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| StdInChIKey = QZUDBNBUXVUHMW-UHFFFAOYSA-N
| melting_point = 183
| melting_point = 183
| solubility = 0.1889<ref name ="Hopfinger"/>}}
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<!-- Definition and medical uses -->
'''Clozapine''' is an [[atypical antipsychotic]] medication used in the treatment of [[schizophrenia]], and is also sometimes used [[off-label]] for the treatment of [[bipolar disorder]] and [[borderline personality disorder]]. The first of the atypical antipsychotics to be developed, it was first introduced in Europe in 1971, but was voluntarily withdrawn by the manufacturer in 1975 after it was shown to cause [[agranulocytosis]], a condition involving a dangerous decrease in the number of [[white blood cells]], that led to death in some patients. In 1989 after studies demonstrated that it was effective in treating treatment-resistant schizophrenia<ref>{{cite journal | vauthors = Kane J, Honigfeld G, Singer J, Meltzer H | title = Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine | journal = Archives of General Psychiatry | volume = 45 | issue = 9 | pages = 789–796 | date = Sep 1988 | pmid = 3046553 | doi = 10.1001/archpsyc.1988.01800330013001 }}</ref> the United States [[Food and Drug Administration]] (FDA) approved the use of clozapine solely for that use, requiring regular [[Complete blood count#White cells|white blood cell]] and [[absolute neutrophil count]]s.<ref>{{cite web | url = http://www.clozapineregistry.com/insert.pdf.ashx | format = pdf | publisher = TEVA Clozapine Patient Registry | title = From Clozapine Package Insert: Frequency of Monitoring based on Stage of Therapy or Results from WBC Count and ANC Monitoring Tests | accessdate = 2012-08-18 }}</ref><ref>{{cite journal |url=http://www.time.com/time/magazine/article/0,9171,975910-5,00.html |title=Awakenings Schizophrenia a New Drug Brings Patients Back to Life |journal=Time |author=Wallis C & Willwerth J |date= July 6, 1992 |accessdate=2008-10-09}}</ref> The FDA also requires clozapine to carry five [[black box warnings]] for agranulocytosis, [[seizures]], [[myocarditis]], for "other adverse cardiovascular and respiratory effects", and for "increased mortality in elderly patients with dementia-related psychosis."<ref>{{cite web|url=http://www.rxlist.com/cgi/generic/clozapine.htm |title=Clozaril (Clozapine) drug description - FDA approved labeling for prescription drugs and medications at RxList |publisher=Rxlist.com |accessdate=2008-10-09}}</ref> In 2002 the FDA approved clozapine for reducing the risk of [[suicidal behavior]] for patients with schizophrenia.
'''Clozapine''', sold under the brand name '''Clozaril''' among others, is an [[atypical antipsychotic]] medication.<ref name=AHFS2015>{{cite web|title=Clozapine|url=http://www.drugs.com/monograph/clozapine.html|publisher=The American Society of Health-System Pharmacists|accessdate=Dec 1, 2015}}</ref> It is mainly used for [[schizophrenia]] that does not improve following the use of other antipsychotic medication.<ref name=AHFS2015/> In those with schizophrenia and [[schizoaffective disorder]] it may decrease the rate of [[suicidal behavior]].<ref name=AHFS2015/> It maybe more effective than [[typical antipsychotic]]s.<ref>{{cite journal|last1=Essali|first1=A|last2=Al-Haj Haasan|first2=N|last3=Li|first3=C|last4=Rathbone|first4=J|title=Clozapine versus typical neuroleptic medication for schizophrenia.|journal=The Cochrane database of systematic reviews|date=21 January 2009|issue=1|pages=CD000059|pmid=19160174}}</ref> It is taken by mouth.<ref name=AHFS2015/>


