Clozapine: Difference between revisions

Clozapine
Clinical data
Trade names	Clozaril, Leponex, Versacloz, others
AHFS/Drugs.com	Monograph
MedlinePlus	a691001
License data	US DailyMed: Clozapine;
Pregnancy; category	AU: C; ;
Routes of; administration	By mouth, intramuscular injection
Drug class	Atypical antipsychotic
ATC code	N05AH02 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); US: WARNINGRx-only;
Pharmacokinetic data
Bioavailability	60 to 70%
Metabolism	Liver, by several CYP isozymes
Elimination half-life	4 to 26 hours (mean value 14.2 hours in steady state conditions)
Excretion	80% in metabolized state: 30% biliary and 50% kidney
Identifiers
	IUPAC name 8-Chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine;
CAS Number	5786-21-0 ;
PubChem CID	2818;
IUPHAR/BPS	38;
DrugBank	DB00363 ;
ChemSpider	10442628 ;
UNII	J60AR2IKIC;
KEGG	D00283 ;
ChEBI	CHEBI:3766 ;
ChEMBL	ChEMBL42 ;
CompTox Dashboard (EPA)	DTXSID5022855 ;
ECHA InfoCard	100.024.831
Chemical and physical data
Formula	C18H19ClN4
Molar mass	326.83 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	183 °C (361 °F)
Solubility in water	0.1889
	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 ; Key:QZUDBNBUXVUHMW-UHFFFAOYSA-N ;
	(verify)

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Clozapine, sold under the brand name Clozaril among others,^[1] is the first atypical antipsychotic medication.^[5] It 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.^[6]^[7] 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.^[8]^[9]^[10]^[11]^[12]^[13] Compared to other antipsychotics there is an increased risk of blood dyscrasias, in particular agranulocytosis in the first 18 weeks of treatment, after one year this risk reduces to that found in most antipsychotics and so it's use is reserved for people who have not responded to two other antipsychotics and then only with stringent blood monitoring.^[6] Although it was first used in the 1970's eight deaths from agranulocytosis were noted in Finland.^[14] At the time it was not clear if this exceeded the established rate of this side effects which is also found in other antipsychotics and although the drug was not completely withdrawn its use became limited.^[15] 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.^[16]

Compared to other antipsychotics clozapine is associated with an increased risk of low white blood cells. Neutropenia occurs in approximately 3.8% of cases and agranulocytosis in 0.4%.^[17] These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory blood monitoring. The exact schedules and blood count thresholds vary internationally^[18] and the thresholds at which clozapine can be used in the U.S. has been lower than those currently used in the U.K. for some time.^[19] 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.^[20] Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks.^[17] Other serious risks include seizures, inflammation of the heart, high blood sugar levels, constipation, and in older people with psychosis as a result of dementia, an increased risk of death.^[21]^[22]^[23] Common adverse effects include drowsiness, increased saliva production, low blood pressure, blurred vision, weight gain, and dizziness.^[21] The potentially permanent movement disorder tardive dyskinesia occurs in about 5% of people.^[22] Its mechanism of action is not entirely clear.^[21]

In a network comparative meta-analysis of 15 antipsychotic drugs clozapine was significantly more effective than all other drugs.^[24]

It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.^[25] It is available as a generic medication.^[21]

Clinical uses

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.^[6]^[7] 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.^[8]^[9]^[10]^[11]^[12]^[13]^[26] ^[27] Whilst all current guidelines reserve clozapine to individuals when two other antipsychotics evidence indicates that clozapine might be used as a second line drug^[28]. 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 has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia. ^[29]^[30]^[31] Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics.^[32] Very long term follow-up studies reveal multiple benefits in terms of reduced mortality,^[33]^[34] with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of attempted or completed suicide.^[35] Clozapine has a significant anti-aggressive effect.^[36]^[37]^[38]^[39]^[40]

It is used by mouth^[21] or by injection into a muscle.^[41]^[42]^[43] is an atypical antipsychotic drug primarily used on people who are unresponsive to or intolerant to other antipsychotics.^[44] This means that doctors were unsatisfied with how they responded to at least two different antipsychotics.^[45] It may also be used for the treatment of psychosis secondary to Parkinson's disease.^[46]

Clozapine is usually prescribed in tablet or liquid form,^[21] however an unlicensed short-acting intramuscular injectable formulation is available.^[42] It is not a depot injection and instead has a similar duration of action as clozapine by mouth. In the US, the injectable formulation is used on people diagnosed as schizophrenic who may refuse clozapine by mouth.^[41]

The symptomatic relapse rate is lower and patient adherence is higher in those taking Clozapine.^[44]^[47] There is some evidence clozapine may reduce frequency of criminalized drug use.^[48]

In treating patients who are diagnosed with both schizophrenia and Parkinson's disease, clozapine may be more effective at reducing symptoms without introducing extrapyramidal side effects.^[49]^[50]

Adverse effects

Clozapine may cause serious and potentially fatal adverse effects. Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, hyperglycemia, 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.^[51]

Clozapine carries five black box warnings, including warnings for agranulocytosis, central nervous system depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension (with or without syncope), and seizures.^[52] Lowering of the seizure threshold may be dose related. Slow initial titration may decrease the risk for precipitating seizures and orthostatic hypotension.^[53]

Many males have experienced cessation of ejaculation during orgasm as a side effect of clozapine, though this is not documented in official drug guides.^[54]

However, many side-effects can be managed and may not warrant discontinuation.^[55]

Agranulocytosis

Clozapine carries a black box warning for drug-induced agranulocytosis (lowered white blood cell count). Without monitoring, agranulocytosis occurs in about 1% of people who take clozapine during the first few months of treatment;^[56] the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year.^[57]

Clozapine-induced agranulocytosis can be transient.^[58]

Rapid point-of-care tests may simplify the monitoring for agranulocytosis.^[59]

Early findings suggest that the concurrent use of granulocyte colony-stimulating factor (GCSF) to maintain the neutrophil count whilst on rechallenge following neutropenia, is safe and effective. But, if agranulocytosis was later to occur there would be little if any therapeutic alternative which would ordinarily be GCSF.^[60]^[61]

Cardiac toxicity

Myocarditis is a sometimes fatal effect of clozapine, which usually develops within the first month of commencement.^[62] 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.^[63] 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.^[64]

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.^[65] Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers.^[66] Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis.^[67] A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication.^[68] 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.^[69]

Hypersalivation

Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30-80%).^[70] 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.^[70] 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.^[71] Clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication.^[70] Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically-absorbed anticholinergic medications like diphenhydramine^[70] and topical anticholinergic medications like ipratropium bromide.^[72] Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.^[72]

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.^[73]

Urinary incontinence

Clozapine is linked to urinary incontinence,^[74] though its appearance may be under-recognized.^[75]

Withdrawal effects

Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhea, nausea, vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation.^[76] It can also cause severe movement disorders, catatonia, and psychosis.^[77] 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.^[78]^[79]

Weight gain and diabetes

In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.^[80] 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.^[81] A study has established that olanzapine and clozapine disturb the metabolism by making the body take preferentially its energy from fat (instead of privileging carbohydrates). Levels of carbohydrates remaining high, the body develops insulin resistance (causing diabetes).^[82]

Overdose

Fatalities have been reported due to clozapine overdose, though overdoses > 4000 mg have been survived.^[83]

Drug interactions

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.^[84]

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.^[85]^[86] 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.^[87]

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.^[88] 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.^[89]

Pharmacology

Pharmacodynamics

Clozapine and norclozapine binding^[90]^[91]
Protein	CZP K_i (nM)	NDMCTooltip N-Desmethylclozapine K_i (nM)
5-HT_1A	123.7	13.9
5-HT_1B	519	406.8
5-HT_1D	1,356	476.2
5-HT_2A	5.35	10.9
5-HT_2B	8.37	2.8
5-HT_2C	9.44	11.9
5-HT₃	241	272.2
5-HT_5A	3,857	350.6
5-HT₆	13.49	11.6
5-HT₇	17.95	60.1
α_1A	1.62	104.8
α_1B	7	85.2
α_2A	37	137.6
α_2B	26.5	95.1
α_2C	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
SERTTooltip Serotonin transporter	1,624	316.6
NETTooltip Norepinephrine transporter	3,168	493.9
DATTooltip Dopamine transporter	>10,000	>10,000
The smaller the value, the more strongly the drug binds to the site. All data are for cloned human proteins.^[90]^[91]

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.^[92]

Clozapine is an antagonist at the 5-HT_2A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.^[93]^[94]

A direct interaction of clozapine with the GABA_B receptor has also been shown.^[95] GABA_B receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.^[96] GABA_B receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.^[97]

Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,^[98] 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.^[99]

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.^[100] 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.^[101]

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.^[102] 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.^[101]

Chemistry

Clozapine is a dibenzodiazepine that is structurally related to loxapine. 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).^[4] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).^[103]

Synthesis

Detection in body fluids

History^[104]

Clozapine was synthesized in 1956^[105] 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.^[106] 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 Finland in 1975. Early testing was performed in the United States around the same time.^[106] In 1975 16 cases of agranulocytosis leading to 8 deaths in clozapine-treated patients were reported from 6 hospitals, mostly in southwestern Finland led to concern. ^[107] 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. ^[108] 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. ^[109]^[110]^[111] 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 eben in the 1980's the duration of hospitalisation, especially in State Hospitals for those with treatment resistant schizophrenia might often be measured in years rather than days^[112]. 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 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 61mg +/- 14mg/d). Two hundred and sixty eight were randomised were to double blind trials of clozapine (upto 900 mg/d) or chlorpromazine (upto 1800mg/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.^[16] Following this study 1990, the US Food and Drug Administration (FDA) approved its use. 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.^[111]^[113] In December 2002, clozapine was approved in the US for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior.^[114] In 2005, the FDA approved criteria to allow reduced blood monitoring frequency.^[115] 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.^[116]Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and no not include total white cell counts, international monitoring has not been standardised^[117]^[118]^[119].

