clozapine clozapine clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic) to be discovered. it is primarily used to treat people with schizophrenia and schizoaffective disorder (according to dsm v) 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. clozapine is regarded as the gold-standard treatment when most other medications are ineffective and its use is recommended by multiple international treatment guidelines, after resistance to earlier neuroleptic treatment is established. not to be confused with clonazepam or clonidine. clozapineclinical datatrade namesclozaril, leponex, versacloz, othersahfs/drugs.commonographmedlineplusa691001license data us dailymed: clozapine pregnancycategory au: c routes ofadministrationby mouth, intramuscular injectiondrug classatypical antipsychoticatc coden05ah02 (who) legal statuslegal status au: s4 (prescription only) us: ℞-only pharmacokinetic databioavailability60 to 70%metabolismliver, by several cyp isozymeselimination half-life4 to 26 hours (mean value 14.2 hours in steady state conditions)excretion80% in metabolized state: 30% biliary and 50% kidneyidentifiers iupac name 8-chloro-11-(4-methylpiperazin-1-yl)-5h-dibenzodiazepine cas number5786-21-0 ypubchem cid2818iuphar/bps38drugbankdb00363 ychemspider10442628 yuniij60ar2ikickeggd00283 ychebichebi:3766 ychemblchembl42 ycomptox dashboard (epa)dtxsid5022855 echa infocard100.024.831 chemical and physical dataformulac18h19cln4molar mass326.83 g·mol−13d model (jsmol)interactive imagemelting point183 °c (361 °f)solubility in water0.1889 smiles cn1ccn(cc1)c2=nc3cc(ccc3nc4c2cccc4)cl inchi inchi=1s/c18h19cln4/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20h,8-11h2,1h3 ykey:qzudbnbuxvuhmw-uhfffaoysa-n y (verify) the role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark study in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis who had already shown an inadequate response to other antipsychotics. 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. in a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs. 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. in a 2000 canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness. compared to other antipsychotics, clozapine has an increased risk of blood dyscrasias, in particular agranulocytosis, in the first 18 weeks of treatment. after one year, this risk reduces to that associated with most antipsychotics. clozapine's use is therefore usually reserved for people who have not responded to at least two other antipsychotics and is only done with stringent blood monitoring. 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. 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. the association between clozapine use and specific bloods dyscrasias was first noted in the 1970s when eight deaths from agranulocytosis were noted in finland. 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. clozapine became widely available in the early 1990s and remains the only treatment likely to be effective in treating resistant schizophrenia. common adverse effects include drowsiness, constipation, hypersalivation (increased saliva production), tachycardia, low blood pressure, blurred vision, weight gain, and dizziness. 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. other serious risks include seizures, myocarditis (inflammation of the heart), hyperglycemia (high blood glucose levels), and constipation. the use of this drug can rarely result in clozapine-induced gastric hypomotility syndrome which may lead to bowel obstruction and death, and in older people with psychosis, as a result of dementia it may lead to an increased risk of death. the mechanism of action is not entirely clear in the current medical literature. clozapine 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. 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. further trials took place in 1972 when clozapine was released in switzerland and austria as leponex. two years later it was released in west germany and in finland in 1975. early testing was performed in the united states around the same time. 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. 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. 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 diversity in the region. 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. 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. 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. 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. in 2005, the fda approved criteria to allow reduced blood monitoring frequency. 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. 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. 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). its manufacturer, novartis, claims a solubility of <0.01% in water (<100 mg/l). clinical uses schizophrenia 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. 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. 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. 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. despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics. very long term follow-up studies reveal multiple benefits in terms of reduced mortality, 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. clozapine has a significant anti-aggressive effect. 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. 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. 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. clozapine has also been used off-label to treat catatonia with success in over 80% of cases. 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. bipolar disorder is an unlicensed indication for clozapine. severe personality disorders clozapine is also used in emotionally unstable personality disorder and a randomised controlled trial is currently underway. the use of clozapine to treat personality disorder is uncommon and unlicensed. initiation whilst clozapine is usually initiated in hospital setting community initiation is also available. 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. 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. a number of service protocols are available and there are variations in the extent of preclozapine 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