Antipsychotic drugs

What are antipsychotic medicines used for?
Antipsychotic drugs are mainly used to treat mental health conditions such as schizophrenia and other psychoses, agitation, severe anxiety, mania and violent or dangerously impulsive behaviour.

They are also used to treat nausea and vomiting, intractable hiccough and for the management of pain and associated restlessness in palliative care.

How do antipsychotic medicines work?
Antipsychotics work by increasing or reducing the effects of natural chemicals (called neurotransmitters) in the brain, including dopamine, serotonin, noradrenaline and acetylcholine. These neurotransmitters regulate numerous aspects of behaviour including mood and emotions, control of sleeping and wakefulness and control of feeding.

Antipsychotics can be classified by their chemical structure, but can also be distinguished by their pharmacology (their action at different neurotransmitters receptors) and by their clinical properties. The most commonly used system of classification refers to antipsychotics as either ‘typical’ or ‘atypical’ antipsychotics.

The older typical antipsychotics (also called conventional antipsychotics) were first developed in the 1950s and act primarily to decrease the level of the neurotransmitter dopamine in the brain.

The atypical antipsychotics were first developed in the 1970s, and a new generation of atypical antipsychotics appeared in the 1990s. Atypical antipsychotics are less likely than typical antipsychotics to cause movement disorders as a side effect, although they may still cause movement disorders when used at higher doses.

The following atypical antipsychotics are licensed for use in the UK: amisulpride (brand name Solian), aripiprazole (Abilify), clozapine (Clozaril, Denzapine), olanzapine (Zyprexa), paliperidone (Invega), risperidone (Risperdal, Risperdal Consta) and zotepine (Zoleptil).

Typical antipsychotics licensed for use in the UK include chlorpromazine, flupentixol, haloperidol, levomepromazine, pericyazine, perphenazine, pimozide, prochlorperazine, promazine, sulpiride, trifluperazine and zuclopenthixol.

Side effects of antipsychotic drugs
As with all medicines antipsychotics can produce side effects in some people. The most common include movement disorders that may resemble Parkinson’s disease (referred to as extrapyramidal side effects); dry mouth, blurred vision and constipation (referred to as anticholinergic effects) so called as they are due to the action of these drugs on cholinergic receptors); feelings of dizziness or light headedness; and weight gain.

Rarely, antipsychotics may cause more serious side effects such as diabetes or metabolic syndrome, neuroleptic malignant syndrome (fever, faster breathing, sweating, muscle stiffness and reduced consciousness), and cardiac arrhythmias (irregular heart beat). A Europe-wide review of effects of antipsychotics on the heart was completed in 2005:
› Pharmacovigilance Working Party Public Assessment Report on neuroleptics and cardiac safety (60Kb)

Antipsychotics can also increase the risk of stroke in elderly people with dementia and in any patient with pre-existing risk factors for stroke (see the section on antipsychotic use in the elderly below).

This is not a complete list of all of the known side effects of antipsychotics - full guidance on prescribing and use, including information on possible side effects of antipsychotics is provided in the Summary of Product Characteristics (SPC) for health professionals and the patient information leaflet (PIL) that should accompany the medicine for patients. Further guidance can be found on the electronic Medicines Compendium website:
› electronic Medicines Compendium (external link)

Antipsychotic use in elderly people with dementia
Elderly people with dementia are at risk from serious and life-threatening side effects when treated with antipsychotics – there is a clear increased risk of stroke and a small increased risk of death when antipsychotics (atypical and typical) are used in elderly people with dementia.

Only one antipsychotic, risperidone (Risperdal), is licensed for treatment of dementia-related behavioural disturbances in the UK: and then only specifically for short-term (up to 6 weeks’) treatment of persistent aggression in moderate to severe Alzheimer’s dementia unresponsive to non-pharmacological approaches (i.e. those that do not involve use of medicines) and where there is risk of harm to the patient or others. The risperidone (Risperdal) licence for the short-term treatment of persistent aggression in Alzheimer’s dementia was granted in 2008 after a new analysis of three randomised controlled trials1-3 conducted on behavioural problems in the elderly showed a clear benefit for the short-term use of risperidone when aggression only was considered.

Increased risk of stroke
In 2004 the Committee on Safety of Medicines (the predecessor to the Commission on Human Medicines) advised of a clear increase in the risk of stroke with the use of the atypical antipsychotics risperidone or olanzapine in elderly people with dementia (approximately 3-fold increased risk compared with placebo), and that the magnitude of risk outweighed any likely benefit of treating dementia-related behavioural problems with these drugs. This increased risk is also a cause for concern in any patient with a high baseline risk of stroke. A year later a Europe-wide review concluded that this risk could not be excluded for other antipsychotics (atypical or typical):
› Pharmacovigilance Working Party Public Assessment Report on antipsychotics and cerebrovascular accident (85Kb)

Increased mortality
In 2005, an analysis of 17 placebo-controlled trials found that atypical antipsychotics are associated with increased mortality when used in elderly people with dementia (about 1-2% increased risk compared with no treatment). For risperidone, there is an additional increase in the risk when co-prescribed with furosemide.

Subsequently in November 2008, a European assessment of published observation data concluded that a similar increased risk of death could not be excluded for the typical (conventional) antipsychotics. 5,6

1. Katz IR, et al. J Clin Psychiatry 1999; 60: 107–15.
2. De Deyn PP, et al. Neurology 1999; 53: 946–55.
3. Brodaty H, et al. J Clin Psychiatry 2003; 64: 134–43.
4. US FDA Public Health Advisory. Deaths with antipsychotics in elderly patients with behavioural disturbances, April 11 2005 (external link) (accessed Jan 29, 2009).
5. Schneeweiss S, et al. CAMJ 2007; 176: 627–32.
6. Gill SS, et al. Ann Intern Med 2007; 146: 775–86.

Further information:
› Committee for Medicinal Products for Human Use (CHMP): Opinion following an Article 30 referral for Risperdal and associated names (external link)
› List of the names, pharmaceutical forms, strengths of the medicinal products, routes of administration, marketing authorisation holders in the member states (external link) page 48

See statement from the European Medicines Agency at:
› Opinion of the Committee for Medicinal Products for Human Use pursuant to Article 5(3) of Regulation (EC) No 726/2004, on conventional antipsychotics (external link)
and accompanying report and question and answer document at:
› CHMP assessment report on conventional antipsychotics (external link)
› Questions and answers on the review of the use of conventional antipsychotic medicines in elderly patients with dementia (external link)

Antipsychotics: risk of venous thromboembolic events
A Europe-wide review of UK Yellow Card data and worldwide published epidemiological studies on antipsychotics and venous thromboembolic events (VTE) has concluded that an increase in risk of VTE cannot be excluded. The following report summarises the data assessed in this review:
› MHRA Public Assessment Report: The risk of venous thromboembolism associated with antipsychotics - June 2009 (636Kb)