Antipsychotics: types, mechanism of action, clinical effects, adverse effects, long-acting injectable (depot) antipsychotics, indications, and monitoring

01Drug classification

Antipsychotics, once called neuroleptics or major tranquillisers, treat psychosis whatever its cause: schizophrenia, mania, psychotic depression, delirium and psychosis from drugs. Their story begins with a drug that calmed surgical patients.

1. 1952

   Chlorpromazine

   Synthesised as an antihistamine and tried in anaesthesia, chlorpromazine is given to psychotic patients in Paris by Jean Delay and Pierre Deniker. Within a few years it is used worldwide, and it helps empty the asylums over the following decades.

2. 1958

   Haloperidol

   Paul Janssen's laboratory in Belgium makes haloperidol, a far more potent D2 blocker, still in use worldwide.

3. 1975

   Clozapine withdrawn

   Clozapine, which hardly causes stiffness, is withdrawn in many countries after deaths from agranulocytosis in Finland.

4. 1988

   Clozapine returns

   John Kane's trial shows it helps patients whom other antipsychotics have failed, and it returns with compulsory blood monitoring.

5. 1990s and 2000s

   Second generation and partial agonists

   Risperidone, olanzapine and quetiapine bring fewer movement disorders but more weight gain; aripiprazole, which partly stimulates D2 receptors, follows.

6. 2024

   A muscarinic drug

   The US licenses xanomeline–trospium, the first antipsychotic that does not act on dopamine receptors.

The drugs are grouped as first generation (typical) or second generation (atypical). The split is by date and by how easily a drug causes extrapyramidal effects, not a clean difference in how they work, and the first-generation drugs are themselves grouped by chemistry.

02Pharmacokinetics

Antipsychotics are taken by mouth, most once a day, and are fat-soluble, widely distributed and largely protein-bound. Most are cleared by the liver's cytochromes, so CYP2D6, CYP3A4 and CYP1A2 decide their interactions. Paliperidone and amisulpride are the exceptions, leaving mostly unchanged in the urine.

Asenapine is a tablet that dissolves under the tongue, as almost none is absorbed if swallowed, and nothing is eaten or drunk for 10 minutes after.

A depot is the drug as an ester in oil, or as crystals or microspheres in water, injected into a muscle and released over weeks; the oily decanoates take months to reach a steady level.

03Pharmacodynamics

Every antipsychotic in wide use acts at the D2 receptor. Blocking it in the mesolimbic pathway relieves the positive symptoms of psychosis. Blocking it elsewhere explains much of what goes wrong, because dopamine has four main pathways in the brain.

D2 occupancy, above which psychosis is likely to respond

65per centD2 occupancy, above which psychosis is likely to respond

above which prolactin rises

72per centabove which prolactin rises

above which extrapyramidal effects become likely

78per centabove which extrapyramidal effects become likely

This window, from positron emission tomography in first-episode patients, is why more drug is rarely better: a dose that pushes occupancy past about 80 per cent adds side effects, not benefit. Clozapine and quetiapine work at occupancies below the window, as they let go of the receptor quickly.

What else each drug blocks predicts its other effects.

Partial agonists

Aripiprazole, brexpiprazole and cariprazine bind D2 receptors tightly but stimulate them only partly. Where dopamine is high, as in the striatum in psychosis, they lower its effect; where it is low, they raise it a little. Prolactin falls, and they cause little parkinsonism, but restlessness (akathisia) and nausea are common. Because they occupy the receptor so tightly, they can block other antipsychotics when added and can be hard to switch from quickly.

Muscarinic agonism

Xanomeline stimulates M1 and M4 receptors in the brain, which lowers dopamine release in the striatum indirectly, through cholinergic neurons and their circuits, and may help cognition. Alone it causes nausea, vomiting, sweating and salivation, so it is paired with trospium, a muscarinic blocker that stays outside the brain. It eased psychotic symptoms against placebo in three five-week trials; added to another antipsychotic, in a later trial, it did not.

Clozapine

Clozapine blocks D2 receptors weakly and briefly and acts on D1, D4, 5-HT2A, muscarinic, histamine and α receptors, and its metabolite norclozapine stimulates muscarinic receptors. Why it works where others have failed is not known.

Time course and tolerance

1. 1

   Hours to days

   Sedation and calming come first, which is why antipsychotics help in acute agitation.
2. 2

   First 2 weeks

   Psychotic symptoms begin to ease in those who will respond; little improvement by 2 to 3 weeks at a good dose makes response less likely.
3. 3

   4 to 6 weeks

   Most of the response has come. A drug is judged after this long at an adequate dose before it is called a failure.
4. 4

   Months

   Negative and cognitive symptoms change little; continued treatment prevents relapse.