Society and culture

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

Clozapine is available as a generic medication.^[21] In the United Kingdom, the injectable form is approximately £100.00 per dose.^[41]

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External links

"Clozapine". Drug Information Portal. U.S. National Library of Medicine.
"Clozapine Risk Evaluation and Mitigation Strategy (REMS) requirements will change on November 15, 2021". U.S. Food and Drug Administration (FDA). 29 July 2021.
"Clozapine REMS Modification Frequently Asked Questions". U.S. Food and Drug Administration (FDA). 29 July 2021.

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[119] Oloyede, Ebenezer; Casetta, Cecilia; Dzahini, Olubanke; Segev, Aviv; Gaughran, Fiona; Shergill, Sukhi; Mijovic, Alek; Helthuis, Marinka; Whiskey, Eromona; MacCabe, James Hunter; Taylor, David (1 July 2021). "There Is Life After the UK Clozapine Central Non-Rechallenge Database". Schizophrenia Bulletin. 47 (4): 1088–1098. doi:10.1093/schbul/sbab006. ISSN 0586-7614. PMC 8266568. PMID 33543755.{{cite journal}}: CS1 maint: PMC format (link)

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 <!-- Definition and medical uses -->
-'''Clozapine''', sold under the brand name '''Clozaril''' among others,<ref name=brands/> is the first [[atypical antipsychotic]] medication.<ref>{{Cite book|last=author.|first=Stahl, Stephen M., 1951-|url=http://worldcat.org/oclc/1222779588|title=The clozapine handbook|isbn=978-1-108-44746-1|oclc=1222779588}}</ref> It 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|Parkinson's Disease]].<ref name="medicines.org.uk">{{Cite web|title=Clozaril 25 mg Tablets - Summary of Product Characteristics (SmPC) - (emc)|url=https://www.medicines.org.uk/emc/product/4411/smpc|access-date=2021-09-14|website=www.medicines.org.uk}}</ref><ref>{{Cite book|last=author.|first=National Institute for Health and Care Excellence (Great Britain),|url=http://worldcat.org/oclc/1105250833|title=Parkinson's disease in adults : diagnosis and management : full guideline|oclc=1105250833}}</ref> It is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines.<ref>{{cite journal | vauthors = Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ | display-authors = 6 | title = 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 | journal = The World Journal of Biological Psychiatry | volume = 13 | issue = 5 | pages = 318–78 | date = July 2012 | pmid = 22834451 | doi = 10.3109/15622975.2012.696143 }}</ref><ref>{{cite journal | vauthors = Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W | display-authors = 6 | title = The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements | journal = Schizophrenia Bulletin | volume = 36 | issue = 1 | pages = 71–93 | date = January 2010 | pmid = 19955390 | pmc = 2800144 | doi = 10.1093/schbul/sbp116 }}</ref><ref>{{cite journal | vauthors = Gaebel W, Weinmann S, Sartorius N, Rutz W, McIntyre JS | title = Schizophrenia practice guidelines: international survey and comparison | journal = The British Journal of Psychiatry | volume = 187 | issue = 3 | pages = 248–55 | date = September 2005 | pmid = 16135862 | doi = 10.1192/bjp.187.3.248 }}</ref><ref>{{cite journal | vauthors = Kuipers E, Yesufu-Udechuku A, Taylor C, Kendall T | title = Management of psychosis and schizophrenia in adults: summary of updated NICE guidance | journal = BMJ | volume = 348 | pages = g1173 | date = February 2014 | pmid = 24523363 | doi = 10.1136/bmj.g1173 }}</ref><ref>{{cite journal | vauthors = Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, Bloomfield MA, Bressan RA, Buchanan RW, Carpenter WT, Castle DJ, Citrome L, Daskalakis ZJ, Davidson M, Drake RJ, Dursun S, Ebdrup BH, Elkis H, Falkai P, Fleischacker WW, Gadelha A, Gaughran F, Glenthøj BY, Graff-Guerrero A, Hallak JE, Honer WG, Kennedy J, Kinon BJ, Lawrie SM, Lee J, Leweke FM, MacCabe JH, McNabb CB, Meltzer H, Möller HJ, Nakajima S, Pantelis C, Reis Marques T, Remington G, Rossell SL, Russell BR, Siu CO, Suzuki T, Sommer IE, Taylor D, Thomas N, Üçok A, Umbricht D, Walters JT, Kane J, Correll CU | display-authors = 6 | title = Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology | journal = The American Journal of Psychiatry | volume = 174 | issue = 3 | pages = 216–229 | date = March 2017 | pmid = 27919182 | pmc = 6231547 | doi = 10.1176/appi.ajp.2016.16050503 }}</ref><ref>{{cite journal | vauthors = Galletly C, Castle D, Dark F, Humberstone V, Jablensky A, Killackey E, Kulkarni J, McGorry P, Nielssen O, Tran N | display-authors = 6 | title = Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders | journal = The Australian and New Zealand Journal of Psychiatry | volume = 50 | issue = 5 | pages = 410–72 | date = May 2016 | pmid = 27106681 | doi = 10.1177/0004867416641195 }}</ref> Compared to other antipsychotics there is an increased risk of [[blood dyscrasia]]s, in particular [[agranulocytosis]] in the first 18 weeks of treatment, after one year this risk reduces to that found in most antipsychotics and so it's use is reserved for people who have not responded to two other antipsychotics and then only with stringent blood monitoring.<ref name="medicines.org.uk"/>  Although it was first used in the 1970's eight deaths from agranulocytosis were noted in Finland.<ref>{{Cite journal|last=Griffith|first=R.W.|last2=Saameli|first2=K.|date=October 1975|title=CLOZAPINE AND AGRANULOCYTOSIS|url=https://linkinghub.elsevier.com/retrieve/pii/S014067367590135X|journal=The Lancet|language=en|volume=306|issue=7936|pages=657|doi=10.1016/S0140-6736(75)90135-X}}</ref> At the time it was not clear if this exceeded the established rate of this side effects which is also found in other antipsychotics and although the drug was not completely withdrawn its use became limited.<ref>{{Cite journal|last=Crilly|first=John|date=2007-03-01|title=The history of clozapine and its emergence in the US market: a review and analysis|url=https://doi.org/10.1177/0957154X07070335|journal=History of Psychiatry|language=en|volume=18|issue=1|pages=39–60|doi=10.1177/0957154X07070335|issn=0957-154X}}</ref> The role of clozapine in treatment resistant schizophrenia was established by the landmark  Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics.<ref name=":0">{{Cite journal|last=Kane|first=John|date=1988-09-01|title=Clozapine for the Treatment-Resistant Schizophrenic: A Double-blind Comparison With Chlorpromazine|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archpsyc.1988.01800330013001|journal=Archives of General Psychiatry|language=en|volume=45|issue=9|pages=789|doi=10.1001/archpsyc.1988.01800330013001|issn=0003-990X}}</ref>
+'''Clozapine''', sold under the brand name '''Clozaril''' among others,<ref name=brands/> is the first [[atypical antipsychotic]] medication.<ref>{{Cite book|last=author.|first=Stahl, Stephen M., 1951-|url=http://worldcat.org/oclc/1222779588|title=The clozapine handbook|isbn=978-1-108-44746-1|oclc=1222779588}}</ref> It 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|Parkinson's Disease]].<ref name="medicines.org.uk">{{Cite web|title=Clozaril 25 mg Tablets - Summary of Product Characteristics (SmPC) - (emc)|url=https://www.medicines.org.uk/emc/product/4411/smpc|access-date=2021-09-14|website=www.medicines.org.uk}}</ref><ref name=":1">{{Cite book|last=author.|first=National Institute for Health and Care Excellence (Great Britain),|url=http://worldcat.org/oclc/1105250833|title=Parkinson's disease in adults : diagnosis and management : full guideline|oclc=1105250833}}</ref> It is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines.<ref name=":2">{{cite journal | vauthors = Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ | display-authors = 6 | title = 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 | journal = The World Journal of Biological Psychiatry | volume = 13 | issue = 5 | pages = 318–78 | date = July 2012 | pmid = 22834451 | doi = 10.3109/15622975.2012.696143 }}</ref><ref name=":3">{{cite journal | vauthors = Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W | display-authors = 6 | title = The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements | journal = Schizophrenia Bulletin | volume = 36 | issue = 1 | pages = 71–93 | date = January 2010 | pmid = 19955390 | pmc = 2800144 | doi = 10.1093/schbul/sbp116 }}</ref><ref name=":4">{{cite journal | vauthors = Gaebel W, Weinmann S, Sartorius N, Rutz W, McIntyre JS | title = Schizophrenia practice guidelines: international survey and comparison | journal = The British Journal of Psychiatry | volume = 187 | issue = 3 | pages = 248–55 | date = September 2005 | pmid = 16135862 | doi = 10.1192/bjp.187.3.248 }}</ref><ref name=":5">{{cite journal | vauthors = Kuipers E, Yesufu-Udechuku A, Taylor C, Kendall T | title = Management of psychosis and schizophrenia in adults: summary of updated NICE guidance | journal = BMJ | volume = 348 | pages = g1173 | date = February 2014 | pmid = 24523363 | doi = 10.1136/bmj.g1173 }}</ref><ref name=":6">{{cite journal | vauthors = Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, Bloomfield MA, Bressan RA, Buchanan RW, Carpenter WT, Castle DJ, Citrome L, Daskalakis ZJ, Davidson M, Drake RJ, Dursun S, Ebdrup BH, Elkis H, Falkai P, Fleischacker WW, Gadelha A, Gaughran F, Glenthøj BY, Graff-Guerrero A, Hallak JE, Honer WG, Kennedy J, Kinon BJ, Lawrie SM, Lee J, Leweke FM, MacCabe JH, McNabb CB, Meltzer H, Möller HJ, Nakajima S, Pantelis C, Reis Marques T, Remington G, Rossell SL, Russell BR, Siu CO, Suzuki T, Sommer IE, Taylor D, Thomas N, Üçok A, Umbricht D, Walters JT, Kane J, Correll CU | display-authors = 6 | title = Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology | journal = The American Journal of Psychiatry | volume = 174 | issue = 3 | pages = 216–229 | date = March 2017 | pmid = 27919182 | pmc = 6231547 | doi = 10.1176/appi.ajp.2016.16050503 }}</ref><ref name=":7">{{cite journal | vauthors = Galletly C, Castle D, Dark F, Humberstone V, Jablensky A, Killackey E, Kulkarni J, McGorry P, Nielssen O, Tran N | display-authors = 6 | title = Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders | journal = The Australian and New Zealand Journal of Psychiatry | volume = 50 | issue = 5 | pages = 410–72 | date = May 2016 | pmid = 27106681 | doi = 10.1177/0004867416641195 }}</ref> Compared to other antipsychotics there is an increased risk of [[blood dyscrasia]]s, in particular [[agranulocytosis]] in the first 18 weeks of treatment, after one year this risk reduces to that found in most antipsychotics and so it's use is reserved for people who have not responded to two other antipsychotics and then only with stringent blood monitoring.