123168da-3735-4007-886f-6087bef72040).html. Retrieved 22 September 2021. 
  142. ↑ "Systematic review and meta-analysis of rates of clozapine-associated myocarditis and cardiomyopathy". The Australian and New Zealand Journal of Psychiatry 54 (5): 467–481. May 2020. doi:10.1177/0004867419898760. PMID 31957459. 
  143. ↑ "A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls". The Australian and New Zealand Journal of Psychiatry 45 (6): 458–465. June 2011. doi:10.3109/00048674.2011.572852. PMID 21524186. 
  144. ↑ "Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study". Schizophrenia Research 141 (2–3): 173–178. November 2012. doi:10.1016/j.schres.2012.08.018. PMID 23010488. 
  145. ↑ "Clozapine-induced myocarditis: electronic health register analysis of incidence, timing, clinical markers and diagnostic accuracy". The British Journal of Psychiatry 219 (6): 644–651. December 2021. doi:10.1192/bjp.2021.58. PMID 35048875. 
  146. ↑ "Clozapine-Associated Myocarditis: A Protocol for Monitoring Upon Clozapine Initiation and Recommendations for How to Conduct a Clozapine Rechallenge". Journal of Clinical Psychopharmacology 41 (2): 180–185. March 2021. doi:10.1097/JCP.0000000000001358. PMID 33587399. 
  147. ↑ "Clozapine-induced myocarditis and patient outcomes after drug rechallenge following myocarditis: A systematic case review". Psychiatry Research 305: 114247. November 2021. doi:10.1101/2021.09.03.21263094. PMID 34715441. 
  148. ↑ "Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases". The Journal of Clinical Psychiatry 69 (5): 759–768. May 2008. doi:10.4088/JCP.v69n0509. PMID 18452342. 
  149. ↑ "Clozapine-treated Patients Have Marked Gastrointestinal Hypomotility, the Probable Basis of Life-threatening Gastrointestinal Complications: A Cross Sectional Study". eBioMedicine 5: 125–134. March 2016. doi:10.1016/j.ebiom.2016.02.020. PMID 27077119. 
  150. ↑ "Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy". The Journal of Clinical Psychiatry 73 (10): 1307–1312. October 2012. doi:10.4088/JCP.11r06977. PMID 23140648. 
  151. ↑ "Pharmacological treatment for antipsychotic-related constipation". The Cochrane Database of Systematic Reviews 1 (1): CD011128. January 2017. doi:10.1002/14651858.CD011128.pub2. PMID 28116777. 
  152. ↑ "The Porirua Protocol in the Treatment of Clozapine-Induced Gastrointestinal Hypomotility and Constipation: A Pre- and Post-Treatment Study". CNS Drugs 31 (1): 75–85. January 2017. doi:10.1007/s40263-016-0391-y. PMID 27826741. 
  153. ↑ 153.0 153.1 153.2 153.3 "Pharmacological interventions for clozapine-induced hypersalivation". The Cochrane Database of Systematic Reviews (3): CD005579. July 2008. doi:10.1002/14651858.CD005579.pub2. PMID 18646130. 
  154. ↑ "Treatment of Clozapine-Induced Sialorrhea". http://www.medscape.com/viewarticle/409612_2. 
  155. ↑ "Hyoscine for clozapine-induced hypersalivation: a double-blind, randomized, placebo-controlled cross-over trial". International Clinical Psychopharmacology 34 (2): 101–107. March 2019. doi:10.1097/YIC.0000000000000251. PMID 30614850. https://kclpure.kcl.ac.uk/portal/en/publications/hyoscine-for-clozapineinduced-hypersalivation(0575f794-ce85-4b57-81aa-14fb64045b3c).html. 
  156. ↑ 156.0 156.1 "Current treatment strategies for clozapine-induced sialorrhea". The Annals of Pharmacotherapy 45 (5): 667–675. May 2011. doi:10.1345/aph.1P761. PMID 21540404. 
  157. ↑ "ClozarilSide Effects & Drug Interactions". https://www.rxlist.com/script/main/notfoundstatic.asp?refurl=/cgi/generic/clozapine_ad.htm. 
  158. ↑ "Clozapine safety, 35 years later". Current Drug Safety 6 (3): 164–184. July 2011. doi:10.2174/157488611797579230. PMID 22122392. 
  159. ↑ "Nocturnal enuresis with antipsychotic medication". The British Journal of Psychiatry 200 (1): 7–9. January 2012. doi:10.1192/bjp.bp.111.095737. PMID 22215862. 
  160. ↑ 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.
  161. ↑ "Serotonin syndrome associated with clozapine withdrawal". JAMA Neurology 70 (8): 1054–1055. August 2013. doi:10.1001/jamaneurol.2013.95. PMID 23753931. 
  162. ↑ "Clozapine-withdrawal catatonia". Psychosomatics 51 (4): 355–355.e2. July 2010. doi:10.1176/appi.psy.51.4.355. PMID 20587767. 
  163. ↑ "Clozapine withdrawal-emergent dystonias and dyskinesias: a case series". The Journal of Clinical Psychiatry 59 (9): 472–477. September 1998. doi:10.4088/JCP.v59n0906. PMID 9771818. 
  164. ↑ "[Clozapine withdrawal. A review]". Psychiatria Polska 33 (1): 51–67. 1999. PMID 10786215. 
  165. ↑ "Novel antipsychotics: comparison of weight gain liabilities". The Journal of Clinical Psychiatry 60 (6): 358–363. June 1999. doi:10.4088/JCP.v60n0602. PMID 10401912. 
  166. ↑ "Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles". Molecular Psychiatry 13 (1): 27–35. January 2008. doi:10.1038/sj.mp.4002066. PMID 17848919. 
  167. ↑ "Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis". PLOS ONE 11 (6): e0156208. 2016-06-15. doi:10.1371/journal.pone.0156208. PMID 27304831. Bibcode: 2016PLoSO..1156208S. 
