Synonyms: neuroleptics or major tranquillisers.

These drugs basically tranquillise without impairing consciousness or causing paradoxical excitement.

Antipsychotics were discovered in the 1950s. The more traditional antipsychotics reduce the action of dopamine, whereas the atypical antipsychotics reduce other chemicals, such as serotonin. Both traditional and atypical antipsychotics are effective against positive symptoms in schizophrenia, but the latter are possibly more effective against negative symptoms.

Classifications of antipsychotics

All are effective in treating psychotic symptoms - but they vary in terms of potency and ability to produce side-effects.¹
There are many methods of classifying the antipsychotics, such as:

1. Typical and atypical antipsychotics:
   • Typical - e.g. phenothiazines (chlorpromazine), thioxanthines (flupentixol), butyrophenones (haloperidol), diphenylbutylpiperidines (pimozide), substituted benzamides (sulpiride).
   • Atypical - e.g. amisulpiride, olanzapine, quetiapine, risperidone and zotepine. These are on the whole better tolerated with fewer extra-pyramidal side-effects.
2. According to potency:
   • High potency - e.g. haloperidol and fluphenazine.
   • Intermediate potency - e.g. perphenazine.
   • Low potency - e.g. chlorpromazine.
3. Preparations:
   • Oral - the majority.
   • Depot preparations.

Indications

Used to quieten disturbed patients, for example in:

• Schizophrenia (adults and children).¹
• Acute schizophrenic episode.
• Brain injury.
• Bipolar affective disorder - antipsychotics are used in the acute phase, during maintenance in pregnancy and when rapid cycling present. Depot preparations can be used in the maintenance phase but they should be avoided in those patients with predominantly depressive symptoms.^2,3
• Schizoaffective disorder.
• Psychotic states (depot preparations may be useful).⁴
• Delirium (acute confusion).
• Anxiety.
• Restlessness and agitation in elderly.
• Depression with agitation.
• Intractable hiccup.
• Risperidone is indicated for the short-term treatment of severe aggression and violence (whether directed towards self or others) in autistic children where available non-pharmacological methods have first been tried and failed.⁵

All antipsychotics are better at treating positive symptoms (such as hallucinations and delusions), but they are less helpful in controlling negative symptoms (amisulpiride and clozapine are useful). Acute schizophrenia responds better than chronic states.⁶ The atypical antipsychotics may be better at treating negative symptoms and have fewer side-effects, especially in patients who have responded poorly to other antipsychotics. The current preferred first line treatment is low dose atypical antipsychotics, although if a patient is stable on a typical antipsychotic then the drug does not need to be changed.

Depot antipsychotic agents were developed in the 1960s.⁶ Antipsychotic depot injections are an ester formulation of high-potency antipsychotics which provide slow release of the medicine, usually over 1-4 weeks when given intramuscularly. They are a good choice in patients with adherence problems towards oral antipsychotics.

Method of action

Most conventional neuroleptics act by blocking post synaptic D2 receptors and cholinergic receptors in the brain. Phenothiazines mostly act on D2 receptors (the piperazine group has higher D2 affinity compared with the aliphatic and piperidine group). In comparison the aliphatic and piperidine phenothiazines have moderate anticholinergic affinity compared with the piperazine group.

Thioxanthines, butyrophenones, diphenylbutylpiperdines and the dibenzoxapine are similar to the piperazine group in terms of receptor blockade.

Atypical antipsychotics have less affinity for dopamine receptors and more for serotonin (5HT₂) receptors.

Initiation of treatment

Considerations prior to starting antipsychotics¹

1. Ensure working diagnosis is correct.
2. Ensure Mental Health Team referral has taken place:
   • Has the patient the capacity to make decisions about their treatment (Mental Capacity Act)?
   • If there is any risk of harm to self or others then urgent admission is necessary (voluntary admission or under The Mental Health Act)?
   • If there is likely to be a delay in assessment, a specialist may occasionally advise starting with an atypical antipsychotic (beware antipsychotics may make some situations worse and will significantly affect initial psychiatric assessment in hospital).
3. Also remember the use of concomitant psychological approaches, e.g. social skills training, cognitive behavioural therapy and psychotherapy.

Multidisciplinary approach with patient and carer education.

• Once the patient is diagnosed, involve family and carers at patient's consent.
• Educate regarding the disorder, management options and local services available, e.g. support groups.
• Warn about driving and other skilled tasks - patients must stop driving during an acute episode. DVLA will consider relicensing if patient stable on treatment for 3 months and compliant with medication. All antipsychotics can also impair the ability to perform skilled tasks.

Things to consider prior to starting depot antipsychotics (done in hospital)

Baseline parameters¹

• Check pulse rate; consider a 12 lead ECG if tachycardia present.
• Check blood pressure and lying and standing blood pressure.
• Check temperature.
• Monitor weight.
• Baseline FBC, renal function and liver function tests.