<ref name="medicines.org.uk"/>  Although it was first used in the 1970's eight deaths from agranulocytosis were noted in Finland.<ref>{{Cite journal|last=Griffith|first=R.W.|last2=Saameli|first2=K.|date=October 1975|title=CLOZAPINE AND AGRANULOCYTOSIS|url=https://linkinghub.elsevier.com/retrieve/pii/S014067367590135X|journal=The Lancet|language=en|volume=306|issue=7936|pages=657|doi=10.1016/S0140-6736(75)90135-X}}</ref> At the time it was not clear if this exceeded the established rate of this side effects which is also found in other antipsychotics and although the drug was not completely withdrawn its use became limited.<ref>{{Cite journal|last=Crilly|first=John|date=2007-03-01|title=The history of clozapine and its emergence in the US market: a review and analysis|url=https://doi.org/10.1177/0957154X07070335|journal=History of Psychiatry|language=en|volume=18|issue=1|pages=39–60|doi=10.1177/0957154X07070335|issn=0957-154X}}</ref> The role of clozapine in treatment resistant schizophrenia was established by the landmark  Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics.<ref name=":0">{{Cite journal|last=Kane|first=John|date=1988-09-01|title=Clozapine for the Treatment-Resistant Schizophrenic: A Double-blind Comparison With Chlorpromazine|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archpsyc.1988.01800330013001|journal=Archives of General Psychiatry|language=en|volume=45|issue=9|pages=789|doi=10.1001/archpsyc.1988.01800330013001|issn=0003-990X}}</ref>
+Compared to other antipsychotics clozapine is associated with an increased risk of [[agranulocytosis|low white blood cells]]. Neutropenia occurs in approximately 3.8% of cases and agranulocytosis in 0.4%.<ref name="Myles 101–109">{{cite journal | vauthors = Myles N, Myles H, Xia S, Large M, Kisely S, Galletly C, Bird R, Siskind D | display-authors = 6 | title = Meta-analysis examining the epidemiology of clozapine-associated neutropenia | journal = Acta Psychiatrica Scandinavica | volume = 138 | issue = 2 | pages = 101–109 | date = August 2018 | pmid = 29786829 | doi = 10.1111/acps.12898 }}</ref> These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory blood monitoring. The exact schedules and blood count thresholds vary internationally<ref>{{cite journal | vauthors = Nielsen J, Young C, Ifteni P, Kishimoto T, Xiang YT, Schulte PF, Correll CU, Taylor D | display-authors = 6 | title = Worldwide Differences in Regulations of Clozapine Use | journal = CNS Drugs | volume = 30 | issue = 2 | pages = 149–61 | date = February 2016 | pmid = 26884144 | doi = 10.1007/s40263-016-0311-1 }}</ref> and the thresholds at which clozapine can be used in the U.S. has been lower than those currently used in the U.K. for some time.<ref>{{cite journal | vauthors = Whiskey E, Dzahini O, Ramsay R, O'Flynn D, Mijovic A, Gaughran F, MacCabe J, Shergill S, Taylor D | display-authors = 6 | title = Need to bleed? Clozapine haematological monitoring approaches a time for change | journal = International Clinical Psychopharmacology | volume = 34 | issue = 5 | pages = 264–268 | date = September 2019 | pmid = 30882426 | doi = 10.1097/yic.0000000000000258 }}</ref> The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7700 patients treated.<ref>{{cite journal | vauthors = Li XH, Zhong XM, Lu L, Zheng W, Wang SB, Rao WW, Wang S, Ng CH, Ungvari GS, Wang G, Xiang YT | display-authors = 6 | title = The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies | journal = Psychological Medicine | volume = 50 | issue = 4 | pages = 583–594 | date = March 2020 | pmid = 30857568 | doi = 10.1017/s0033291719000369 }}</ref> Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks.<ref name="Myles 101–109" /> Other serious risks include [[epileptic seizure|seizures]], [[myocarditis|inflammation of the heart]], [[hyperglycemia|high blood sugar levels]], [[constipation]], and in older people with psychosis as a result of [[dementia]], an increased risk of death.<ref name="AHFS2015">{{cite web|title=Clozapine|url=https://www.drugs.com/monograph/clozapine.html|url-status=live|archive-url=https://web.archive.org/web/20151208103801/http://www.drugs.com/monograph/clozapine.html|archive-date=8 December 2015|access-date=1 December 2015|publisher=The American Society of Health-System Pharmacists}}</ref><ref name="Hart2012">{{cite journal | vauthors = Hartling L, Abou-Setta AM, Dursun S, Mousavi SS, Pasichnyk D, Newton AS | title = Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis | journal = Annals of Internal Medicine | volume = 157 | issue = 7 | pages = 498–511 | date = October 2012 | pmid = 22893011 | doi = 10.7326/0003-4819-157-7-201210020-00525 | doi-access = free }}</ref><ref name="FDA2020">{{cite web |title=Clozaril, Fazaclo ODT, Versacloz (clozapine): Drug Safety Communication - FDA Strengthens Warning That Untreated Constipation Can Lead to Serious Bowel Problems |url=https://www.fda.gov/safety/medical-product-safety-information/clozaril-fazaclo-odt-versacloz-clozapine-drug-safety-communication-fda-strengthens-warning-untreated |website=FDA |access-date=30 January 2020 |date=28 January 2020}}</ref> Common adverse effects include [[sedation|drowsiness]], increased saliva production, [[hypotension|low blood pressure]], [[blurred vision]], weight gain, and [[dizziness]].<ref name="AHFS2015" /> The potentially permanent movement disorder [[tardive dyskinesia]] occurs in about 5% of people.<ref name="Hart2012" /> Its mechanism of action is not entirely clear.<ref name="AHFS2015" />
-In those diagnosed with schizophrenia and [[schizoaffective disorder]] it may decrease the rate of [[suicide|suicidal behavior]].<ref name="AHFS2015">{{cite web|title=Clozapine|url=https://www.drugs.com/monograph/clozapine.html|url-status=live|archive-url=https://web.archive.org/web/20151208103801/http://www.drugs.com/monograph/clozapine.html|archive-date=8 December 2015|access-date=1 December 2015|publisher=The American Society of Health-System Pharmacists}}</ref> It is the only drug treatment likely to be effective if there is treatment resistant schizophrenia, meaning that other antipsychotics have been unsuccessful.<ref>{{cite journal | vauthors = Raguraman J, Vijay Sagar KJ, Chandrasekaran R | title = Effectiveness of clozapine in treatment-resistant schizophrenia | journal = Indian Journal of Psychiatry | volume = 47 | issue = 2 | pages = 102–5 | date = April 2005 | pmid = 20711291 | pmc = 2918292 | doi = 10.4103/0019-5545.55955  }}</ref><ref name="ReferenceB" /><ref>{{cite journal | vauthors = Siskind D, McCartney L, Goldschlager R, Kisely S | title = Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis | journal = The British Journal of Psychiatry | volume = 209 | issue = 5 | pages = 385–392 | date = November 2016 | pmid = 27388573 | doi = 10.1192/bjp.bp.115.177261 | doi-access = free }}</ref> As well as symptomatic improvement, clozapine is related to reduced rates of hospitalisation and shorter admissions.<ref>{{cite journal | vauthors = Masuda T, Misawa F, Takase M, Kane JM, Correll CU | title = 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 | journal = JAMA Psychiatry | volume = 76 | issue = 10 | pages = 1052–1062 | date = October 2019 | pmid = 31365048 | pmc = 6669790 | doi = 10.1001/jamapsychiatry.2019.1702 }}</ref><ref>{{cite journal | vauthors = Nyakyoma K, Morriss R | title = Effectiveness of clozapine use in delaying hospitalization in routine clinical practice: a 2 year observational study | journal = Psychopharmacology Bulletin | volume = 43 | issue = 2 | pages = 67–81 | date = 2010 | pmid = 21052043 | url = https://pubmed.ncbi.nlm.nih.gov/21052043/ }}</ref><ref>{{cite journal | vauthors = Siskind D, Reddel T, MacCabe JH, Kisely S | title = The impact of clozapine initiation and cessation on psychiatric hospital admissions and bed days: a mirror image cohort study | journal = Psychopharmacology | volume = 236 | issue = 6 | pages = 1931–1935 | date = June 2019 | pmid = 30715572 | doi = 10.1007/s00213-019-5179-6 }}</ref>  Whilst there are side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics.<ref>{{cite journal | vauthors = Gaszner P, Makkos Z | title = Clozapine maintenance therapy in schizophrenia | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 28 | issue = 3 | pages = 465–9 | date = May 2004 | pmid = 15093952 | doi = 10.1016/j.pnpbp.2003.11.011 }}</ref> Very long term follow-up studies reveal multiple benefits in terms of reduced mortality,<ref>{{cite journal | vauthors = Taipale H, Tanskanen A, Mehtälä J, Vattulainen P, Correll CU, Tiihonen J | title = 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) | journal = World Psychiatry | volume = 19 | issue = 1 | pages = 61–68 | date = February 2020 | pmid = 31922669 | pmc = 6953552 | doi = 10.1002/wps.20699 }}</ref><ref>{{cite journal | vauthors = Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, Haukka J | title = 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study) | journal = Lancet | volume = 374 | issue = 9690 | pages = 620–7 | date = August 2009 | pmid = 19595447 | doi = 10.1016/S0140-6736(09)60742-X }}</ref> with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of attempted or completed suicide.<ref>{{cite journal | vauthors = Taipale H, Lähteenvuo M, Tanskanen A, Mittendorfer-Rutz E, Tiihonen J | title = Comparative Effectiveness of Antipsychotics for Risk of Attempted or Completed Suicide Among Persons With Schizophrenia | journal = Schizophrenia Bulletin | volume = 47 | issue = 1 | pages = 23–30 | date = January 2021 | pmid = 33428766 | pmc = 7824993 | doi = 10.1093/schbul/sbaa111 }}</ref> Clozapine has a significant anti-aggressive effect.