Clozapine

What it is

Clozapine is an antipsychotic for treatment-resistant schizophrenia. This means symptoms have not improved enough after two different antipsychotics, each taken at a proper dose for long enough.² Between a quarter and a third of people with schizophrenia are treatment-resistant.³ Guidelines recommend offering them clozapine.⁴

It is also used, at much lower doses, for psychosis in Parkinson’s disease when other treatments have failed.² That psychosis comes partly from the medicines that raise dopamine, and partly from the disease itself: it becomes more common the longer someone has Parkinson’s.⁵ At low doses, clozapine eases it without making movement worse.⁶

How it works

Most antipsychotics work mainly by blocking dopamine D2 receptors. In a brain-scan study of haloperidol, people were likely to respond once the medicine occupied more than 65 in 100 of these receptors, and stiffness and tremor became likely above 78 in 100.⁷ At the doses used in practice, clozapine occupies only 16 to 68 in 100 D2 receptors. It occupies even more of the serotonin 5-HT2 receptors, at every dose.⁸

Clozapine binds to many receptors more strongly than to D2. It binds most strongly to receptors for noradrenaline (α1), histamine (H1) and serotonin (5-HT2A and 5-HT2C), then to the acetylcholine receptor M1 and the dopamine receptor D4. It binds to D2 about 70 times more weakly than haloperidol does.⁹

The D4 receptor was discovered in 1991, when it turned out that clozapine binds to it more strongly than to D2.¹⁰ D4 receptors sit in different parts of the brain. D2 receptors are concentrated in the striatum, deep in the brain, which helps control movement. D4 receptors are found mainly in the prefrontal cortex, the hippocampus and the thalamus, and hardly at all in the striatum.^11,12 That made D4 look like the reason clozapine works without causing stiffness. But in a 1997 trial, a medicine that blocks only D4 did not help people with schizophrenia.¹³

Clozapine’s main breakdown product in the body, norclozapine (N-desmethylclozapine), does something no other antipsychotic does: it activates M1 receptors for acetylcholine instead of blocking them.¹⁴ The newer medicine Cobenfy also works by activating these receptors: see what its trial found (opens in a new tab).

Which of these actions explains why clozapine works when other antipsychotics have not is still unknown. Its effect on acetylcholine probably causes constipation.²

History

Clozapine was discovered in 1958,¹⁵ in a Swiss laboratory, among compounds related to the antidepressant imipramine. Trials in the 1960s showed that it treated psychosis without the stiffness and tremor that older antipsychotics caused.¹⁶ It went on sale in Europe in the 1970s.¹⁷

In 1975, within six months of its introduction in Finland, 17 of about 3,000 people taking it developed a dangerous drop in white blood cells, and 8 of them died.¹⁸ Clozapine was withdrawn in Finland and the rest of Europe, and kept for people with no other option.¹⁶

It was approved in the Netherlands in January 1988.² Later that year, a US trial showed that it worked when other antipsychotics had failed,¹ and the United States approved it in 1989.¹⁹ In 2025, the European Medicines Agency made blood tests less frequent after the first year, because the risk falls over time.²⁰ The same year, the US regulator ended its special monitoring programme, though blood tests are still advised there.²¹

How well it works

Outcome	Clozapine	Chlorpromazine
Responded to treatment	30	4

The 1988 trial included 268 people.¹ Later reviews point the same way:

• In 21 trials, clozapine helped more than other antipsychotics, in the short and the long term, especially with hallucinations and delusions.²²
• About 40 in 100 people with treatment-resistant schizophrenia respond to it. On average, their symptoms fall by about a quarter.³
• In a two-year trial of 980 people at high risk of suicide, fewer attempted suicide on clozapine than on olanzapine: 34 against 55.²³ In the United States, it is also approved to reduce suicidal behaviour.²⁴
• In long-term studies, people who stayed on clozapine were less likely to die of any cause than people on other antipsychotics.²⁵ These studies observed people rather than assigning treatments, so other differences may explain part of this.

Not every analysis agrees. Across 40 blinded trials, clozapine was clearly better than haloperidol and sertindole, but not clearly better than most newer antipsychotics.²⁶ Its authors suggest that trials with higher doses and more severely ill people are needed to settle the question.

