Clozapine, sold under the brand name Clozaril among others, is a psychiatric medication and was the first atypical antipsychotic to be discovered.[4] It is used primarily to treat people with schizophrenia and schizoaffective disorder who have had an inadequate response to two other antipsychotics, or who have been unable to tolerate other drugs due to extrapyramidal side effects. In the US, clozapine is also approved for use in people with recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder.[5] It is also used for the treatment of psychosis in Parkinson's disease.
Clozapine is recommended by multiple international treatment guidelines, after resistance to two other antipsychotic medications, and is the only treatment likely to result in improvement if two (or one) other antipsychotic has not had a satisfactory effect.[6] Long term follow-up studies from Finland show significant improvements in terms of overall mortality including from suicide and all causes. Clozapine is on the World Health Organization's List of Essential Medicines.[7] It is available as a generic medication. Common adverse effects include drowsiness, constipation, hypersalivation (increased saliva production), tachycardia, low blood pressure, blurred vision, significant weight gain, and dizziness. Clozapine is not normally associated with tardive dyskinesia and is recommended as the drug of choice when this is present, although some case reports describe clozapine-induced tardive dyskinesia.[8] Serious adverse effects include agranulocytosis, seizures, myocarditis (inflammation of the heart), and hyperglycemia (high blood glucose levels). The use of clozapine may result rarely in clozapine-induced, gastric hypomotility syndrome, which may lead to bowel obstruction and death.[9][10] The mechanism of action is not clear.
Medical uses
Schizophrenia
The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark multicenter double blind study[11] in which clozapine (up to 900 mg/d) showed marked benefits compared to chlorpromazine (up to 1800 mg/d) in a group of patients with protracted psychosis who had already shown an inadequate response to at least three previous antipsychotics including a prior single blind trial of haloperidol (mean 61+/− 14 mg/d for six weeks). While there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response. The use of clozapine is associated with multiple improved outcomes, including a reduced rate of all-cause mortality, suicide and hospitalization.[12] In a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs.[13] In a 2021 UK study, the majority of patients (over 85% of respondents) who took clozapine preferred it to their previous therapies, felt better on it and wanted to keep taking it. In a 2000 Canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness. UK studies into the perspectives of people taking clozapine and their families following treatment with and discontinuation of clozapine describe significant stress and fearfulness of clozapine being stopped.
Administration
Initiation
Whilst clozapine is usually initiated in hospital setting community initiation is also available.[52][53] Before clozapine can be initiated multiple assessments and baseline investigations are performed. In the UK and Ireland there must be an assessment that the patient satisfies the criteria for prescription; treatment resistant schizophrenia, intolerance due to extrapyramidal symptoms of other antipsychotics or psychosis in Parkinson's disease. Establishing a history of treatment resistance may include careful review of the medication history including the durations, doses and compliance of previous antipsychotic therapy and that these did not have an adequate clinical effect. A diagnostic review may also be performed. That could include review of antipsychotic plasma concentrations if available. The prescriber, patient, pharmacy and the laboratory performing blood counts are all registered with a specified clozapine provider who must be advised that there is no history of neutropenia from any cause. The clozapine providers collaborate by sharing information regarding patients who have had clozapine related neutropenia or agranulocytosis so that clozapine cannot be used again on license. Clozapine may only be dispensed after a satisfactory blood result has been received by the risk monitoring agency at which point an individual prescription may be released to an individual patient only.[54]
Adverse effects
Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries boxed warnings, including severe neutropenia (low levels of neutrophils); orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting; seizures; myocarditis (inflammation of the heart); and risk of death when used in elderly people with dementia-related psychosis.[85] Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.
However overall mortality for people with schizophrenia prescribed clozapine is lower than those prescribed other drugs and much lower than those who are unmedicated.[32]
Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, high blood sugar, increased rate of infections,[86] and weight gain.
Drug interactions
Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.[152]
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.[153][154] 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.[155]
Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate.
Pharmacology
Pharmacodynamics
Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.[164] It acts as an antagonist at both receptors.
Clozapine is an inverse agonist at the 5-HT2A subtype of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.[165][166]
A direct interaction of clozapine with the GABAB receptor has also been shown.[167] GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.
Chemistry
Clozapine is a dibenzodiazepine[164][175] that is structurally very similar to loxapine (originally deemed a typical antipsychotic). It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C).[176] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).[177]
History
Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine.[178] The first test in humans in 1962 was considered a failure. Trials in Germany in 1965 and 1966 as well as a trial in Vienna in 1966 were successful. In 1967, Wander AG was acquired by Sandoz. Further trials took place in 1972 when clozapine was released in Switzerland and Austria as Leponex. Two years later, it was released in West Germany and in Finland in 1975. Early testing was performed in the United States around the same time. In 1975, 16 cases of agranulocytosis leading to 8 deaths in clozapine-treated patients, reported from 6 hospitals mostly in southwestern Finland, led to concern.[179] 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.[180] 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 variant in the region.[181][182]
Society and culture
Research
Further reading
References
- Anvisa. RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial Diário Oficial da União, 31 March 2023, retrieved 16 August 2023^
- Clozaril Product information Health Canada, 8 April 2016, retrieved 16 February 2025^
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/019758s101lbl.pdf, p.23^