<ref>{{cite journal | vauthors = Brown D, Larkin F, Sengupta S, Romero-Ureclay JL, Ross CC, Gupta N, Vinestock M, Das M | display-authors = 6 | title = Clozapine: an effective treatment for seriously violent and psychopathic men with antisocial personality disorder in a UK high-security hospital | journal = CNS Spectrums | volume = 19 | issue = 5 | pages = 391–402 | date = October 2014 | pmid = 24698103 | pmc = 4255317 | doi = 10.1017/S1092852914000157 }}</ref><ref>{{cite journal | vauthors = Krakowski MI, Czobor P, Citrome L, Bark N, Cooper TB | title = Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder | journal = Archives of General Psychiatry | volume = 63 | issue = 6 | pages = 622–9 | date = June 2006 | pmid = 16754835 | doi = 10.1001/archpsyc.63.6.622 }}</ref><ref>{{Cite journal| vauthors = Dalal B, Larkin E, Leese M, Taylor PJ |date=June 1999|title=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|url=https://onlinelibrary.wiley.com/doi/10.1002/cbm.304|journal=Criminal Behaviour and Mental Health|language=en|volume=9|issue=2|pages=168–178|doi=10.1002/cbm.304|issn=0957-9664}}</ref><ref>{{cite journal | vauthors = Topiwala A, Fazel S | title = The pharmacological management of violence in schizophrenia: a structured review | journal = Expert Review of Neurotherapeutics | volume = 11 | issue = 1 | pages = 53–63 | date = January 2011 | pmid = 21158555 | doi = 10.1586/ern.10.180 }}</ref><ref>{{cite journal | vauthors = Frogley C, Taylor D, Dickens G, Picchioni M | title = A systematic review of the evidence of clozapine's anti-aggressive effects | journal = The International Journal of Neuropsychopharmacology | volume = 15 | issue = 9 | pages = 1351–71 | date = October 2012 | pmid = 22339930 | doi = 10.1017/S146114571100201X }}</ref> It is used by mouth<ref name="AHFS2015" /> or by [[intramuscular|injection into a muscle]].<ref name="Sus2019">{{Cite web |url= https://www.sussexpartnership.nhs.uk/sites/default/files/documents/im_cloz_-_trust_protocol_-v1_-_0417_-_final_0.pdf |title=Protocol for the use of intramuscular (IM) clozapine injection | vauthors = Hewitt J, Haste J |date=April 2017 |website=Sussex Partnership NHS Foundation Trust |access-date=15 March 2019 }}</ref><ref name="Evaluation of the effectiveness and">{{cite journal | vauthors = Henry R, Massey R, Morgan K, Deeks J, Macfarlane H, Holmes N, Silva E | title = Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series | journal = BJPsych Bulletin | volume = 44 | issue = 6 | pages = 239–243 | date = December 2020 | pmid = 32081110 | pmc = 7684781 | doi = 10.1192/bjb.2020.6 }}</ref><ref>{{cite journal | vauthors = Schulte PF, Stienen JJ, Bogers J, Cohen D, van Dijk D, Lionarons WH, Sanders SS, Heck AH | display-authors = 6 | title = Compulsory treatment with clozapine: a retrospective long-term cohort study | journal = International Journal of Law and Psychiatry | volume = 30 | issue = 6 | pages = 539–45 | date = 2007-11-01 | pmid = 17928054 | doi = 10.1016/j.ijlp.2007.09.003 }}</ref>
-Compared to other antipsychotics clozapine is associated with an increased risk of [[agranulocytosis|low white blood cells]]. Neutropenia occurs in approximately 3.8% of cases and agranulocytosis in 0.4%.<ref name="Myles 101–109">{{cite journal | vauthors = Myles N, Myles H, Xia S, Large M, Kisely S, Galletly C, Bird R, Siskind D | display-authors = 6 | title = Meta-analysis examining the epidemiology of clozapine-associated neutropenia | journal = Acta Psychiatrica Scandinavica | volume = 138 | issue = 2 | pages = 101–109 | date = August 2018 | pmid = 29786829 | doi = 10.1111/acps.12898 }}</ref> These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory blood monitoring. The exact schedules and blood count thresholds vary internationally<ref>{{cite journal | vauthors = Nielsen J, Young C, Ifteni P, Kishimoto T, Xiang YT, Schulte PF, Correll CU, Taylor D | display-authors = 6 | title = Worldwide Differences in Regulations of Clozapine Use | journal = CNS Drugs | volume = 30 | issue = 2 | pages = 149–61 | date = February 2016 | pmid = 26884144 | doi = 10.1007/s40263-016-0311-1 }}</ref> and the thresholds at which clozapine can be used in the U.S. has been lower than those currently used in the U.K. for some time.<ref>{{cite journal | vauthors = Whiskey E, Dzahini O, Ramsay R, O'Flynn D, Mijovic A, Gaughran F, MacCabe J, Shergill S, Taylor D | display-authors = 6 | title = Need to bleed? Clozapine haematological monitoring approaches a time for change | journal = International Clinical Psychopharmacology | volume = 34 | issue = 5 | pages = 264–268 | date = September 2019 | pmid = 30882426 | doi = 10.1097/yic.0000000000000258 }}</ref> The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7700 patients treated.<ref>{{cite journal | vauthors = Li XH, Zhong XM, Lu L, Zheng W, Wang SB, Rao WW, Wang S, Ng CH, Ungvari GS, Wang G, Xiang YT | display-authors = 6 | title = The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies | journal = Psychological Medicine | volume = 50 | issue = 4 | pages = 583–594 | date = March 2020 | pmid = 30857568 | doi = 10.1017/s0033291719000369 }}</ref> Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks.<ref name="Myles 101–109"/> Other serious risks include [[epileptic seizure|seizures]], [[myocarditis|inflammation of the heart]], [[hyperglycemia|high blood sugar levels]], [[constipation]], and in older people with psychosis as a result of [[dementia]], an increased risk of death.<ref name=AHFS2015/><ref name=Hart2012>{{cite journal | vauthors = Hartling L, Abou-Setta AM, Dursun S, Mousavi SS, Pasichnyk D, Newton AS | title = Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis | journal = Annals of Internal Medicine | volume = 157 | issue = 7 | pages = 498–511 | date = October 2012 | pmid = 22893011 | doi = 10.7326/0003-4819-157-7-201210020-00525 | doi-access = free }}</ref><ref name=FDA2020>{{cite web |title=Clozaril, Fazaclo ODT, Versacloz (clozapine): Drug Safety Communication - FDA Strengthens Warning That Untreated Constipation Can Lead to Serious Bowel Problems |url=https://www.fda.gov/safety/medical-product-safety-information/clozaril-fazaclo-odt-versacloz-clozapine-drug-safety-communication-fda-strengthens-warning-untreated |website=FDA |access-date=30 January 2020 |date=28 January 2020}}</ref> Common adverse effects include [[sedation|drowsiness]], increased saliva production, [[hypotension|low blood pressure]], [[blurred vision]], weight gain, and [[dizziness]].<ref name=AHFS2015/> The potentially permanent movement disorder [[tardive dyskinesia]] occurs in about 5% of people.<ref name=Hart2012/> Its mechanism of action is not entirely clear.<ref name=AHFS2015/>
 In a network comparative meta-analysis of 15 antipsychotic drugs clozapine was significantly more effective than all other drugs.<ref name=Lancet2013>{{cite journal | vauthors = Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM | display-authors = 6 | title = Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis | journal = Lancet | volume = 382 | issue = 9896 | pages = 951–62 | date = September 2013 | pmid = 23810019 | doi = 10.1016/S0140-6736(13)60733-3 | s2cid = 32085212 }}</ref>
 <!-- History, society and culture -->
-Clozapine was first made in 1956, and sold commercially in 1972.<ref name=Stat2019>{{cite book | vauthors = Haidary HA, Padhy RK | chapter = Clozapine | title = StatPearls | publisher = StatPearls Publishing | location = Treasure Island (FL) | date = January 2019 | pmid = 30571020 }}</ref><ref name=Cri2007>{{cite journal | vauthors = Crilly J | title = The history of clozapine and its emergence in the US market: a review and analysis | journal = History of Psychiatry | volume = 18 | issue = 1 | pages = 39–60 | date = March 2007 | pmid = 17580753 | doi = 10.1177/0957154X07070335 | s2cid = 21086497 }}</ref> It was the first atypical antipsychotic.<ref name=Cor2013>{{cite book| veditors = Li JJ, Corey JJ | chapter = Chapter 7: CNS Drugs |title=Drug discovery practices, processes, and perspectives |date=2013 |publisher=John Wiley & Sons |location=Hoboken, N.J. |isbn=9781118354469 |page=248 | chapter-url= https://books.google.com/books?id=mIyxO5cLEAcC&pg=PA248 }}</ref> It is on the [[World Health Organization's List of Essential Medicines]], the safest and most effective medicines needed in a [[health system]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO }}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/>
+It is on the [[World Health Organization's List of Essential Medicines]], the safest and most effective medicines needed in a [[health system]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO }}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/>
 ==Clinical uses==
+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|Parkinson's Disease]].<ref name="medicines.org.uk" /><ref name=":1" /> It is regarded as the [[Gold standard therapy|gold-standard]] treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, supported by [[Systematic review|systematic reviews]] and [[meta-analysis]].<ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" /><ref name=":6" /><ref name=":7" /><ref>{{Cite journal|last=Essali|first=Adib|last2=Al-Haj Haasan|first2=Nahla|last3=Li|first3=Chunbo|last4=Rathbone|first4=John|date=2009-01-21|editor-last=Cochrane Schizophrenia Group|title=Clozapine versus typical neuroleptic medication for schizophrenia|url=https://doi.wiley.com/10.1002/14651858.CD000059.pub2|journal=Cochrane Database of Systematic Reviews|language=en|doi=10.1002/14651858.CD000059.pub2|pmc=PMC7065592|pmid=19160174}}</ref> <ref>{{Cite journal|last=Siskind|first=Dan|last2=McCartney|first2=Lara|last3=Goldschlager|first3=Romi|last4=Kisely|first4=Steve|date=2016-11|title=Clozapine v . first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis|url=https://www.cambridge.org/core/product/identifier/S0007125000245406/type/journal_article|journal=British Journal of Psychiatry|language=en|volume=209|issue=5|pages=385–392|doi=10.1192/bjp.bp.115.177261|issn=0007-1250}}</ref> Whilst all current guidelines reserve clozapine to individuals when two other antipsychotics evidence indicates that clozapine might be used as a second line drug<ref>{{Cite journal|last=Kahn|first=René S|last2=Winter van Rossum|first2=Inge|last3=Leucht|first3=Stefan|last4=McGuire|first4=Philip|last5=Lewis|first5=Shon W|last6=Leboyer|first6=Marion|last7=Arango|first7=Celso|last8=Dazzan|first8=Paola|last9=Drake|first9=Richard|last10=Heres|first10=Stephan|last11=Díaz-Caneja|first11=Covadonga M|date=2018-10|title=Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study|url=https://linkinghub.elsevier.com/retrieve/pii/S2215036618302529|journal=The Lancet Psychiatry|language=en|volume=5|issue=10|pages=797–807|doi=10.1016/S2215-0366(18)30252-9}}</ref>. 