Antipsychotic drugs

Antipsychotic drugs are also known as ‘neuroleptics’ and (misleadingly) as ‘major tranquillisers’. Antipsychotic drugs generally tranquillise without impairing consciousness and without causing paradoxical excitement but they should not be regarded merely as tranquillisers. For conditions such as schizophrenia the tranquillising effect is of secondary importance.

In the short term they are used to calm disturbed patients whatever the underlying psychopathology which may be schizophrenia, brain damage, mania, toxic delirium, or agitated depression. Antipsychotic drugs are used to alleviate severe anxiety but this too should be a short-term measure.

Schizophrenia

Antipsychotic drugs relieve florid psychotic symptoms such as thought disorder, hallucinations, and delusions, and prevent relapse. Although they are usually less effective in apathetic withdrawn patients, they sometimes appear to have an activating influence. Patients with acute schizophrenia generally respond better than those with chronic symptoms.

Long-term treatment of a patient with a definite diagnosis of schizophrenia may be necessary even after the first episode of illness in order to prevent the illness from becoming chronic. Withdrawal of drug treatment requires careful surveillance because the patient who appears well on medication may suffer a disastrous relapse if treatment is withdrawn inappropriately. In addition the need for continuation of treatment may not become immediately evident because relapse is often delayed for several weeks after cessation of treatment.

Antipsychotic drugs are considered to act by interfering with dopaminergic transmission in the brain by blocking dopamine D₂ receptors, which may give rise to the extrapyramidal effects described below, and also to hyperprolactinaemia. Antipsychotic drugs may also affect cholinergic, alpha-adrenergic, histaminergic, and serotonergic receptors.

Cautions and contra-indications

Antipsychotic drugs should be used with caution in patients with hepatic impairment, renal impairment, cardiovascular disease, Parkinson’s disease (may be exacerbated by antipsychotics), epilepsy (and conditions predisposing to epilepsy), depression, myasthenia gravis, prostatic hypertrophy, or a susceptibility to angle-closure glaucoma. Caution is also required in severe respiratory disease and in patients with a history of jaundice or who have blood dyscrasias (perform blood counts if unexplained infection or fever develops). As photosensitisation may occur with higher dosages, patients should avoid direct sunlight.

Antipsychotic drugs may be contra-indicated in comatose states, CNS depression, and phaeochromocytoma. Most antipsychotic drugs are best avoided during pregnancy, unless essential and it is advisable to discontinue breast-feeding during treatment.

Prescribing for the elderly The balance of risks and benefit should be considered before prescribing antipsychotic drugs for elderly patients. In elderly patients with dementia, antipsychotic drugs are associated with a small increased risk of mortality and an increased risk of stroke or transient ischaemic attack. Furthermore, elderly patients are particularly susceptible to postural hypotension and to hyper- and hypothermia in hot or cold weather. It is recommended that:

• Antipsychotic drugs should not be used in elderly patients to treat mild to moderate psychotic symptoms.
• Treatment should be reviewed regularly.

Driving

Drowsiness may affect performance of skilled tasks (e.g. driving or operating machinery), especially at start of treatment; effects of alcohol are enhanced.

Withdrawal

Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.

Side-effects

Extrapyramidal symptoms are the most troublesome. They occur most frequently with the piperazine phenothiazines (fluphenazine, perphenazine, prochlorperazine, and trifluoperazine), the butyrophenones (benperidol and haloperidol), and the depot preparations. They are easy to recognise but cannot be predicted accurately because they depend on the dose, the type of drug, and on individual susceptibility.

Extrapyramidal symptoms consist of:

• parkinsonian symptoms (including tremor), which may occur more commonly in adults or the elderly and may appear gradually;
• dystonia (abnormal face and body movements) and dyskinesia, which occur more commonly in children or young adults and appear after only a few doses;
• akathisia (restlessness), which characteristically occurs after large initial doses and may resemble an exacerbation of the condition being treated; and
• tardive dyskinesia (rhythmic, involuntary movements of tongue, face, and jaw), which usually develops on long-term therapy or with high dosage, but it may develop on short-term treatment with low doses— short-lived tardive dyskinesia may occur after withdrawal of the drug.

Parkinsonian symptoms remit if the drug is withdrawn and may be suppressed by the administration of antimuscarinic drugs. However, routine administration of such drugs is not justified because not all patients are affected and because they may unmask or worsen tardive dyskinesia.

Tardive dyskinesia is of particular concern because it may be irreversible on withdrawing therapy and treatment is usually ineffective. However, some manufacturers suggest that drug withdrawal at the earliest signs of tardive dyskinesia (fine vermicular movements of the tongue) may halt its full development. Tardive dyskinesia occurs fairly frequently, especially in the elderly and treatment must be carefully and regularly reviewed.

Hypotension and interference with temperature regulation are dose-related side-effects and are liable to cause dangerous falls and hypothermia or hyperthermia in the elderly.