Clozapine is usually used only in patients that have not responded to other anti-psychotic treatments due to its danger of causing [[agranulocytosis]] as well as the costs of having to have blood tests continually during treatment. It is, however, one of the most effective anti-psychotic treatment choices.<ref>{{cite web | url = http://www.nimh.nih.gov/health/publications/mental-health-medications/what-medications-are-used-to-treat-schizophrenia.shtml | title = What medications are used to treat schizophrenia? | accessdate = 2012-08-18 | author = [[National Institute of Mental Health]]}}</ref> Patients are monitored weekly for the first six months. If there are no low counts the patient can be monitored every two weeks for an additional six months. Afterwards, the patient may qualify for every four-week monitoring.<ref>{{cite web | url = http://www.clozapineregistry.com/Table1.pdf.ashx | format = pdf | publisher = TEVA Clozapine Patient Registry | title = From Clozapine Package Insert: Frequency of Monitoring based on Stage of Therapy or Results from WBC Count and ANC Monitoring Tests | accessdate = 2012-08-18 }}</ref> Clozapine has numerous severe side effects including agranulocytosis, and seizures,<ref>{{cite journal | vauthors = Devinsky O, Honigfeld G, Patin J | title = Clozapine-related seizures | journal = Neurology | volume = 41 | issue = 3 | pages = 369–371 | date = Mar 1991 | pmid = 2006003 | doi = 10.1212/wnl.41.3.369 }}</ref> and has been associated with myocarditis<ref>{{cite journal | vauthors = De Berardis D, Serroni N, Campanella D, Olivieri L, Ferri F, Carano A, Cavuto M, Martinotti G, Cicconetti A, Piersanti M, Saverio Moschetta F, Di Giannantonio M | title = Update on the adverse effects of clozapine: focus on myocarditis | journal = Current Drug Safety | volume = 7 | issue = 1 | pages = 55–62 | date = Feb 2012 | pmid = 22663959 | doi = 10.2174/157488612800492681 }}</ref> and [[diabetes]]<ref>{{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 = Oct 2012 | pmid = 22893011 | pmc = | doi = 10.7326/0003-4819-157-7-201210020-00525 }}</ref> though those relationships have not been confirmed. Additionally, it also often causes less serious side effects such as [[hypersalivation]] and [[weight gain]]. <!-- Society and culture -->


<!-- Side effects -->
It has one of the least probabilities of causing [[Extrapyramidal symptoms|extrapyramidal side-effects]] compared to typical antipsychotics.<ref>{{cite journal | vauthors = Peacock L, Solgaard T, Lublin H, Gerlach J | title = Clozapine versus typical antipsychotics. A retro- and prospective study of extrapyramidal side effects | journal = Psychopharmacology | volume = 124 | issue = 1-2 | pages = 188–96 | date = Mar 1996 | pmid = 8935815 | doi = 10.1007/bf02245620 }}</ref>
Clozapine is associated with a fairly high risk of [[agranulocytosis|low white blood cells]] which may result in death.<!-- <ref name=AHFS2015/> --> To decrease this risk it is recommended that the blood be regularly monitored.<ref name=AHFS2015/> Other serious risks include [[seizures]], [[myocarditis|inflammation of the heart]], [[hyperglycemia|high blood sugar levels]], and in older people with psychosis as a result of [[dementia]] an increased risk of death.<ref name=AHFS2015/><ref name=Hart2012>{{cite journal|last1=Hartling|first1=L|last2=Abou-Setta|first2=AM|last3=Dursun|first3=S|last4=Mousavi|first4=SS|last5=Pasichnyk|first5=D|last6=Newton|first6=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|date=2 October 2012|volume=157|issue=7|pages=498-511|pmid=22893011}}</ref> Common side effects include [[sedation|sleepiness]], dry mouth, [[low blood pressure]], and trouble seeing, and dizziness.<!-- <ref name=AHFS2015/> --> Its mechanism of action is not entirely clear.<ref name=AHFS2015/> The potentially permanent movement disorder [[tardive dyskinesia]] occurs in about 5% of people.<ref name=Hart2012/>
It is on the [[World Health Organization's List of Essential Medicines]], a list of the most important medication needed in a basic [[health system]].<ref>{{cite web|title=WHO Model List of EssentialMedicines|url=http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1|work=World Health Organization|accessdate=22 April 2014|date=October 2013}}</ref>