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 has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia. <ref>{{cite journal|vauthors=Masuda T, Misawa F, Takase M, Kane JM, Correll CU|date=October 2019|title=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|journal=JAMA Psychiatry|volume=76|issue=10|pages=1052–1062|doi=10.1001/jamapsychiatry.2019.1702|pmc=6669790|pmid=31365048}}</ref><ref>{{cite journal|vauthors=Nyakyoma K, Morriss R|date=2010|title=Effectiveness of clozapine use in delaying hospitalization in routine clinical practice: a 2 year observational study|url=https://pubmed.ncbi.nlm.nih.gov/21052043/|journal=Psychopharmacology Bulletin|volume=43|issue=2|pages=67–81|pmid=21052043}}</ref><ref>{{cite journal|vauthors=Siskind D, Reddel T, MacCabe JH, Kisely S|date=June 2019|title=The impact of clozapine initiation and cessation on psychiatric hospital admissions and bed days: a mirror image cohort study|journal=Psychopharmacology|volume=236|issue=6|pages=1931–1935|doi=10.1007/s00213-019-5179-6|pmid=30715572}}</ref> Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics.<ref>{{cite journal|vauthors=Gaszner P, Makkos Z|date=May 2004|title=Clozapine maintenance therapy in schizophrenia|journal=Progress in Neuro-Psychopharmacology & Biological Psychiatry|volume=28|issue=3|pages=465–9|doi=10.1016/j.pnpbp.2003.11.011|pmid=15093952}}</ref> Very long term follow-up studies reveal multiple benefits in terms of reduced mortality,<ref>{{cite journal|vauthors=Taipale H, Tanskanen A, Mehtälä J, Vattulainen P, Correll CU, Tiihonen J|date=February 2020|title=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)|journal=World Psychiatry|volume=19|issue=1|pages=61–68|doi=10.1002/wps.20699|pmc=6953552|pmid=31922669}}</ref><ref>{{cite journal|vauthors=Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, Haukka J|date=August 2009|title=11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study)|journal=Lancet|volume=374|issue=9690|pages=620–7|doi=10.1016/S0140-6736(09)60742-X|pmid=19595447}}</ref> with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of attempted or completed suicide.<ref>{{cite journal|vauthors=Taipale H, Lähteenvuo M, Tanskanen A, Mittendorfer-Rutz E, Tiihonen J|date=January 2021|title=Comparative Effectiveness of Antipsychotics for Risk of Attempted or Completed Suicide Among Persons With Schizophrenia|journal=Schizophrenia Bulletin|volume=47|issue=1|pages=23–30|doi=10.1093/schbul/sbaa111|pmc=7824993|pmid=33428766}}</ref> Clozapine has a significant anti-aggressive effect.<ref>{{cite journal|display-authors=6|vauthors=Brown D, Larkin F, Sengupta S, Romero-Ureclay JL, Ross CC, Gupta N, Vinestock M, Das M|date=October 2014|title=Clozapine: an effective treatment for seriously violent and psychopathic men with antisocial personality disorder in a UK high-security hospital|journal=CNS Spectrums|volume=19|issue=5|pages=391–402|doi=10.1017/S1092852914000157|pmc=4255317|pmid=24698103}}</ref><ref>{{cite journal|vauthors=Krakowski MI, Czobor P, Citrome L, Bark N, Cooper TB|date=June 2006|title=Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder|journal=Archives of General Psychiatry|volume=63|issue=6|pages=622–9|doi=10.1001/archpsyc.63.6.622|pmid=16754835}}</ref><ref>{{Cite journal|vauthors=Dalal B, Larkin E, Leese M, Taylor PJ|date=June 1999|title=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|url=https://onlinelibrary.wiley.com/doi/10.1002/cbm.304|journal=Criminal Behaviour and Mental Health|language=en|volume=9|issue=2|pages=168–178|doi=10.1002/cbm.304|issn=0957-9664}}</ref><ref>{{cite journal|vauthors=Topiwala A, Fazel S|date=January 2011|title=The pharmacological management of violence in schizophrenia: a structured review|journal=Expert Review of Neurotherapeutics|volume=11|issue=1|pages=53–63|doi=10.1586/ern.10.180|pmid=21158555}}</ref><ref>{{cite journal|vauthors=Frogley C, Taylor D, Dickens G, Picchioni M|date=October 2012|title=A systematic review of the evidence of clozapine's anti-aggressive effects|journal=The International Journal of Neuropsychopharmacology|volume=15|issue=9|pages=1351–71|doi=10.1017/S146114571100201X|pmid=22339930}}</ref>
-Clozapine is an atypical antipsychotic drug primarily used on people who are unresponsive to or intolerant to other antipsychotics.<ref name="ReferenceB">{{cite journal | vauthors = Essali A, Al-Haj Haasan N, Li C, Rathbone J | title = Clozapine versus typical neuroleptic medication for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD000059 | date = January 2009 | pmid = 19160174 | doi = 10.1002/14651858.CD000059.pub2 | pmc = 7065592 }}</ref> This means that doctors were unsatisfied with how they responded to at least two different [[antipsychotic]]s.<ref>{{cite journal | vauthors = Meltzer HY | title = Treatment-resistant schizophrenia--the role of clozapine | journal = Current Medical Research and Opinion | volume = 14 | issue = 1 | pages = 1–20 | year = 1997 | pmid = 9524789 | doi = 10.1185/03007999709113338 }}</ref> It may also be used for the treatment of psychosis secondary to [[Parkinson's disease]].<ref name=BNF74>{{cite book|title=British national formulary : BNF 74|date=2017|publisher=British Medical Association|isbn=978-0857112989|page=377|edition=74}}</ref>
+It is used by mouth<ref name="AHFS2015" /> or by [[intramuscular|injection into a muscle]].<ref name="Sus2019">{{Cite web|date=April 2017|title=Protocol for the use of intramuscular (IM) clozapine injection|url=https://www.sussexpartnership.nhs.uk/sites/default/files/documents/im_cloz_-_trust_protocol_-v1_-_0417_-_final_0.pdf|access-date=15 March 2019|website=Sussex Partnership NHS Foundation Trust|vauthors=Hewitt J, Haste J}}</ref><ref name="Evaluation of the effectiveness and">{{cite journal|vauthors=Henry R, Massey R, Morgan K, Deeks J, Macfarlane H, Holmes N, Silva E|date=December 2020|title=Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series|journal=BJPsych Bulletin|volume=44|issue=6|pages=239–243|doi=10.1192/bjb.2020.6|pmc=7684781|pmid=32081110}}</ref><ref>{{cite journal|display-authors=6|vauthors=Schulte PF, Stienen JJ, Bogers J, Cohen D, van Dijk D, Lionarons WH, Sanders SS, Heck AH|date=2007-11-01|title=Compulsory treatment with clozapine: a retrospective long-term cohort study|journal=International Journal of Law and Psychiatry|volume=30|issue=6|pages=539–45|doi=10.1016/j.ijlp.2007.09.003|pmid=17928054}}</ref> is an atypical antipsychotic drug primarily used on people who are unresponsive to or intolerant to other antipsychotics.<ref name="ReferenceB">{{cite journal | vauthors = Essali A, Al-Haj Haasan N, Li C, Rathbone J | title = Clozapine versus typical neuroleptic medication for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD000059 | date = January 2009 | pmid = 19160174 | doi = 10.1002/14651858.CD000059.pub2 | pmc = 7065592 }}</ref> This means that doctors were unsatisfied with how they responded to at least two different [[antipsychotic]]s.<ref>{{cite journal | vauthors = Meltzer HY | title = Treatment-resistant schizophrenia--the role of clozapine | journal = Current Medical Research and Opinion | volume = 14 | issue = 1 | pages = 1–20 | year = 1997 | pmid = 9524789 | doi = 10.1185/03007999709113338 }}</ref> It may also be used for the treatment of psychosis secondary to [[Parkinson's disease]].<ref name="BNF74">{{cite book|title=British national formulary : BNF 74|date=2017|publisher=British Medical Association|isbn=978-0857112989|page=377|edition=74}}</ref>
 Clozapine is usually prescribed in tablet or liquid form,<ref name="AHFS2015" /> however an unlicensed short-acting [[Intramuscular injection|intramuscular injectable]] formulation is available.<ref name="Evaluation of the effectiveness and"/> It is not a depot injection and instead has a similar duration of action as clozapine by mouth. In the US, the injectable formulation is used on people diagnosed as schizophrenic who may refuse clozapine by mouth.<ref name=Sus2019 />
@@ Line 287: / Line 287: @@
 ==History<ref>{{Cite journal|last=Kane|first=John|date=1988-09-01|title=Clozapine for the Treatment-Resistant Schizophrenic: A Double-blind Comparison With Chlorpromazine|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archpsyc.1988.01800330013001|journal=Archives of General Psychiatry|language=en|volume=45|issue=9|pages=789|doi=10.1001/archpsyc.1988.01800330013001|issn=0003-990X}}</ref>==
-Clozapine was synthesized in 1956<ref name=Stat2019/> 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 Laboratories|Sandoz]].<ref name=Cri2007 /> 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 Finland in 1975. Early testing was performed in the United States around the same time.<ref name="Cri2007"/><!-- cites previous three sentences --> In 1975  16 cases of [[agranulocytosis]] leading to 8 deaths in clozapine-treated patients were reported from 6 hospitals, mostly in southwestern Finland led to concern. <ref>{{Cite journal|last=Idänpään-Heikkilä|first=Juhana|last2=Alhava|first2=Eeva|last3=Olkinuora|first3=Martti|last4=Palva|first4=Ilmari|date=1975-09|title=CLOZAPINE AND AGRANULOCYTOSIS|url=https://doi.org/10.1016/S0140-6736(75)90206-8|journal=The Lancet|volume=306|issue=7935|pages=611|doi=10.1016/s0140-6736(75)90206-8|issn=0140-6736}}</ref> Analysis of the Finnish cases revealed that all the agranulocytosis cases had occurred within the first 18 weeks of treatment and the authors proposed blood monitoring during this period. <ref>{{Cite journal|last=Amsler|first=H. A.|last2=Teerenhovi|first2=L.|last3=Barth|first3=E.|last4=Harjula|first4=K.|last5=Vuopio|first5=P.|date=1977-10|title=Agranulocytosis in patients treated with clozapine.: A STUDY OF THE FINNISH EPIDEMIC|url=https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0447.1977.tb00224.x|journal=Acta Psychiatrica Scandinavica|language=en|volume=56|issue=4|pages=241–248|doi=10.1111/j.1600-0447.1977.tb00224.x|issn=0001-690X}}</ref> The rate of agranulocytosis in Finland appeared to be 20 times higher than in the rest of the world and there was speculation that this may have been due a unique genetic diversity in the region.  <ref>{{cite journal|vauthors=Griffith RW, Saameli K|date=October 1975|title=Letter: Clozapine and agranulocytosis|journal=Lancet|volume=2|issue=7936|pages=657|doi=10.1016/s0140-6736(75)90135-x|pmid=52022|s2cid=53296036}}</ref><ref name="Legge2019">{{cite journal|vauthors=Legge SE, Walters JT|date=March 2019|title=Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective|journal=Pharmacogenomics|volume=20|issue=4|pages=279–290|doi=10.2217/pgs-2018-0188|pmc=6563116|pmid=30767710}}</ref><ref name="deWith2017">{{cite journal|vauthors=de With SA, Pulit SL, Staal WG, Kahn RS, Ophoff RA|date=July 2017|title=More than 25 years of genetic studies of clozapine-induced agranulocytosis|journal=The Pharmacogenomics Journal|volume=17|issue=4|pages=304–311|doi=10.1038/tpj.2017.6|pmid=28418011|s2cid=5007914}}</ref> Whilst the drug continued to be manufactured by [[Sandoz]] and remained available in Europe development in the U.S. halted.   