Choice of drug¹

• 30-50 % of schizophrenic patients with positive symptoms are not responsive or only partially responsive to the typical antipsychotics.⁶ Thus the atypical antipsychotics are first line, e.g. amisulpiride, olanzapine, quetiapine, risperidone, and zotepine. Atypical antipsychotics also have fewer extrapyramidal side-effects adding to their use as first line agents.
• The main differences are in the potency and side-effect spectrum of antipsychotics. Thus, high potency antipsychotics (haloperidol and fluphenazine) have a greater tendency to produce extrapyramidal side-effects. In comparison, the low potency antipsychotics (chlorpromazine) cause fewer extrapyramidal side-effects - but tend to cause sedation (potency is indirectly proportional to sedation) and postural hypotension, which are more difficult to manage.
• Clinically significant superiority of efficacy between typical and atypical antipsychotics has not been definitely shown (except for olanzapine).
• Risperidone or olanzapine should not be used in patients with known or suspected cerebrovascular disease. They should not be used for the long term treatment of behavioural symptoms of vascular dementia^7,8 and careful consideration of the risk of cerebrovascular events should be made before treating any patient with a previous history of stroke or transient ischaemic attack.
  Consideration should also be given to other risk factors for cerebrovascular disease, including hypertension, diabetes, current smoking and atrial fibrillation.
  Risperidone is licensed for the short-term treatment of persistent aggression (up to 6 weeks) in patients with moderate to severe Alzheimer's dementia unresponsive to non-drug approaches and when there is a risk of harm to self or others.
• Depot preparations should only be started under specialist guidance as there is a risk of relapse as oral antipsychotics are withdrawn. Keep the following points in mind:
  • There is no clear advantage of one depot over another.
  • Always consider using a test dose to begin with.
  • Wait 4-10 days after the test dose before starting to titrate the dose.
  • Always administer by deep intramuscular injection (rotate sites to avoid reactions).
  • It can take several weeks to achieve steady state levels with depot antipsychotics.
  • Increased doses of depot medication do not lead to better outcome.

Route of administration

• Antipsychotics are available in oral preparations and some are available as depot formulations.
• Depot injections are given intramuscularly and include flupentixol decanoate,⁹ fluphenazine decanoate,¹⁰ haloperidol decanoate,¹¹ zuclopenthixol decanoate,¹² pipotiazine palmitate,¹³ risperidone (the only atypical antipsychotic available as a depot).¹⁴ They are contraindicated in children and may be associated with greater extrapyramidal side-effects. The advantages and disadvantages include:¹
  
  Advantages:
  • Increased adherence - no need for daily tablets.
  • Long duration of therapy - ranges from 1-6 weeks.
  • Clopixol can be used in acute psychotic/manic states and may be useful in aggressive patients.
  • Possibly reduced relapse rate.
  • Consistent delivery.
  • Not dependent on first-pass metabolism.
  Disadvantages:
  • Pain, erythema, swelling and nodule formation at site of injection.
  • Unable to terminate therapy if side-effects occur - need to wait for it to wear off; therefore, always start with a test dose.
  • Takes many weeks to reach steady state plasma levels.
• Efficacy of depot preparations - one meta-analysis in 2001 reported the following:¹⁵
  • Relapse rates were significantly less in the group of patients taking depot medication in comparison to placebo or oral antipsychotics. However, data is limited in this area.
  • Furthermore, side-effect frequency was similar to oral antipsychotics - including the occurrence of tardive dyskinesias.
  • Higher doses do not produce any further benefits compared with lower doses - in fact they can be more harmful due to increased risk of side-effects.

Correct dosage

• Always start at the lowest possible dose.
• Aim for the minimum effective dose.
• Doses should be increased every one to two weeks.
• Most will have an improvement within 6 weeks - but some may take up to 6 months.
• After six to eight weeks if the patient is not responding switch to another antipsychotic.

Withdrawing or changing antipsychotics

• Antipsychotics should usually continue for one to two years to prevent further relapses.
• Withdraw antipsychotics gradually - never abruptly. Some patients will relapse within a year once antipsychotics are stopped.
• Aim to reduce the dose over 8 weeks or even slower (for all antipsychotic drugs).
• At the same time regularly monitor for signs and symptoms that might suggest a relapse.
• Some atypical antipsychotics may increase prolactin - if fertility is desired, patients may be switched to aripiprazole, clozapine, olanzapine or quetiapine, which have no significant effect on prolactin concentration.

Monitoring

Patients should have a named community psychiatric nurse (CPN) who they can contact. Some general practitioners who have special interest are specially trained to help CPN with their caseload and may be the point of contact for the patient.

