Clozapine, sold under the brand name Clozaril among others,[1] is an atypical antipsychotic medication.[2] It is mainly used for schizophrenia that does not improve following the use of other antipsychotic medications.[2] In those with schizophrenia and schizoaffective disorder it may decrease the rate of suicidal behavior.[2] It is more effective than typical antipsychotics, particularly in those who are treatment-resistant.[4][5][6] It is used by mouth,[2] or by injection into a muscle.[7]

Clinical data
Trade namesClozaril, Leponex, Versacloz, others[1]
  • AU: C
  • US: B (No risk in non-human studies) [2]
    Routes of
    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-life6 to 26 hours (mean value 14.2 hours in steady state conditions)
    Excretion80% in metabolized state: 30% biliary and 50% kidney
    CAS Number
    PubChem CID
    CompTox Dashboard (EPA)
    ECHA InfoCard100.024.831
    Chemical and physical data
    Molar mass326.83 g·mol−1
    3D model (JSmol)
    Melting point183 °C (361 °F)
    Solubility in water0.1889[3] mg/mL (20 °C)

    Clozapine is associated with a relatively high risk of low white blood cells (agranulocytosis), a condition of suppressed immunity which may result in death.[2] To decrease this risk, it is recommended that the white blood cell count be regularly monitored.[2] 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.[2][8] Common side effects include drowsiness, decreased or increased saliva production, low blood pressure, blurred vision, and dizziness.[2] The potentially permanent movement disorder tardive dyskinesia occurs in about 5% of people.[8] Its mechanism of action is not entirely clear.[2]

    Clozapine was first made in 1956 and sold commercially in 1972.[9][10] It was the first atypical antipsychotic.[11] It is on the WHO Model List of Essential Medicines, which lists the most effective and safe medicines needed in a health system.[12] It is available as a generic medication.[2] The wholesale cost in the developing world is between US$0.05 and US$2.10 per day as of 2014.[13]

    Medical uses

    Clozapine is an atypical antipsychotic drug primarily used in people who are unresponsive to or intolerant to other antipsychotics.[5] This means that they have failed to respond satisfactorily to at least two different antipsychotics.[14] It has been shown to be more effective in reducing symptoms of schizophrenia than typical antipsychotics, with more pronounced effects in those who have responded poorly to other medication.[4]

    Clozapine is usually given by mouth in tablet or liquid form,[2] however an unlicensed short-acting intramuscular injectable formulation is available. It is not a depot injection, and instead has a similar duration of action as clozapine by mouth. The injectable formulation may be used in highly agitated people with schizophrenia who consistently refuse clozapine by mouth, but are predicted to respond well to clozapine therapy, with the injection being administered with the intention of transitioning the person to oral clozapine.[7] The injectable form is reportedly difficult to use due to painful administration, higher doses requiring injection into multiple sites simultaneously, and even more stringent monitoring than oral clozapine (with the additional difficulty of withdrawing blood samples for testing from agitated individuals).[7]

    In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, clozapine was ranked first and demonstrated very high effectiveness. 25% more effective than amisulpride (2nd), 33% more effective than olanzapine (3rd), and twice as effective as haloperidol, quetiapine, and aripiprazole.[4]

    The effect of clozapine, however, is not (at least in the short term) reflected in measures of global functioning such as ability to leave the hospital and maintain an occupation. The relapse rate is lower and patient acceptability is better.[5] There is some evidence clozapine may reduce propensity for substance abuse in schizophrenic patients.[15]

    It may be better than other antipsychotics in people with both schizophrenia and Parkinson's disease.[16]

    Clozapine is not recommended for the treatment of behavior problems in older adults with dementia.

    Side effects

    Clozapine may cause side effects, some of which are serious and potentially fatal. Common side 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.[17]

    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.[18] 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.[19]

    Many males have experienced cessation of ejaculation during orgasm as a side effect of clozapine, though this is not documented in official drug guides.[20]

    However, many side-effects can be managed and do not necessarily warrant discontinuation.[21]


    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;[22] the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year.[23] Within the context of trials, the potentially dangerous white blood cell decline seems to be more frequent in children and adolescents and in the elderly than in young adults or people of middle age.

    Clozapine-induced agranulocytosis can be transient.[24]

    Cardiac toxicity

    Myocarditis is a sometimes fatal side effect of clozapine, which usually develops within the first month of commencement.[25] 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.[26] 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.[27]

    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.[28] Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers.[29] Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis.[30] A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication.[31] 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.[32]


    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.[33]

    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.[34]

    Urinary incontinence

    Clozapine is linked to urinary incontinence,[35] though its appearance may be under-recognized.[36]

    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 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.[37][38]

    Weight gain and diabetes

    In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.[39] 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.[40] 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).[41]


    Fatalities have been reported due to clozapine overdose, though overdoses > 4000 mg have been survived.[42]

    Drug interactions

    Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.[43]

    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.[44][45] 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.[46]

    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.[47]

    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.[48] 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.[49]



    Clozapine and norclozapine binding[50][51]
    Protein CZP Ki (nM) NDMC Ki (nM)
    The smaller the value, the more strongly the drug binds to the site. All data are for cloned human proteins.[50][51]

    Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.[52]

    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.[53][54]

    A direct interaction of clozapine with the GABAB receptor has also been shown.[55] GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.[56] GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.[57]

    Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,[58] 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.[59]


    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. 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.[60]

    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.[61] 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.[60]


    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).[3] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).[62]


    Detection in body fluids


    Clozapine was synthesized in 1956[9] 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.[10] 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.[10] In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer.[63] Clozapine fell out of favor for more than a decade despite unclear reasons for the agranulocytosis which occurred in Finland, the rate of which was 20 times higher[64] than had been reported in any other country. 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 Restricted Distribution, a Patient Registry and 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.[65] In 2005 FDA approved criteria to allow reduced blood monitoring frequency.[66] In 2015 the individual manufacturer Patient Registries were consolidated by FDA request into a single shared Patient Registry Called The Clozapine REMS Registry.

    Society and culture


    It is available as a generic medication.[2] The wholesale cost in the developing world is between 0.05 and US$2.10 per day as of 2014.[13] In the United Kingdom the injectable form is about 100 pounds per dose.[7]

    Brand names

    List of trade names for clozapine[1]
    AAlemoxan, Azaleptine, Azaleptol
    CCloment, Clonex, Clopin, Clopine, Clopsine, Cloril, Clorilex, Clozamed, Clozapex, Clozapin, Clozapina, Clozapinum, Clozapyl, Clozarem, Clozaril
    DDenzapine, Dicomex
    EElcrit, Excloza
    FFazaClo, Froidir
    LLanolept, Lapenax, Leponex, Lodux, Lozapine, Lozatric, Luften
    MMedazepine, Mezapin
    NNemea, Nirva
    OOzadep, Ozapim
    RRefract, Refraxol
    SSanosen, Schizonex, Sensipin, Sequax, Sicozapina, Sizoril, Syclop, Syzopin
    ZZaclo, Zapenia, Zapine, Zaponex, Zaporil, Ziproc, Zopin

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    Further reading

    • Benkert O, Hippius H. Kompendium der Psychiatrischen Pharmakotherapie (in German) (4th ed.). Springer Verlag.
    • Bandelow B, Bleich S, Kropp S. Handbuch Psychopharmaka (in German) (2nd ed.). Hogrefe.
    • Crilly J (March 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.
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