Long blockade makes D2 receptors more numerous and sensitive. This is thought to underlie tardive dyskinesia and the rebound psychosis that can follow stopping suddenly, and it is why antipsychotics are tapered, not stopped at once.

04Clinical indications

Antipsychotics treat psychosis in schizophrenia and the other psychotic disorders, calm the mania of bipolar disorder and help prevent its return. Smaller doses have many uses beyond psychiatry.

Choosing and starting

The trials of the last decade found the antipsychotics close in effect, clozapine apart, with amisulpride, olanzapine and risperidone slightly ahead in some comparisons. They differ far more in their side effects, and the choice is made with the patient, often with a carer, on which harms matter most to them.

Clozapine

Clozapine is the one antipsychotic shown to work in treatment-resistant schizophrenia: in Kane's trial 30 per cent improved against 4 per cent on chlorpromazine, and around 40 per cent respond in later studies. It also lowers suicide in schizophrenia and helps persistent aggression. Yet it is offered late or not at all in many services, and patients lose years to drugs that do not work.

1. 1

   Before starting

   The patient, the prescriber and the pharmacy are registered with a clozapine monitoring service. A baseline full blood count with a neutrophil count, an ECG, weight, waist, blood pressure, glucose or HbA1c, lipids, liver function and often troponin and CRP. Bowel habit is asked about.
2. 2

   Titration

   12.5 mg once or twice on the first day, then up by 25 to 50 mg a day towards about 300 mg a day over 2 to 3 weeks, more slowly in older people and outpatients. Pulse, blood pressure and temperature are checked during it. The usual dose is 200 to 450 mg a day, at most 900 mg.
3. 3

   Judging the response

   At least 8 to 12 weeks at a dose giving a plasma level of about 350 µg/L or more. Smoking, sex and age change the level a given dose gives.
4. 4

   Missed doses

   After more than 48 hours without it, clozapine is restarted at 12.5 mg and titrated up again, as the first dose can cause collapse. A longer break also restarts more frequent blood counts.

Agranulocytosis affects under 1 in 100 patients and neutropenia about 4 in 100, most often in the first 18 weeks. Monitoring is set nationally.

Long-acting injectable (depot) antipsychotics

A depot helps when relapses follow missed tablets, or when a patient prefers it. It guarantees that the drug is taken, or shows at once that it was not, and some studies find fewer relapses and admissions than with tablets.