Interest in clozapine continued in an investigational capacity in the United States because eben in the 1980's the duration of hospitalisation, especially in [[State hospital|State Hospitals]] for those with treatment resistant schizophrenia might often be measured in years rather than days<ref>{{Cite journal|last=Crilly|first=John|date=2007-03|title=The history of clozapine and its emergence in the US market: a review and analysis|url=http://journals.sagepub.com/doi/10.1177/0957154X07070335|journal=History of Psychiatry|language=en|volume=18|issue=1|pages=39–60|doi=10.1177/0957154X07070335|issn=0957-154X}}</ref>.  The role of clozapine in treatment resistant schizophrenia was established by the landmark  Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. This involved both stringent blood monitoring and a double blind design with 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 61mg +/- 14mg/d). Two hundred and sixty eight were randomised were  to double blind trials of clozapine (upto 900 mg/d)  or chlorpromazine (upto 1800mg/d).  30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas.<ref name=":0" />   Following this study 1990, the US [[Food and Drug Administration]] (FDA) approved its use. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.<ref name="deWith2017" /><ref>{{cite book | vauthors = Healy D |title=The Psychopharmacologists |date=8 May 2018 |doi=10.1201/9780203736159 |isbn=9780203736159  }}</ref> In December 2002, clozapine was approved in the US for reducing the risk of suicide in schizophrenic or [[schizoaffective]] patients judged to be at chronic risk for suicidal behavior.<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/19758se1-047ltr.pdf |title=Supplemental NDA Approval Letter for Clozaril, NDA 19-758 / S-047 |date=18 December 2002 |publisher=United States Food and Drug Administration |access-date=23 November 2012 |archive-url=https://web.archive.org/web/20131108024629/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/19758se1-047ltr.pdf |archive-date=8 November 2013 |url-status=dead }}</ref> In 2005, the FDA approved criteria to allow reduced blood monitoring frequency.<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019758s054ltr.pdf |title=Letter to Novartis Pharmaceuticals Corporation |access-date=20 September 2009 |url-status=live |archive-url=https://web.archive.org/web/20110511063325/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019758s054ltr.pdf |archive-date=11 May 2011 }}</ref>
+Clozapine was synthesized in 1956<ref name="Stat2019">{{cite book|title=StatPearls|vauthors=Haidary HA, Padhy RK|date=January 2019|publisher=StatPearls Publishing|location=Treasure Island (FL)|chapter=Clozapine|pmid=30571020}}</ref> 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 Laboratories|Sandoz]].<ref name="Cri2007">{{cite journal|vauthors=Crilly J|date=March 2007|title=The history of clozapine and its emergence in the US market: a review and analysis|journal=History of Psychiatry|volume=18|issue=1|pages=39–60|doi=10.1177/0957154X07070335|pmid=17580753|s2cid=21086497}}</ref> 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 Finland in 1975. Early testing was performed in the United States around the same time.<ref name="Cri2007"/><!-- cites previous three sentences --> In 1975  16 cases of [[agranulocytosis]] leading to 8 deaths in clozapine-treated patients were reported from 6 hospitals, mostly in southwestern Finland led to concern. <ref>{{Cite journal|last=Idänpään-Heikkilä|first=Juhana|last2=Alhava|first2=Eeva|last3=Olkinuora|first3=Martti|last4=Palva|first4=Ilmari|date=1975-09|title=CLOZAPINE AND AGRANULOCYTOSIS|url=https://doi.org/10.1016/S0140-6736(75)90206-8|journal=The Lancet|volume=306|issue=7935|pages=611|doi=10.1016/s0140-6736(75)90206-8|issn=0140-6736}}</ref> Analysis of the Finnish cases revealed that all the agranulocytosis cases had occurred within the first 18 weeks of treatment and the authors proposed blood monitoring during this period. <ref>{{Cite journal|last=Amsler|first=H. A.|last2=Teerenhovi|first2=L.|last3=Barth|first3=E.|last4=Harjula|first4=K.|last5=Vuopio|first5=P.|date=1977-10|title=Agranulocytosis in patients treated with clozapine.: A STUDY OF THE FINNISH EPIDEMIC|url=https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0447.1977.tb00224.x|journal=Acta Psychiatrica Scandinavica|language=en|volume=56|issue=4|pages=241–248|doi=10.1111/j.1600-0447.1977.tb00224.x|issn=0001-690X}}</ref> The rate of agranulocytosis in Finland appeared to be 20 times higher than in the rest of the world and there was speculation that this may have been due a unique genetic diversity in the region.  <ref>{{cite journal|vauthors=Griffith RW, Saameli K|date=October 1975|title=Letter: Clozapine and agranulocytosis|journal=Lancet|volume=2|issue=7936|pages=657|doi=10.1016/s0140-6736(75)90135-x|pmid=52022|s2cid=53296036}}</ref><ref name="Legge2019">{{cite journal|vauthors=Legge SE, Walters JT|date=March 2019|title=Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective|journal=Pharmacogenomics|volume=20|issue=4|pages=279–290|doi=10.2217/pgs-2018-0188|pmc=6563116|pmid=30767710}}</ref><ref name="deWith2017">{{cite journal|vauthors=de With SA, Pulit SL, Staal WG, Kahn RS, Ophoff RA|date=July 2017|title=More than 25 years of genetic studies of clozapine-induced agranulocytosis|journal=The Pharmacogenomics Journal|volume=17|issue=4|pages=304–311|doi=10.1038/tpj.2017.6|pmid=28418011|s2cid=5007914}}</ref> Whilst the drug continued to be manufactured by [[Sandoz]] and remained available in Europe development in the U.S. halted.   Interest in clozapine continued in an investigational capacity in the United States because eben in the 1980's the duration of hospitalisation, especially in [[State hospital|State Hospitals]] for those with treatment resistant schizophrenia might often be measured in years rather than days<ref>{{Cite journal|last=Crilly|first=John|date=2007-03|title=The history of clozapine and its emergence in the US market: a review and analysis|url=http://journals.sagepub.com/doi/10.1177/0957154X07070335|journal=History of Psychiatry|language=en|volume=18|issue=1|pages=39–60|doi=10.1177/0957154X07070335|issn=0957-154X}}</ref>.  The role of clozapine in treatment resistant schizophrenia was established by the landmark  Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. This involved both stringent blood monitoring and a double blind design with 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 61mg +/- 14mg/d). Two hundred and sixty eight were randomised were  to double blind trials of clozapine (upto 900 mg/d)  or chlorpromazine (upto 1800mg/d).  30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas.<ref name=":0" />   Following this study 1990, the US [[Food and Drug Administration]] (FDA) approved its use. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.<ref name="deWith2017" /><ref>{{cite book | vauthors = Healy D |title=The Psychopharmacologists |date=8 May 2018 |doi=10.1201/9780203736159 |isbn=9780203736159  }}</ref> In December 2002, clozapine was approved in the US for reducing the risk of suicide in schizophrenic or [[schizoaffective]] patients judged to be at chronic risk for suicidal behavior.<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/19758se1-047ltr.pdf |title=Supplemental NDA Approval Letter for Clozaril, NDA 19-758 / S-047 |date=18 December 2002 |publisher=United States Food and Drug Administration |access-date=23 November 2012 |archive-url=https://web.archive.org/web/20131108024629/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/19758se1-047ltr.pdf |archive-date=8 November 2013 |url-status=dead }}</ref> In 2005, the FDA approved criteria to allow reduced blood monitoring frequency.<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019758s054ltr.pdf |title=Letter to Novartis Pharmaceuticals Corporation |access-date=20 September 2009 |url-status=live |archive-url=https://web.archive.org/web/20110511063325/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019758s054ltr.pdf |archive-date=11 May 2011 }}</ref>
 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.<ref>{{cite news |title=FDA Modifies REMS Program for Clozapine |url=https://www.raps.org/news-and-articles/news-articles/2019/1/fda-modifies-rems-program-for-clozapine |access-date=14 August 2021 |work=www.raps.org}}</ref>Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and no not include total white cell counts, international monitoring has not been standardised<ref>{{Cite journal|last=Sultan|first=Ryan S.|last2=Olfson|first2=Mark|last3=Correll|first3=Christoph U.|last4=Duncan|first4=Erica J.|date=2017-10-25|title=Evaluating the Effect of the Changes in FDA Guidelines for Clozapine Monitoring|url=http://dx.doi.org/10.4088/jcp.16m11152|journal=The Journal of Clinical Psychiatry|volume=78|issue=8|pages=e933–e939|doi=10.4088/jcp.16m11152|issn=0160-6689}}</ref><ref>{{Cite journal|last=Nielsen|first=Jimmi|last2=Young|first2=Corina|last3=Ifteni|first3=Petru|last4=Kishimoto|first4=Taishiro|last5=Xiang|first5=Yu-Tao|last6=Schulte|first6=Peter F. J.|last7=Correll|first7=Christoph U.|last8=Taylor|first8=David|date=2016-02|title=Worldwide Differences in Regulations of Clozapine Use|url=http://dx.doi.org/10.1007/s40263-016-0311-1|journal=CNS Drugs|volume=30|issue=2|pages=149–161|doi=10.1007/s40263-016-0311-1|issn=1172-7047}}</ref><ref>{{Cite journal|last=Oloyede|first=Ebenezer|last2=Casetta|first2=Cecilia|last3=Dzahini|first3=Olubanke|last4=Segev|first4=Aviv|last5=Gaughran|first5=Fiona|last6=Shergill|first6=Sukhi|last7=Mijovic|first7=Alek|last8=Helthuis|first8=Marinka|last9=Whiskey|first9=Eromona|last10=MacCabe|first10=James Hunter|last11=Taylor|first11=David|date=2021-07-01|title=There Is Life After the UK Clozapine Central Non-Rechallenge Database|url=https://doi.org/10.1093/schbul/sbab006|journal=Schizophrenia Bulletin|volume=47|issue=4|pages=1088–1098|doi=10.1093/schbul/sbab006|issn=0586-7614|pmc=PMC8266568|pmid=33543755}}</ref>.