Monitor the patient, both their physical health, and any symptoms or side-effects:

• Monitor for drug side-effects:
  
  This should include regular review looking for the following:
  • Abnormal movements (it is good to ask the patient if anyone else has commented on this).
  • Any difficulty mobilising or writing (looking for bradykinesia).
  • Orthostatic hypotension - particularly a problem with chlorpromazine and risperidone.
  • Blackouts.
  • For atypical antipsychotics, especially olanzapine and clozapine, monitor weight and plasma glucose regularly (i.e. screen for any diabetes).
  • Side-effects such as, oligomenorrhoea,¹⁶ sexual dysfunction and itching - these are a common cause for poor adherence.
  • Of course if any abnormality is detected then a full examination should follow with possible referral for investigations and to a specialist, e.g. arrhythmias may warrant cardiology follow-up.¹⁷
• Monitor for potential drug interactions:
  • Antipsychotics pose a potential problem for drug interactions. Some examples are antibiotics (such as, ciprofloxacin and erythromycin) which increase the levels of antipsychotics and carbamazepine which reduces the level. Other interactions occur with antivirals, betablockers, diuretics and sibutramine.
  • Sedation will be increased with other sedatives, e.g. alcohol, and similarly there is increased risk of hypotension with concomitant administration of anti-hypertensives.
  • With atypical antipsychotics care is needed when co-prescribing other drugs that increase the QT interval.
• Adherence:
  • Poor adherence is a major reason for patients to have relapses which can lead to severe psychosocial dysfunction. Always try to determine patient adherence to medication and look for any causes which might lead to poor adherence, e.g. poor insight or side-effects.

Poor response to therapy¹

Also click here to see article on schizophrenia.

• 40% of patients have a poor response to conventional antipsychotics.
• Clozapine is the only antipsychotic licensed for those who have not responded well.
• Patients who do not respond should be reviewed regarding reassessment of the diagnosis, adherence, use of other psychological methods and possible substance misuse.
• If the patient still fails to respond then either therapeutic drug monitoring needs to be employed for clozapine or a second agent might need to be added.

Caution in the elderly⁶

• There is little data on the use and safety of antipsychotics in elderly patients.
• They appear to be more susceptible to side-effects, e.g. haloperidol more readily causes extrapyramidal side-effects.¹⁸
• Tardive dyskinesias are 3-5 times more likely.
• Toxicity from drug interactions due to co-morbidity is also increased.
• Antipsychotics may be associated with early death in the elderly - but this has not been clearly established.¹⁹
• Therefore, in elderly patients the starting dose should be small and the dose titrated up slowly.
• Depot preparations can also be used in the elderly and again lower doses should be tried, such as 25-50% of the recommended dose.

Reasons to discontinue antipsychotics

Document references

1. Schizophrenia, NICE Clinical Guideline (March 2009); Core interventions in the treatment and management of schizophrenia in primary and secondary care
2. Bond DJ, Pratoomsri W, Yatham LN; Depot antipsychotic medications in bipolar disorder: a review of the literature. Acta Psychiatr Scand Suppl. 2007;(434):3-16. [abstract]
3. El-Mallakh RS; Medication adherence and the use of long-acting antipsychotics in bipolar disorder. J Psychiatr Pract. 2007 Mar;13(2):79-85. [abstract]
4. The Management of bipolar disorder in adults, children and adolescents, in primary and secondary care, NICE (2006)
5. MHRA - Risperidone and Autism; Proposed new indication. Oct 2006; As PDF
6. Lambert TJ, Castle DJ; Pharmacological approaches to the management of schizophrenia. Med J Aust. 2003 May 5;178 Suppl:S57-61. [abstract]
7. Atypical Antipsychotic Drugs and Stroke.; MHRA:Safety Information; Atypical Antipsychotic Drugs and Stroke. March 2004
8. MHRA; Pharmacovigilance Working Party Public Assessment Report on antipsychotics and cerebrovascular accident. Oct 2006; As PDF
9. Summary of Product Characteristics - Depixol®; Lundbeck Ltd; updated Aug 2007, electronic Medicines Compendium.
10. Summary of Product Characteristics - Fluphenazine®; Mayne Pharma plc; updated May 2003, electronic Medicines Compendium.
11. Summary of Product Characteristics - Haldol Decanoate®; Janssen-Cilag Ltd; updated Sept 2007, electronic Medicines Compendium.
12. Summary of Product Characteristics - Zuclopenthixol decanoate®; Lundbeck Ltd; updated Aug 2007, electronic Medicines Compendium.
13. Summary of Product Characteristics - Pipothiazine palmitate®; Sanofi-aventis; updated Aug 2007, electronic Medicines Compendium.
14. Summary of Product Characteristics - Risperdal Consta ®;; Janssen-Cilag Ltd; updated Oct 2007, electronic Medicines Compendium
15. David AS, Adams C; Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) meta-review; (2) patient and nurse attitudes.; Health Technol Assess. 2001;5(34):1-61.
16. Adnet P, Lestavel P, Krivosic-Horber R; Neuroleptic malignant syndrome. Br J Anaesth. 2000 Jul;85(1):129-35.
17. Yap YG, Camm AJ; Drug induced QT prolongation and torsades de pointes. Heart. 2003 Nov;89(11):1363-72.
18. Lieberman JA 3rd; Managing anticholinergic side effects. Prim Care Companion J Clin Psychiatry. 2004;6(Suppl 2):20-3. [abstract]
19. Wang PS, Schneeweiss S, Avorn J, et al; Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005 Dec 1;353(22):2335-41. [abstract]

Internet and further reading

• Schizophrenia, Clinical Knowledge Summaries (October 2009)
• NYRDTC; Additional information on risperidone depot

Acknowledgements