05Adverse drug reactions

• Life-threatening
  Neuroleptic malignant syndrome: fever, lead-pipe rigidity, confusion and an unstable pulse and blood pressure, with a high creatine kinase, often in the thousands, a raised white count and myoglobin in the urine. It occurs in about 1 to 2 in 10,000 patients treated (older series give up to 2 in 1,000), usually in the first two weeks of a new drug or dose, and is likelier with potent drugs, injections, fast increases, dehydration and exhaustion. Every antipsychotic is stopped; cooling, fluids and benzodiazepines, often in intensive care; dantrolene or bromocriptine in severe cases. Up to 1 in 10 die.
• Life-threatening
  Agranulocytosis with clozapine, under 1 in 100, mostly in the first 18 weeks. Any sore throat, fever or flu-like illness means a neutrophil count the same day. Rarer with chlorpromazine and other phenothiazines.
• Life-threatening
  Myocarditis with clozapine, mostly in the first 2 months: fever, a fast pulse, chest pain, breathlessness, a raised troponin and CRP. Myocarditis means clozapine is stopped. A dilated cardiomyopathy can appear later.
• Life-threatening
  Constipation, ileus and bowel obstruction with clozapine, which kill a larger share of those affected than agranulocytosis does: 172 of 527 patients in UK reports from 1992 to 2017 died. Bowels are asked about at each visit, and laxatives (a softener with a stimulant, or macrogol) given early; abdominal pain, vomiting or no stool for days is an emergency.
• Life-threatening
  A long QT interval, torsades de pointes and sudden death. Sudden cardiac death is about twice as common in people on antipsychotics. A QTc above 500 ms, or a rise of more than 60 ms, means the drug is changed.
• Life-threatening
  Stroke and death in older people with dementia. In trials of antipsychotics in dementia lasting 10 to 12 weeks, 3.5 per cent died on the drug against 2.3 per cent on placebo, mostly from heart failure, sudden death and pneumonia, and strokes were about three times as common.
• Life-threatening
  Severe sensitivity in Lewy body dementia and Parkinson's disease: sudden worse parkinsonism, confusion, falls and collapse, sometimes fatal.
• Serious
  Diabetes, weight gain and high lipids, most with clozapine and olanzapine: often several kilograms in the first months, and in some, diabetes, rarely with ketoacidosis. They add to the 15 to 20 years of life lost in severe mental illness, mostly to heart disease.
• Serious
  Seizures, more likely the higher the dose; most with clozapine, above all over about 600 mg a day or at high levels, and chlorpromazine.
• Serious
  Venous thromboembolism, deep vein thrombosis and pulmonary embolism, more often with clozapine and the low-potency drugs, and in sedated, immobile patients.
• Serious
  Pneumonia, from sedation, drooling and a weak swallow, which kills many older patients on antipsychotics and is a leading cause of death on clozapine.
• Serious
  Extrapyramidal effects (below): acute dystonia, dangerous when it closes the larynx; akathisia, linked with suicide and violence; parkinsonism; and tardive dyskinesia, which can be permanent.
• Serious
  A high prolactin, with absent periods, milk from the breast, low libido, erectile problems, infertility and, over years, thin bones.
• Serious
  Priapism, from α1 blockade, an emergency within hours.
• Serious
  Antimuscarinic toxicity: urinary retention, confusion and delirium in older people, and worse narrow-angle glaucoma.
• Serious
  Cholestatic jaundice, rare, with chlorpromazine; liver tests rising on clozapine or olanzapine.
• Serious
  Olanzapine post-injection syndrome after the pamoate depot, when some of the dose enters a vessel, under 1 in 1,000 injections: sedation up to coma, or delirium, slurred speech, unsteadiness and stiffness, within hours. Each patient is watched for 3 hours in a clinic and goes home accompanied, not driving, that day.
• Serious
  Urinary retention, and a fast pulse and higher blood pressure, with xanomeline–trospium, early in treatment.

Extrapyramidal effects

Extrapyramidal effects come from D2 blockade in the striatum. Each has its own timing and treatment, and an antimuscarinic helps only some of them.

Tardive dyskinesia appears in roughly 4 to 5 per cent a year on first-generation drugs and less often on second-generation ones, and older people, women and those with mood disorders and early parkinsonism are at greater risk. Movements are rated before treatment and each year, with a scale such as the Abnormal Involuntary Movement Scale.

Monitoring

People with severe mental illness die years early, mostly from heart disease, so their physical health is checked as part of their treatment, and anything found is treated, not left to others.

06Side effects

• Mild
  Sleepiness, most with clozapine, olanzapine, quetiapine and chlorpromazine. A night-time dose helps.
• Mild
  Dry mouth, blurred vision and constipation, from muscarinic blockade.
• Mild
  Dizziness on standing, from α1 blockade, above all early and in older people.
• Mild
  Increased appetite and weight gain, starting in the first weeks; advice on diet and activity from the start, and metformin can limit it.
• Mild
  Sexual problems: lower desire, erectile and ejaculation problems, from prolactin and α1 blockade.
• Mild
  Drooling, mostly at night, with clozapine, in up to half of patients.
• Mild
  A fast pulse with clozapine, common early, though myocarditis is ruled out first.
• Mild
  A raised temperature in the first 3 weeks of clozapine, usually harmless, once infection and myocarditis are ruled out.
• Mild
  Bedwetting with clozapine.
• Mild
  Nausea, insomnia and restlessness with aripiprazole and cariprazine.
• Mild
  Sensitivity to sunlight with chlorpromazine.
• Mild
  Nausea, indigestion, vomiting and constipation with xanomeline–trospium, mostly in the first weeks.

