Antipsychotics

Antipsychotics (formerly called ‘neuroleptics’ or ‘major tranquillisers’) are used to treat symptoms of psychotic illnesses such as schizophrenia¹ and paranoid psychoses. Antipsychotics are also used for other psychiatric disorders, such as bipolar disorder², anxiety states, and short-term treatment of agitation or aggression. In addition, certain antipsychotics are licensed for other uses, such as nausea and vomiting, treatment of anxiety and agitation, and treatment of intractable hiccoughs.

Psychosis describes an objective loss of contact with reality. Antipsychotics can be effective for treating ‘positive’ psychotic features (such as delusions, hallucinations and disorders of the structure of thought, and hyperarousal³), whether they arise in the context of the schizophrenias, mania, severe depressive illness and drug-associated psychoses or other psychiatric disorders. However, the role of antipsychotics is unclear for treating other symptoms of psychotic disorders including ‘negative’ symptoms such as apathy and social withdrawal, and cognitive symptoms such as difficulty with concentration and memory.

Antipsychotics act on a variety of receptors in the brain. Most antipsychotics act as antagonists⁴ at dopamine D₂ receptors; these receptors are involved in several neurological systems including those responsible for cognition, perception, reward, movement, temperature regulation by the hypothalamus, and regulation of the pituitary hormone prolactin.

Antipsychotics vary in the degree of antagonistic action at the D₂ receptor, and also in their antagonist or sometimes agonist action on other receptors possibly associated with antipsychotic effect, including dopaminergic D₁ receptors and serotonergic⁵ 5-HT_2A and 5-HT_2C receptors. Their effects on muscarinic, noradrenergic and histaminergic transmission also determine many of their adverse effects. In contrast to many antipsychotics, clozapine is a fairly weak D₂ antagonist and aripiprazole is a partial agonist at the D₂ receptor.

The antipsychotics are often subdivided into ‘generations’— see classification of antipsychotics. ‘First generation’ (also termed ‘conventional’ or ‘typical’) antipsychotics include chlorpromazine and haloperidol. Development of ‘second-generation’ (or ‘atypical’) antipsychotics followed the reintroduction of clozapine into clinical practice and the class includes olanzapine, risperidone, and quetiapine.

The value of dividing antipsychotics into first- and second-generations is not proven, but the classification is commonly encountered in clinical practice and in clinical literature. We have used the classification where it might help with understanding. Specific information has been included on clozapine because it has more restricted use and distinct adverse effect profile.

While second-generation antipsychotics may be less liable to impair extrapyramidal function, they carry a higher risk for other adverse effects than most first-generation antipsychotics. Rigorous assessment of benefits (especially outcome measures such as quality of life) suggests no clear superiority of second-generation antipsychotics over older antipsychotics.

Antipsychotics have serious and potentially irreversible adverse effects and, therefore, should be used for specific and serious indications—see summary of licensed indications of antipsychotics for adults. Over 7.7 million prescriptions for antipsychotics were dispensed in the community in England in 2011. Additionally, over 170 thousand prescriptions were dispensed for prolonged-release (‘depot’) injections of antipsychotics.

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