  168. ↑ "Data From the World Health Organization's Pharmacovigilance Database Supports the Prominent Role of Pneumonia in Mortality Associated With Clozapine Adverse Drug Reactions". Schizophrenia Bulletin 46 (1): 1–3. January 2020. doi:10.1093/schbul/sbz093. PMID 31901099. 
  169. ↑ "Clozapine is associated with secondary antibody deficiency". The British Journal of Psychiatry 214 (2): 83–89. September 2018. doi:10.1192/bjp.2018.152. PMID 30259827. 
  170. ↑ "A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43". International Journal of Molecular Sciences 21 (19): 7019. September 2020. doi:10.3390/ijms21197019. PMID 32987640. 
  171. ↑ "Clinical pharmacodynamics and pharmacokinetics of antimanic and mood-stabilizing medications". The Journal of Clinical Psychiatry 63 (Suppl 4): 3–11. 2002. PMID 11913673. 
  172. ↑ "Acute clozapine overdose: plasma concentration and outcome". Pharmacopsychiatry 31 (4): 149–151. July 1998. doi:10.1055/s-2007-979318. PMID 9754851. 
  173. ↑ "Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence". Clinical Pharmacokinetics 33 (6): 454–471. December 1997. doi:10.2165/00003088-199733060-00004. PMID 9435993. 
  174. ↑ "Carbamazepine-induced changes in plasma levels of neuroleptics". Pharmacopsychiatry 28 (1): 26–28. January 1995. doi:10.1055/s-2007-979584. PMID 7746842. 
  175. ↑ "Interactions between antiepileptic and antipsychotic drugs". Drug Safety 29 (2): 95–118. 2006. doi:10.2165/00002018-200629020-00001. PMID 16454538. 
  176. ↑ "Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service". Therapeutic Drug Monitoring 16 (4): 368–374. August 1994. doi:10.1097/00007691-199408000-00006. PMID 7974626. 
  177. ↑ "Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia". European Journal of Clinical Pharmacology 56 (8): 585–589. November 2000. doi:10.1007/s002280000192. PMID 11151749. 
  178. ↑ Prescribing information. Clozaril (clozapine). East Hanover, NJ: Novartis Pharmaceuticals Corporation, September 2014.
  179. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  180. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named PDSP-2
  181. ↑ "Focus on clozapine". Current Medical Research and Opinion 17 (3): 223–229. 2001. doi:10.1185/0300799039117069. PMID 11900316. 
  182. ↑ "CNS Receptor Partial Agonists: A New Approach to Drug Discovery". Primary Psychiatry 14 (8): 22–24. 2007. http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=1149. 
  183. ↑ "Clozapine | C18H19ClN4". PubChem. U.S. Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2818. 
  184. ↑ "Evidence that clozapine directly interacts on the GABAB receptor". NeuroReport 22 (13): 637–641. September 2011. doi:10.1097/WNR.0b013e328349739b. PMID 21753741. 
  185. ↑ "Hyperdopaminergia and altered locomotor activity in GABAB1-deficient mice". Journal of Neurochemistry 97 (4): 979–991. May 2006. doi:10.1111/j.1471-4159.2006.03806.x. PMID 16606363. 
  186. ↑ "The GABA B receptor agonist CGP44532 and the positive modulator GS39783 reverse some behavioural changes related to positive syndromes of psychosis in mice". British Journal of Pharmacology 163 (5): 1034–1047. July 2011. doi:10.1111/j.1476-5381.2011.01301.x. PMID 21371011. 
  187. ↑ "Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes". British Journal of Pharmacology 165 (5): 1543–1555. March 2012. doi:10.1111/j.1476-5381.2011.01638.x. PMID 21880034. 
  188. ↑ "Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3β pathway in adult rat prefrontal cortex". Neuropsychopharmacology 36 (6): 1260–1274. May 2011. doi:10.1038/npp.2011.12. PMID 21326193. 
  189. ↑ "Effect of food on the pharmacokinetics of clozapine orally disintegrating tablet 12.5 mg: a randomized, open-label, crossover study in healthy male subjects". Clinical Drug Investigation 29 (8): 539–549. 1 August 2009. doi:10.2165/00044011-200929080-00004. PMID 19591515. 
  190. ↑ 190.0 190.1 "Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients". Journal of Clinical Psychopharmacology 24 (1): 70–78. February 2004. doi:10.1097/01.jcp.0000106221.36344.4d. PMID 14709950. 
  191. ↑ "Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics". The Journal of Clinical Psychiatry 60 (1): 36–40. January 1999. doi:10.4088/JCP.v60n0108. PMID 10074876. 
  192. ↑ "Pharmacoeconomic evaluation of clozapine in treatment-resistant schizophrenia: a cost-utility analysis". The Canadian Journal of Clinical Pharmacology 8 (4): 199–206. 2001. PMID 11743592. 
  193. ↑ "Evaluation of the Cost-effectiveness of Services for Schizophrenia in the UK Across the Entire Care Pathway in a Single Whole-Disease Model". JAMA Network Open 3 (5): e205888. May 2020. doi:10.1001/jamanetworkopen.2020.5888. PMID 32459356. 
  194. ↑ "The cost-effectiveness of clozapine: a survey of the literature". Clinical Drug Investigation 15 (2): 137–152. 1998. doi:10.2165/00044011-199815020-00007. PMID 18370477. 
  195. ↑ "Clozapine". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/clozapine.html. 

Further reading

External links



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