07Contraindications

• Contraindicated
  Clozapine in anyone who cannot have regular blood counts, with past agranulocytosis or neutropenia from a drug or clozapine, a bone marrow disorder, uncontrolled epilepsy, paralytic ileus, active or progressive liver disease, severe kidney or heart disease, myocarditis, circulatory collapse, coma or drug intoxication; and with carbamazepine or other drugs that can cause agranulocytosis, or with a depot antipsychotic.
• Contraindicated
  Haloperidol with a known long QT, a recent heart attack, uncompensated heart failure, past ventricular arrhythmia or torsades, uncorrected low potassium, or other drugs that lengthen the QT; in Parkinson's disease, Lewy body dementia and progressive supranuclear palsy; and in coma or a lowered consciousness from other causes.
• Contraindicated
  Pimozide with a long QT, and with drugs that block CYP3A4 or CYP2D6, among them clarithromycin, azole antifungals and several SSRIs.
• Contraindicated
  Amisulpride and sulpiride with a prolactin-dependent tumour (a prolactinoma, breast cancer) or a phaeochromocytoma.
• Contraindicated
  Quetiapine and lurasidone with strong CYP3A4 inhibitors, such as HIV protease inhibitors, azole antifungals and clarithromycin; lurasidone also with strong inducers such as carbamazepine, rifampicin and St John's wort.
• Contraindicated
  Olanzapine with a known risk of narrow-angle glaucoma.
• Contraindicated
  Xanomeline–trospium with urinary retention, gastric retention, moderate or severe liver disease, or untreated narrow-angle glaucoma.
• Avoid
  Dementia, and above all Lewy body dementia, unless the patient or others are at serious risk and other measures have failed; then the lowest dose, briefly, reviewed.
• Avoid
  A depot in someone who has never taken the drug by mouth, as it cannot be withdrawn once given.
• Avoid
  Olanzapine by injection within an hour of a benzodiazepine by injection, for the risk of slowed breathing and collapse.
• Caution
  Heart disease, a long QT in the family, low potassium or magnesium, and other drugs that lengthen the QT, such as citalopram, methadone, macrolides and antiarrhythmics. An ECG first.
• Caution
  Epilepsy, as most antipsychotics lower the seizure threshold, clozapine and chlorpromazine most.
• Caution
  Diabetes, obesity and high lipids, which most drugs worsen; one with less metabolic effect is preferred.
• Caution
  Older people, an enlarged prostate and glaucoma: lower doses for falls, postural hypotension, confusion and pneumonia, and care with the antimuscarinic drugs.
• Caution
  Kidney and liver disease: paliperidone and amisulpride need lower doses as the kidneys fail, most others as the liver does.
• Caution
  Lithium, with which haloperidol and other antipsychotics have rarely caused neurotoxicity and neuroleptic malignant syndrome; lithium levels are watched (Mood stabilisers).
• Caution
  Enzyme inhibitors and inducers: fluvoxamine and ciprofloxacin raise clozapine and olanzapine; fluoxetine and paroxetine raise risperidone and aripiprazole; carbamazepine and rifampicin lower most antipsychotics. Aripiprazole is halved with strong inhibitors and doubled with strong inducers. Starting or stopping smoking changes clozapine and olanzapine levels.
• Caution
  Alcohol, opioids, benzodiazepines and other sedatives, which add to sedation and slowed breathing; clozapine with a benzodiazepine by injection has caused collapse.
• Caution
  Levodopa and dopamine agonists, which antipsychotics oppose.

08Pregnancy and lactation

• Caution
  Pregnancy. Large studies have not found that antipsychotics cause malformations, apart from a small possible rise with risperidone, while stopping one risks a relapse that harms mother and baby. The drug that keeps the woman well is usually continued, at the lowest effective dose, rather than switched; olanzapine, quetiapine, haloperidol and aripiprazole have the most data. Many product informations advise use only if clearly needed.
• Caution
  Gestational diabetes, more likely with olanzapine, quetiapine and clozapine, so glucose is checked early and a glucose tolerance test offered.
• Caution
  The newborn after use in the last trimester: restlessness, stiffness or floppiness, tremor, sleepiness, breathing and feeding problems, so the baby is watched after birth.
• Caution
  Clozapine in pregnancy, continued if it is what works, with glucose and levels checked, as they change towards term and after birth.
• Avoid
  Starting a depot in pregnancy or before a planned one, unless a depot is already working for a woman who has missed tablets before.
• Avoid
  Xanomeline–trospium in pregnancy and breastfeeding, for want of data.
• Compatible
  Breastfeeding with olanzapine or quetiapine, which pass into milk in small amounts; the baby is watched for sleepiness. Olanzapine's licence advises against breastfeeding, and quetiapine's asks that the benefit to mother and baby be weighed.
• Caution
  Breastfeeding with aripiprazole, probably compatible for the baby, but it lowers prolactin and so can reduce the milk supply.
• Avoid
  Breastfeeding with clozapine, which collects in milk and could cause sedation and agranulocytosis in the baby. e-lactancia rates it probably compatible but prefers olanzapine or quetiapine, above all for a newborn or premature baby; UK lactation services advise case by case, and the licence says not to breastfeed.