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==Adverse effects==
==Adverse effects==
Clozapine may cause serious and potentially fatal adverse effects. Common effects include [[constipation]], bed-wetting, night-time [[drooling]], [[muscle stiffness]], [[sedation]], [[tremor]]s, [[orthostatic hypotension]] (low blood pressure upon changing positions), 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.<ref>{{cite web |url=https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril |title=Clozapine |url-status=live |archive-url=https://web.archive.org/web/20131110214051/https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril |archive-date=10 November 2013 }}</ref>
Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries five [[Boxed warning|black box warnings]], including (1) severe [[neutropenia]] (low levels of neutrophils), (2) orthostatic hypotension, including [[bradycardia|slow heart rate]] and [[syncope|fainting]], (3) seizures, (4) [[myocarditis]] (inflammation of the heart), and (5) risk of death when used in elderly people with dementia-related psychosis.<ref name="Clozaril FDA label"/> Lowering of the [[seizure threshold]] may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.<ref name="MCQ">{{Cite web|url=https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril|title=Clozapine|url-status=live|archive-url=https://web.archive.org/web/20131110214051/https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril|archive-date=10 November 2013}}</ref>


Clozapine carries five [[Boxed warning|black box warnings]], including (1) severe [[neutropenia]] (low levels of neutrophils), (2) orthostatic hypotension, including [[bradycardia|slow heart rate]] and [[syncope|fainting]], (3) seizures, (4) [[myocarditis]] (inflammation of the heart), and (5) risk of death when used in elderly people with dementia-related psychosis.<ref name="Clozaril FDA label"/> Lowering of the [[seizure threshold]] may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.<ref name="MCQ">{{Cite web|url=https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril|title=Clozapine|url-status=live|archive-url=https://web.archive.org/web/20131110214051/https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril|archive-date=10 November 2013}}</ref>
Common effects include [[constipation]], bed-wetting, night-time [[drooling]], [[muscle stiffness]], [[sedation]], [[tremor]]s, [[orthostatic hypotension]] (low blood pressure upon changing positions), 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.<ref>{{cite web |url=https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril |title=Clozapine |url-status=live |archive-url=https://web.archive.org/web/20131110214051/https://sites.google.com/site/pharmacologymcqs/clozapine-clozaril |archive-date=10 November 2013 }}</ref> Sexual problems, like [[retrograde ejaculation]], have been reported while taking clozapine.<ref name="Clozaril FDA label"/> Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.<ref>{{cite journal | vauthors = Nielsen J, Correll CU, Manu P, Kane JM | title = Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? | journal = The Journal of Clinical Psychiatry | volume = 74 | issue = 6 | pages = 603–13 | date = June 2013 | pmid = 23842012 | doi = 10.4088/JCP.12r08064 }}</ref>

Many males have experienced cessation of [[ejaculation]] during [[orgasm]] as a side effect of clozapine, though this is not documented in official drug guides.<ref>{{cite journal | vauthors = Baggaley M | title = Sexual dysfunction in schizophrenia: focus on recent evidence | journal = Human Psychopharmacology | volume = 23 | issue = 3 | pages = 201–209 | date = April 2008 | pmid = 18338766 | doi = 10.1002/hup.924 | s2cid = 30468671 }}</ref>

However, many side-effects can be managed and may not warrant discontinuation.<ref>{{cite journal | vauthors = Nielsen J, Correll CU, Manu P, Kane JM | title = Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? | journal = The Journal of Clinical Psychiatry | volume = 74 | issue = 6 | pages = 603–13 | date = June 2013 | pmid = 23842012 | doi = 10.4088/JCP.12r08064 }}</ref>


===Agranulocytosis===
===Agranulocytosis===

Revision as of 22:00, 14 September 2021

Not to be confused with clonazepam or clonidine.