v t e Antipsychotics (N05A)
Typical	Butyrophenones: Benperidol Bromperidol Bromperidol decanoate Droperidol Haloperidol^# Haloperidol decanoate Moperone Pipamperone Spiperone Timiperone Trifluperidol Diphenylbutylpiperidines: Fluspirilene Penfluridol Pimozide Phenothiazines: Acepromazine Acetophenazine Butaperazine Carphenazine (carfenazine)^‡ Chlorpromazine Cyamemazine Dixyrazine Fluphenazine Fluphenazine decanoate Fluphenazine enanthate Levomepromazine (methotrimeprazine) Mesoridazine Perazine Periciazine Perphenazine BL-1020 Perphenazine decanoate Perphenazine enanthate Piperacetazine Pipotiazine Pipotiazine palmitate Pipotiazine undecylenate Prochlorperazine Promazine Sulforidazine Thiopropazate Thioproperazine Thioridazine Trifluoperazine Triflupromazine Thioxanthenes: Chlorprothixene Clopenthixol Clopenthixol decanoate Flupentixol Flupentixol decanoate Tiotixene (thiothixene) Zuclopenthixol Zuclopenthixol acetate Zuclopenthixol decanoate
Disputed	Benzamides: Amisulpride Levosulpiride Nemonapride Remoxipride^‡ Sulpiride Sultopride Tiapride Veralipride^‡ Butyrophenones: Melperone Tricyclics: Carpipramine Clocapramine Clorotepine Clotiapine Loxapine Mosapramine Oxyprothepin decanoate Others: Molindone
Atypical	Benzisoxazole/benzisothiazoles: Iloperidone Lurasidone Paliperidone Paliperidone palmitate Perospirone Risperidone^# Ziprasidone Butyrophenones: Lumateperone Phenylpiperazines/quinolinones: Aripiprazole Aripiprazole lauroxil Brilaroxazine^† Brexpiprazole Cariprazine Tricyclics: Asenapine Clozapine^# Olanzapine (+samidorphan) Quetiapine Zotepine Others: Blonanserin Pimavanserin Sertindole
Others	Monoamine-depleting agents: Oxypertine Reserpine Tetrabenazine Others/unknown: Azacyclonol
^#WHO-EM ^‡Withdrawn from market Clinical trials: ^†Phase III ^§Never to phase III