Neuroleptic malignant syndrome (hyperthermia, fluctuating level of consciousness, muscle rigidity, and autonomic dysfunction with pallor, tachycardia, labile blood pressure, sweating, and urinary incontinence) is a rare but potentially fatal side-effect of some drugs. Discontinuation of the antipsychotic is essential because there is no proven effective treatment, but cooling, bromocriptine, and dantrolene have been used. The syndrome, which usually lasts for 5-7 days after drug discontinuation, may be unduly prolonged if depot preparations have been used.

Other side-effects include:

• drowsiness;
• apathy;
• agitation, excitement and insomnia;
• convulsions;
• dizziness;
• headache;
• confusion;
• gastro-intestinal disturbances;
• nasal congestion;
• antimuscarinic symptoms (such as dry mouth, constipation, difficulty with micturition, and blurred vision;
• very rarely, precipitation of angle-closure glaucoma);
• cardiovascular symptoms (such as hypotension, tachycardia, and arrhythmias);
• ECG changes (cases of sudden death have occurred);
• endocrine effects such as menstrual disturbances, galactorrhoea, gynaecomastia, impotence, and weight gain;
• blood dys-crasias (such as agranulocytosis and leucopenia), photo-sensitisation, contact sensitisation and rashes, and jaundice (including cholestatic);
• corneal and lens opacities, and purplish pigmentation of the skin, cornea, conjunctiva, and retina.

Overdosage:

for poisoning with phenothiazines and related compounds.

Classification of antipsychotics

The phenothiazine derivatives can be divided into 3 main groups.

• Group 1: chlorpromazine, levomepromazine (methotrimeprazine), and promazine, generally characterised by pronounced sedative effects and moderate antimuscarinic and extrapyramidal side-effects.
• Group 2: pericyazine and pipotiazine, generally characterised by moderate sedative effects, marked antimuscarinic effects, but fewer extrapyramidal side-effects than groups 1 or 3.
• Group 3: fluphenazine, perphenazine, prochlorperazine, and trifluoperazine, generally characterised by fewer sedative effects, fewer antimuscarinic effects, but more pronounced extrapyramidal side-effects than groups 1 and 2.

Drugs of other chemical groups resemble the phenothiazines of group 3 in their clinical properties. They include the butyrophenones (benperidol and haloperidol); diphenylbutylpiperidines (pimozide); thioxanthenes (flupentixol and zuclopenthixol); and the substituted benzamides (sulpiride).

For details of the newer antipsychotic drugs amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, and zotepine, see under Atypical Antipsychotic Drugs.

Choice

As indicated above, the various drugs differ somewhat in predominant actions and side-effects. Selection is influenced by the degree of sedation required and the patient’s susceptibility to extrapyramidal side-effects. However, the differences between antipsychotic drugs are less important than the great variability in patient response; moreover, tolerance to secondary effects such as sedation usually develops. The atypical antipsychotics may be appropriate if extrapyramidal side-effects are a particular concern (see under Atypical Antipsychotics, below). Clozapine is used for schizophrenia when other antipsychotics are ineffective or not tolerated.

Prescribing of more than one antipsychotic drug at the same time is not recommended; it may constitute a hazard and there is no significant evidence that side-effects are minimised.

Chlorpromazine is still widely used despite the wide range of adverse effects associated with it. It has a marked sedating effect and is useful for treating violent patients without causing stupor. Agitated states in the elderly can be controlled without confusion, a dose of 10 to 25 mg once or twice daily usually being adequate.

Flupentixol (flupenthixol) and pimozide are less sedating than chlorpromazine.

Sulpiride in high doses controls florid positive symptoms, but in lower doses it can have an alerting effect on apathetic withdrawn schizophrenics.

Fluphenazine, haloperidol, and trifluoperazine are also of value but their use is limited by the high incidence of extrapyramidal symptoms. Haloperidol may be preferred for the rapid control of hyperactive psychotic states; it causes less hypotension than chlorpromazine and is therefore also popular for agitation and restlessness in the elderly, despite the high incidence of extrapyramidal side-effects.

Promazine is not sufficiently active by mouth to be used as an antipsychotic drug; it has been used to treat agitation and restlessness in the elderly.

Other uses

Nausea and vomiting, choreas, motor tics, and intractable hiccup (see under Chlorpromazine Hydrochloride and under Haloperidol). Benperidol is used in deviant antisocial sexual behaviour but its value is not established; see also for the role of cyproterone acetate.

Psychomotor agitation should be investigated for an underlying cause; it can be managed with low doses of chlorpromazine or haloperidol used for short periods. Antipsychotic drugs can be used with caution for the short-term treatment of severe agitation and restlessness in the elderly.

Equivalent doses of oral antipsychotics

These equivalences are intended only as an approximate guide; individual dosage instructions should also be checked; patients should be carefully monitored after any change in medication

Antipsychotic drug	Daily dose
Chlorpromazine	100 mg
Clozapine	50 mg
Haloperidol	2-3 mg
Pimozide	2 mg
Risperidone	0.5-1 mg
Sulpiride	200 mg
Trifluoperazine	5 mg

Important

These equivalences must not be extrapolated beyond the maximum dose for the drug. Higher doses require careful titration in specialist units and the equivalences shown here may not be appropriate

Dosage

After an initial period of stabilisation, in most patients, the total daily oral dose can be given as a single dose.

BNF