Clozapine
Skeletal formula of clozapine
Stick-and-ball model of the clozapine molecule
Clinical data
Trade namesClozaril, Leponex, Versacloz, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa691001
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, intramuscular injection
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60 to 70%
MetabolismLiver, by several CYP isozymes
Elimination half-life4 to 26 hours (mean value 14.2 hours in steady state conditions)
Excretion80% in metabolized state: 30% biliary and 50% kidney
Identifiers
  • 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 mass326.83 g·mol−1
3D model (JSmol)
Melting point183 °C (361 °F)
Solubility in water0.1889[4]
  • 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,[1] is the first atypical antipsychotic medication.[5] It is usually used in tablet or liquid form for people diagnosed with schizophrenia who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson's Disease.[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]Whilst there are significant side effects clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response and clozapine use is associated with multiple improved outcomes including all cause mortality, suicide and reduced hospitalisation.[17][18]

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%.[19] 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[20] 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.[21] 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.[22] Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks.[19] 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.[23][24] Common adverse effects include drowsiness, increased saliva production, low blood pressure, blurred vision, weight gain, and dizziness.[25] Clozapine is not normally associated with tardive dyskinesia (TD) and is recommended as the drug of choice when this is present although some case reports describe clozapine-induced TD[26]. Its mechanism of action is not entirely clear.[25]

In a network comparative meta-analysis of 15 antipsychotic drugs clozapine was significantly more effective than all other drugs.[27]

It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[28] It is available as a generic medication.[25]

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][29] [30] Whilst all current guidelines reserve clozapine to individuals when two other antipsychotics evidence indicates that clozapine might be used as a second line drug[31]. Clozapine treatment has been demonstrated to produced improved outcomes in multiple domains including; a reduced risk of hospitalisation, a reduced risk of drug discontinuation, a reduction in overall symptoms and has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia. [32][33][34] Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics.[35] Very long term follow-up studies reveal multiple benefits in terms of reduced mortality,[36][37] 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.[38] Clozapine has a significant anti-aggressive effect.[39][40][41][42][43] Clozapine is widely used in secure and forensic mental health settings where improvements in aggression, shortened admission and reductions in restrictive practice such as seclusion have been found[44][45][46][47][48][49][50][51][52]. In secure hospitals clozapine has also been used in the treatment of borderline and antisocial personality disorder when this has been associated with violence or self-harm. [53][54][55] Although oral treatment is almost universal clozapine has on occasion been enforced using either nasogastric or a short acting injection although in almost 50% of the reported cases patients agreed to take oral medication prior to the use of a coercive intervention.[56] [57][58][59][60][61][62][63][64][65][66]

Clozapine is widely recognised as being underused with wide variation in prescribing [67][68][69][70][71][72][73][74], especially in patients with African heritage[75][76][77][78][79]. Part of the explanation for the underuse of clozapine in patients with African heritage is the presence of benign ethnic neutropenia. Benign reductions in neutrophils are observed in individuals of all ethnic backgrounds. Benign ethnic neutropenia (BEN), neutropenia without immune dysfunction or increased liability to infection is not due to abnormal neutrophil production; although, the exact aetiology of the reduction in circulating cells remains unknown. BEN is associated with several ethnic groups, but in particular those with Black African and West African ancestry.[80] A difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations[81]. For significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use as the thresholds did not take BEN into account.Since 2002, clozapine monitoring services in the UK have used reference ranges 0.5 × 109/l lower for patients with haematologically confirmed BEN and similar adjustments are available in the current US criteria, although with lower permissible minima.[82] [83] The Duffy–Null polymorphism, which protects against some types of malaria, is predictive of BEN[84]

Adverse effects

Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries five black box warnings, including (1) severe neutropenia (low levels of neutrophils), (2) orthostatic hypotension, including slow heart rate and fainting, (3) seizures, (4) myocarditis (inflammation of the heart), and (5) risk of death when used in elderly people with dementia-related psychosis.[3] Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.[85]

Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension (low blood pressure upon changing positions), 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.[86] Sexual problems, like retrograde ejaculation, have been reported while taking clozapine.[3] Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.[87]

Agranulocytosis

Main article: Agranulocytosis

Agranulocytosis is a severe decrease in the amount of a specific kind of white blood cell called granulocytes. Clozapine carries a black box warning for drug-induced agranulocytosis. Without monitoring, agranulocytosis occurs in about 1% of people who take clozapine during the first few months of treatment;[88] the risk of developing it is highest within the first three months of treatment and decreases substantially to less than 0.01% after one year.[89] People that take clozapine undergo routine absolute neutrophil count (ANC) monitoring (neutrophils are the most abundant of the granulocytes); for example, in the United States, the Risk Evaluation and Mitigation Strategy (REMS) for clozapine involves routine ANC monitoring.[90]