Improvement can take time. In one study, about a third of people improved in the first week, and another 44 in 100 by the end of a year.² If there is no response after about six months, reviewers suggest moving to medicines with fewer side effects.²²

Side effects

The side effects above are from the European product information.² Three need particular care:

• White blood cells. About 4 in 100 people develop a drop in neutrophils, the white blood cells that fight infection, and about 1 in 100 a severe drop. The risk is highest in the first months and becomes very small after the first year. About 1 in 7,700 people prescribed clozapine die of it.²⁷ This is what the blood tests are for.
• The heart. The risk of myocarditis is greatest in the first two months.² Across studies of 258,961 people, about 7 in 1,000 people taking clozapine developed it, more than the product information’s “rare” suggests. About 4 in 10,000 died of it. Rates were higher in Australia, partly because doctors there look for it more.²⁸
• The bowel. Constipation can turn into a blocked bowel, which has in rare cases been fatal. That is why it is treated early.²

In trials, between 7 and 16 in 100 people stopped clozapine because of side effects.² Long-term use has been linked to a small rise in blood cancers: 0.7 in 100 people on clozapine against 0.5 in 100 on other antipsychotics, over about 12 years.²

Get medical help straight away for fever, a sore throat, mouth ulcers or other signs of infection; chest pain, palpitations, breathlessness or a racing heart at rest; severe constipation, stomach pain or vomiting; a seizure; yellowing of the skin or eyes; or high fever with stiff muscles and confusion.²

Side effects can be reported to Lareb, the Dutch side-effects centre, or to the manufacturer.

Administration

Clozapine comes as tablets, taken once or twice a day, often with the larger part at bedtime. It is started at a very low dose and raised slowly over two to three weeks, under close medical supervision, to limit low blood pressure, seizures and sleepiness. If more than two days are missed, it is started again from a low dose.²

Neutrophils are counted before the first dose, then weekly for 18 weeks, monthly until the end of the first year, every 12 weeks in the second year, and once a year after that, as long as the counts stay normal.^2,20 Each prescription only covers the time until the next test. Weight, blood sugar and blood fats are checked at the start and regularly afterwards, and a heart trace (ECG) is often done before starting.²

Measuring the level of clozapine in the blood helps to set the dose. This matters most for women, people of Asian origin and non-smokers.¹⁷

Smoking lowers the level of clozapine in the blood. So when someone stops smoking, the clozapine level rises and can bring on side effects. Coffee raises the clozapine level too. Tell the prescriber about any change in smoking or coffee habits, as the dose may need changing.²

Contraindications and cautions

Clozapine is not used in people who:²

• cannot have regular blood tests
• have had a severe drop in white blood cells on clozapine or another medicine (other than chemotherapy), or have a bone marrow disorder
• have epilepsy that is not under control
• have severe heart or kidney disease, active liver disease, or a paralysed bowel
• are intoxicated with alcohol or drugs

It is not combined with carbamazepine, an epilepsy medicine that can also suppress the bone marrow. Alcohol adds to the sleepiness and should be avoided. Some medicines raise clozapine levels, including the antidepressant fluvoxamine, the antibiotic ciprofloxacin and hormonal contraceptives. Taking benzodiazepines, a group of sedatives, at the same time raises the risk of a sudden collapse.²

There is little data on clozapine in pregnancy, so it is prescribed with caution, and babies exposed to it late in pregnancy are watched after birth. Breastfeeding is not advised. Driving should be avoided, especially in the first weeks. People over 60 start on an even lower dose.²

Stopping

Clozapine is stopped gradually, over one to two weeks. Stopping suddenly can bring psychotic symptoms back quickly, and can cause a rebound of sweating, headache, nausea, vomiting and diarrhoea. When it has to stop at once because white blood cells have fallen too low, people are watched closely, and clozapine is not started again.²

Alternatives

When clozapine has not helped enough, specialists may add a second medicine. The best evidence is for aripiprazole, another antipsychotic; fluoxetine, an antidepressant; and sodium valproate, an epilepsy medicine. Most of these trials were small, short and of poor quality.²⁹ Adding electroconvulsive therapy (ECT) helped more people respond in 18 trials, though memory complaints and headaches were more common.³⁰

When side effects rule clozapine out, other antipsychotics are used. In blinded trials in treatment-resistant schizophrenia, olanzapine and risperidone often did about as well.²⁶ Guidelines also recommend cognitive behavioural therapy for psychosis (opens in a new tab) alongside medicine.⁴

What we don’t know yet

• Why clozapine works when other antipsychotics have not.
• How to tell, before starting, who will respond.
• How best to help the people who do not respond to clozapine either.