<!-- History, society and culture -->
The first of the atypical antipsychotics to be developed, it was first introduced in Europe in 1971, but was voluntarily withdrawn by the manufacturer in 1975 after it was shown to cause [[agranulocytosis]], a condition involving a dangerous decrease in the number of [[white blood cells]], that led to death in some patients. In 1989 after studies demonstrated that it was effective in treating treatment-resistant schizophrenia<ref>{{cite journal | vauthors = Kane J, Honigfeld G, Singer J, Meltzer H | title = Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine | journal = Archives of General Psychiatry | volume = 45 | issue = 9 | pages = 789–796 | date = Sep 1988 | pmid = 3046553 | doi = 10.1001/archpsyc.1988.01800330013001 }}</ref> It is on the [[World Health Organization's List of Essential Medicines]], a list of the most important medication needed in a basic [[health system]].<ref>{{cite web|title=WHO Model List of EssentialMedicines|url=http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1|work=World Health Organization|accessdate=22 April 2014|date=October 2013}}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/> The wholesale cost is between 0.05 and 2.10 USD per day as of 2014.<ref>{{cite web|title=Clozapine|url=http://erc.msh.org/dmpguide/resultsdetail.cfm?language=english&code=CLZ100T&s_year=2014&year=2014&str=100%20mg&desc=Clozapine&pack=new&frm=TAB-CAP&rte=PO&class_code2=24%2E1%2E&supplement=&class_name=%2824%2E1%2E%29Medicines%20used%20in%20psychotic%20disorders%3Cbr%3E|website=International Drug Price Indicator Guide|accessdate=2 December 2015}}</ref>


==Medical uses==
==Medical uses==

Revision as of 11:04, 2 December 2015

Clozapine
Skeletal formula of clozapine
Stick-and-ball model of the clozapine molecule
Clinical data
Trade namesClozaril
AHFS/Drugs.comMonograph
MedlinePlusa691001
Pregnancy
category
  • AU: C
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60 to 70%
MetabolismHepatic, by several CYP isozymes
Elimination half-life6 to 26 hours (mean value 14.2 hours in steady state conditions)
Excretion80% in metabolized state: 30% biliary and 50% renal
Identifiers
  • 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.024.831 Edit this at Wikidata
Chemical and physical data
FormulaC18H19ClN4
Molar mass326.823 g/mol g·mol−1
3D model (JSmol)
Melting point183 °C (361 °F)
Solubility in water0.1889[2] mg/mL (20 °C)
  • CN1CCN(CC1)C2=Nc3cc(ccc3Nc4c2cccc4)Cl
  • 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 checkY
  • Key:QZUDBNBUXVUHMW-UHFFFAOYSA-N checkY
  (verify)

Clozapine, sold under the brand name Clozaril among others, is an atypical antipsychotic medication.[3] It is mainly used for schizophrenia that does not improve following the use of other antipsychotic medication.[3] In those with schizophrenia and schizoaffective disorder it may decrease the rate of suicidal behavior.[3] It maybe more effective than typical antipsychotics.[4] It is taken by mouth.[3]


Clozapine is associated with a fairly high risk of low white blood cells which may result in death. To decrease this risk it is recommended that the blood be regularly monitored.[3] Other serious risks include seizures, inflammation of the heart, high blood sugar levels, and in older people with psychosis as a result of dementia an increased risk of death.[3][5] Common side effects include sleepiness, dry mouth, low blood pressure, and trouble seeing, and dizziness. Its mechanism of action is not entirely clear.[3] The potentially permanent movement disorder tardive dyskinesia occurs in about 5% of people.[5]


The first of the atypical antipsychotics to be developed, it was first introduced in Europe in 1971, but was voluntarily withdrawn by the manufacturer in 1975 after it was shown to cause agranulocytosis, a condition involving a dangerous decrease in the number of white blood cells, that led to death in some patients. In 1989 after studies demonstrated that it was effective in treating treatment-resistant schizophrenia[6] It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[7] It is available as a generic medication.[3] The wholesale cost is between 0.05 and 2.10 USD per day as of 2014.[8]

Medical uses

Clozapine is an atypical antipsychotic drug primarily prescribed to patients who are unresponsive to or intolerant of conventional and other atypical neuroleptics.[9] It is used principally in treating treatment-resistant schizophrenia,[10] a term used for the failure of symptoms to respond satisfactorily to at least two different antipsychotics.[11] It has been shown to be more effective in reducing symptoms of schizophrenia than the older typical antipsychotics, with more pronounced effects in those who have responded poorly to other medication. The relapse rate is lower and patient acceptability is better.[10] There is some evidence clozapine may reduce propensity for substance abuse in schizophrenic patients.[12]

There has been one case report of successful use of clozapine in isolated increase in creatine kinase (in absence of neuroleptic malignant syndrome) in a patient with schizophrenia where other atypical antipsychotics were not successful.[13]

A number of case reports indicate that clozapine can be an effective treatment for schizophrenia while at the same time diminishing some symptoms associated with Parkinson's, such as the tremor and dyskinesia. Unlike typical antipsychotics such as haloperidol and some atypical antipsychotics such as risperidone, clozapine does not produce Parkinsonian symptoms, even at high doses. This is in part because it binds relatively weakly to the D2 dopamine receptor, compared to most other antipsychotics.[14] Clozapine is not approved by the Food and Drug Administration (FDA) for the treatment of behavior problems in older adults with dementia.