v t e Mood stabilizers
Anticonvulsants	Carbamazepine Lamotrigine Oxcarbazepine Valproate Valnoctamide Valproate pivoxil Valpromide
Atypical antipsychotics	Aripiprazole Asenapine Cariprazine Clozapine Lurasidone Olanzapine (+fluoxetine) Paliperidone Quetiapine Risperidone Ziprasidone
Others	Ketamine Lithium (lithium acetate, lithium carbonate, lithium chloride, lithium citrate, lithium hydroxide, lithium orotate) Omega-3 fatty acids (docosahexaenoic acid, eicosapentaenoic acid)

v t e Tricyclics
Classes	Acridine Anthracene Dibenzazepine Dibenzocycloheptene Dibenzodiazepine Dibenzothiazepine Dibenzothiepin Dibenzoxazepine Dibenzoxepin Phenothiazine Pyridazinobenzoxazine Pyridinobenzodiazepine Thioxanthene
Antidepressants (Tricyclic antidepressants (TCAs))	Amoxapine Amezepine Amineptine Amitriptyline Amitriptylinoxide Amoxapine Aptazapine Azepindole Batelapine Butriptyline Cianopramine Ciclazindol Cidoxepin Clomipramine Cotriptyline Cyanodothiepin Demexiptiline Depramine (balipramine) (desmethylimipramine) Desmethylclomipramine Desmethyltrimipramine Dibenzepin Dimetacrine Dosulepin (dothiepin) Doxepin Enprazepine Fantridone Fluotracen Hepzidine Homopipramol Imipramine Imipraminoxide Intriptyline Iprindole Ketipramine Litracen Lofepramine Losindole Loxapine Maprotiline Mariptiline Mazindol Melitracen Metapramine Mezepine Mirtazapine Monometacrine Nitroxazepine Norbutriptyline Nordoxepin Northiaden (nordosulepin) Nortriptyline (noramitriptyline) Noxiptiline Octriptyline Opipramol Pipofezine Pirandamine Propizepine Protriptyline Quinupramine Spiroxepin Tandamine Tampramine Tianeptine Tienopramine Trimipramine
Antihistamines	Azatadine Bisulepin Clobenzepam Cyproheptadine Dacemazine Deptropine Desloratadine Epinastine Etymemazine Fenethazine Hydroxyethylpromethazine Isopromethazine Isothipendyl Ketotifen Latrepirdine Loratadine Mebhydrolin Mequitazine Methdilazine Olopatadine Oxomemazine Phenindamine Pimethixene Promethazine Propiomazine Rupatadine Thiazinamium
Antipsychotics	Acetophenazine Alimemazine Amoxapine Asenapine Butaclamol Butaperazine Carfenazine (carphenazine) Carpipramine Chlorpromazine Chlorprothixene Ciclindole Citatepine Clocapramine Clomacran Clorotepine Clotiapine Clozapine Cyanothepin Doclothepin Docloxythepin Erizepine Flucindole Flumezapine Fluotracen Flupentixol Fluphenazine Gevotroline Homopipramol Isofloxythepin Levomepromazine/Methotrimeprazine Loxapine Lurasidone Maroxepin Meperathiepin Mesoridazine Metiapine Metitepine Metoxepin Mosapramine Naranol Octomethothepin Olanzapine Oxyclothepin Oxyprothepin Pentiapine Peradithiepin Perathiepin Perazine Perphenazine Periciazine Pinoxepin Piperacetazine Pipotiazine Piquindone Prochlorperazine Promazine Prothipendyl Quetiapine Savoxepin/Cipazoxapine Sulforidazine Tenilapine Thiethylperazine Thiopropazate Thioridazine Thiothixene Tilozepine Traboxopine Trifluoperazine Triflupromazine Trifluthepin Zotepine Zuclopenthixol
Anticonvulsants	Carbamazepine Dizocilpine Eslicarbazepine Eslicarbazepine acetate Etazepine Licarbazepine Oxcarbazepine Oxitriptyline Rispenzepine
Anticholinergics	Profenamine Tropatepine
Others	Adosopine Aminopromazine Atiprosin Beloxepin Benzoctamine Carvedilol Cidoxepin Cyclobenzaprine Damotepine Darenzepine Elanzepine Fluradoline Methylene blue Monatepil Nuvenzepine Oxetorone Perlapine Pipazethate P7C3 Pinadoline Pirenzepine Pirolate Pitrazepin Pizotifen Serazapine Siltenzepine Telenzepine Tipindole Zolenzepine

Clozapine: Difference between revisions

Revision as of 19:21, 14 September 2021

Clinical uses

Adverse effects

Agranulocytosis

Cardiac toxicity

Gastrointestinal hypomotility

Hypersalivation

Central nervous system

Urinary incontinence

Withdrawal effects

Weight gain and diabetes

Overdose

Drug interactions

Pharmacology

Pharmacodynamics

Pharmacokinetics

Chemistry

Synthesis

Detection in body fluids

History^[104]

Society and culture

Economics

See also

References

Further reading

External links

Revision as of 19:21, 14 September 2021

Clinical uses

Adverse effects

Agranulocytosis

Cardiac toxicity

Gastrointestinal hypomotility

Hypersalivation

Central nervous system

Urinary incontinence

Withdrawal effects

Weight gain and diabetes

Overdose

Drug interactions

Pharmacology

Pharmacodynamics

Pharmacokinetics

Chemistry

Synthesis

Detection in body fluids

History[104]

Society and culture

Economics

See also

References

Further reading

External links

History^[104]