Rapid point-of-care tests may simplify the monitoring for agranulocytosis.[91]

A clozapine "rechallenge" is when someone that experienced agranulocytosis while taking clozapine starts taking the medication again. Early findings suggest that the concurrent use of granulocyte colony-stimulating factor (GCSF) to maintain the neutrophil count during a clozapine rechallenge is safe and effective. However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited.[92][93]

Cardiac toxicity

Myocarditis is a sometimes fatal effect of clozapine, which usually develops within the first month of commencement.[94] 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.[95] 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.[96]

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.[97] Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers.[98] Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis.[99] A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication.[100] 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.[101]

Hypersalivation

Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30-80%).[102] 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.[102] 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.[103] Clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication.[102] Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically-absorbed anticholinergic medications like diphenhydramine[102] and topical anticholinergic medications like ipratropium bromide.[104] Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.[104]

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.[105]

Urinary incontinence

Clozapine is linked to urinary incontinence,[106] though its appearance may be under-recognized.[107]

Withdrawal effects

Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation.[108] Abrupt withdrawal can also cause severe movement disorders, catatonia, and psychosis.[109] 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.[110][111]

Weight gain and diabetes

In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.[112] 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.[113]

Overdose

Fatalities have been reported due to clozapine overdose, though overdoses > 4000 mg have been survived.[114]

Drug interactions

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.[115]

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.[116][117] 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.[118]

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.[119] 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.[120]

Pharmacology

Pharmacodynamics

See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Clozapine and norclozapine binding[121][122]
Protein CZP Ki (nM) NDMCTooltip N-Desmethylclozapine Ki (nM)
5-HT1A 123.7 13.9
5-HT1B 519 406.8
5-HT1D 1,356 476.2
5-HT2A 5.35 10.9
5-HT2B 8.37 2.8
5-HT2C 9.44 11.9
5-HT3 241 272.2
5-HT5A 3,857 350.6
5-HT6 13.49 11.6
5-HT7 17.95 60.1
α1A 1.62 104.8
α1B 7 85.2
α2A 37 137.6
α2B 26.5 95.1
α2C 6 117.7
β1 5,000 6,239
β2 1,650 4,725
D1 266.25 14.3
D2 157 101.4
D3 269.08 193.5
D4 26.36 63.94
D5 255.33 283.6
H1 1.13 3.4
H2 153 345.1
H3 >10,000 >10,000
H4 665 1,028
M1 6.17 67.6
M2 36.67 414.5
M3 19.25 95.7
M4 15.33 169.9
M5 15.5 35.4
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.[121][122]

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.[123]

Clozapine is an antagonist at the 5-HT2A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.[124][125]

A direct interaction of clozapine with the GABAB receptor has also been shown.[126] GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.[127] GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.[128]

Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,[129] 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.[130]

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.[131] 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.[132]

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.[133] 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.[132]

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).[134]

Synthesis

Detection in body fluids

History[135]

Clozapine was synthesized in 1956[136] 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.[137] 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.[137] 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.[138] 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.[139] 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.[140][141][142] Whilst the drug continued to be manufactured by Sandoz and remained available in Europe development in the U.S. halted.

Interest in clozapine continued in an investigational capacity in the United States because even in the 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.[143] 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,[needs copy edit] 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.[142][144]

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.[145] In 2005, the FDA approved criteria to allow reduced blood monitoring frequency.[146] 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.[147] 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.[148][149][150]

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

Despite the expense of the risk monitoring and management systems required clozapine use is highly cost effective with a number of studies suggesting savings of tens of thousands of dollars per patient per year compared to other antipsychotics as well as advantages regarding improvements in quality of life. [151][152][153]Clozapine is available as a generic medication.[25]

Clozapine in the arts

Carrie Mathison, a fictional CIA operative in the television series Homeland secretly takes clozapine supplied by her sister for the treatment of bipolar affective disorder.

In the film Out of Darkness Diana Ross played the protagonist Paulie Cooper, 'a paranoid schizophrenic' who is depicted as having a dramatic improvement on clozapine.

References

  1. ^ a b c "Clozapine International Brands". Drugs.com. Archived from the original on 1 March 2017. Retrieved 28 February 2017.
  2. ^ "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 October 2023.
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Further reading

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