Adverse effects

Clozapine may cause side effects. Some are serious and potentially fatal. Common side effects include extreme 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.[15]

Clozapine also carries five black box warnings, including warnings for agranulocytosis, CNS depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension (with or without syncope) and seizures.[16] Lowering of the seizure threshold may be dose related and slow initial titration of dose may decrease the risk for precipitating seizures. Slow titration of dosing may also decrease the risk for orthostatic hypotension and other adverse cardiovascular side effects.[17]

Many male patients have experienced cessation of ejaculation during orgasm as a side effect of clozapine, though this is not documented in official drug guides.[18]

However, many side-effects can be managed and do not necessarily warrant discontinuation.[19]

Agranulocytosis

Main article: Agranulocytosis

Clozapine carries a black box warning for drug-induced agranulocytosis. Without monitoring, agranulocytosis occurs in about 1% of patients who take clozapine during the first few months of treatment;[20] the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year.[21]

Clozapine induced agranulocytosis can be transient.[22]

Cardiac toxicity

Myocarditis is a sometimes fatal side effect of clozapine, which usually develops within the first month of commencement.[23] 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.[24] Signs of cardiac 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.[25]

Gastrointestinal hypomotility

Another underrecognized and potentially life-threatening side effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis. Monitoring of bowel function is recommended, as untreated cases are occasionally fatal.[26][27]

Hypersalivation

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 the hypersalivation.[28]

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.[29]

Urinary incontinence

Clozapine is linked to urinary incontinence[30] though its appearance may be under-recognized.[31]

Withdrawal effects

Abrupt withdrawal may lead to cholinergic rebound effects, severe movement disorders as well as severe psychotic decompensation. It has been recommended that patients, families, and caregivers are 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.[32][33]

Weight gain and diabetes

In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.[34] 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.[35] 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).[36]

Interactions

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.[37]

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.[38][39] 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.[40]

Published case reports have stated that the use of benzodiazepines and clozapine concomitantly can result in severe adverse reaction such as respiratory arrest, cardiac arrest and sudden death.[41]

Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate. Randomized study reported elevation in clozapine concentration in schizophrenia subjects concurrently taking ciprofloxacin.[42] 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.[43]

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 188.9 mg/L (25 °C).[2] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).[44]

Mechanism of action

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.[45]

Clozapine is a partial agonist[46] at the 5-HT1A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.[47]

A direct interaction of clozapine with the GABAB receptor has also been shown.[48] GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.[49] GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.[50]

Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,[51] 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.[52]

Binding Affinity (Ki [nM]) towards cloned human receptors unless otherwise specified[53]

Receptor/Transporter Protein Clozapine Norclozapine
SERT 1624 316.6
NET 3168 493.9
DAT >10,000 >10,000
5-HT1A 123.7 13.9
5-HT1B 519 406.8
5-HT1D 1356 476.2
5-HT2A 5.35 10.9
5-HT2B 8.37 2.8
5-HT2C 9.44 11.9
5-HT3 241 272.2
5-HT5A 3857 350.6
5-HT6 13.49 11.6
5-HT7 17.95 60.1
D1 266.25 14.3
D2 157 101.4
D3 269.08 193.5
D4 26.36 63.94
D5 255.33 283.6
α1A 1.62 104.8
α1B 7 85.2
α2A 37 137.6
α2B 26.5 95.1
α2C 6 117.7
β1 5000 6239
β2 1650 4725
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
H1 1.13 3.4
H2 153 345.1
H3 >10,000 >10,000
H4 665 1028
δ-opioid 1000 (Mouse receptor) 127.9
μ-opioid 1000 (Rat receptor) >10,000
κ-opioid 1000 (Guinea pig receptor) >10,000
σ1 5000 (Guinea pig receptor) >10,000
σ2 - >10,000

Pharmacokinetics

Norclozapine (N-desmethylclozapine), clozapine's chief active metabolite

The absorption of clozapine is almost complete, 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. 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.[54]

Clozapine and norclozapine plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age.[55] 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 optimization.[54]

History

Clozapine was developed by Sandoz in 1961, and trials took place in 1972, when it 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.[56] In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer.[57] Clozapine fell out of favor for more than a decade. However, when studies demonstrated that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics, the FDA and health authorities in most other countries approved its use only for treatment-resistant schizophrenia, and required regular hematological monitoring to detect granulocytopenia, before agranulocytosis develops. 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.[58] In 2005 FDA approved criteria to allow reduced blood monitoring frequency.[59]

Marketing

As of 2014, three pharmaceutical companies market this drug: Novartis Pharmaceuticals (manufacturer), Mylan Laboratories and Teva Pharmaceuticals (market generic clozapine).[60] In India the drug is manufactured by Sun Pharmaceuticals.

See also

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ a b Hopfinger A, Esposito EX, Llinas A, Glen RC, Goodman JM. (2009). "Findings of the Challenge To Predict Aqueous Solubility". Journal of Chemical Information and Modeling. 49: 1–5. doi:10.1021/ci800436c.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ a b c d e f g h "Clozapine". The American Society of Health-System Pharmacists. Retrieved Dec 1, 2015.
  4. ^ Essali, A; Al-Haj Haasan, N; Li, C; Rathbone, J (21 January 2009). "Clozapine versus typical neuroleptic medication for schizophrenia". The Cochrane database of systematic reviews (1): CD000059. PMID 19160174.
  5. ^ a b Hartling, L; Abou-Setta, AM; Dursun, S; Mousavi, SS; Pasichnyk, D; Newton, AS (2 October 2012). "Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis". Annals of internal medicine. 157 (7): 498–511. PMID 22893011.
  6. ^ Kane J, Honigfeld G, Singer J, Meltzer H (Sep 1988). "Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine". Archives of General Psychiatry. 45 (9): 789–796. doi:10.1001/archpsyc.1988.01800330013001. PMID 3046553.
  7. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  8. ^ "Clozapine". International Drug Price Indicator Guide. Retrieved 2 December 2015.
  9. ^ MIMS Ireland. April 2007.
  10. ^ a b Wahlbeck K, Cheine M, Essali MA (2007). Wahlbeck K (ed.). "Clozapine versus typical neuroleptic medication for schizophrenia". The Cochrane Database of Systematic Reviews (2). John Wiley and Sons, Ltd.: CD000059. doi:10.1002/14651858.CD000059. PMID 10796289.
  11. ^ Meltzer HY (1997). "Treatment-resistant schizophrenia--the role of clozapine". Current Medical Research and Opinion. 14 (1): 1–20. doi:10.1185/03007999709113338. PMID 9524789.
  12. ^ Lee M, Dickson RA, Campbell M, Oliphant J, Gretton H, Dalby JT. (1998). "Clozapine and substance abuse in patients with schizophrenia". Canadian Journal of Psychiatry. 43: 855–856.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ P03-358 Clozapine may be the answer: a case report of elevated serum creatine kinase in the absence of NMS. A. Mohandas, N. Talwar, A. James Langdon Hospital, Devon Partnership NHS Trust, Dawlish, UK
  14. ^ "How would you treat someone who has both schizophrenia and Parkinson's disease?".
  15. ^ "Clozapine".
  16. ^ http://www.clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=142&sec=monadve
  17. ^ "Clozapine".
  18. ^ Baggaley M (Apr 2008). "Sexual dysfunction in schizophrenia: focus on recent evidence". Human Psychopharmacology. 23 (3): 201–209. doi:10.1002/hup.924. PMID 18338766.
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Further reading

  • Benkert, Hippius: Kompendium der Psychiatrischen Pharmakotherapie (German), 4th. ed., Springer Verlag
  • B. Bandelow, S. Bleich, and S. Kropp: Handbuch Psychopharmaka (German), 2nd. ed. Hogrefe
  • Crilly J (Mar 2007). "The history of clozapine and its emergence in the US market: a review and analysis". History of Psychiatry. 18 (1): 39–60. doi:10.1177/0957154X07070335. PMID 17580753.

External links

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