18 Chemist+Druggist 13.04.2013

CPD Zone update

this module covers:

● When antipsychotics are used, including the latest national guidance

● The potential side effects and interactions of antipsychotics

● The signs of neuroleptic malignant syndrome

● The key points to consider when treating a patient prescribed antipsychotics

UPDATEmodule 1650

APriL» mental health month

● Antipsychotics April 13

● Depression case studies April 20

● SSRIs April 27

Antipsychotics

www.chemistanddruggist.co.uk/update

Celia Feetam MRPharmS

Antipsychotics were originally developed as antihistamines. In 1951, chlorpromazine was administered during surgery to reduce cardiovascular shock, but it also reduced arousal and produced a tendency to sleep. Chlorpromazine not only relieved anxiety and agitation but also psychosis, hence the term ‘antipsychotic’. Between 1954 and 1975 more antipsychotics were developed, with clozapine being the first of the atypical, or second-generation, antipsychotics. The term atypical is applied to antipsychotics that:● at therapeutic doses do not cause, or only cause weak, extrapyramidal side effects● are associated with low risk of tardive dyskinesia (TD) ● do not cause sustained prolactin elevation ● do not cause secondary negative symptoms of schizophrenia (apathy and social withdrawal)● may be more effective against primary negative symptoms.

Typical, or classic, antipsychotics are older antipsychotics, and do not have these characteristics.1

Antipsychotic useAntipsychotics are used to treat schizophrenia and mania. Some are also used for acutely disturbed behaviour, as well as behavioural and psychological symptoms of dementia (BPSD), although this is discouraged due to increased mortality. Only risperidone is licensed for aggression in the elderly.2

Antipsychotics are also occasionally prescribed for anxiety, but this is not a licensed indication. Haloperidol, sulpiride and risperidone are prescribed for Tourette’s syndrome. Risperidone is also licensed for young people from the age of five years with persistent aggression associated with conduct disorder,2 and aripiprazole for schizophrenia and mania in adolescents.3

All antipsychotics block dopamine (D)

receptors but to varying degrees. Typicals have a higher affinity for D2 receptors, which corresponds to their clinical potency.

Clozapine acts on many different receptors, including those of the serotonin family, such as 5HT2A receptors, but has very weak affinity for D2 receptors. It remains unclear which are crucial to its atypical profile and superior efficacy. It was once thought that the high 5HT2A/D2 ratio was responsible — leading to the development of risperidone. However, unlike clozapine, risperidone is not effective in treatment-resistant patients. In addition, it causes increased prolactin at quite low doses, as well as extrapyramidal side effects at higher doses. Olanzapine and quetiapine also have high 5HT2A/ D2 ratios.

Aripiprazole, a partial agonist at D2 and 5HT1A receptors and an antagonist at 5HT2 receptors, is the first third-generation antipsychotic. Where levels of dopamine are high, it acts as an antagonist; where dopamine activity is low, it acts as an agonist. This has theoretical advantages in schizophrenia, where positive symptoms (thought disorder, hallucinations, and delusions) are thought to be related to excess dopamine and negative

symptoms (apathy and social withdrawal) to dopaminergic hypofunction.

Antipsychotics are associated with many side effects due to blockade of various receptors. Not only do they block D2 receptors in the limbic system and frontal cortex, which is believed to be responsible for their antipsychotic effect, but they also block D2 receptors in the basal ganglia (causing extrapyramidal side effects), and in the pituitary (raising prolactin levels). Some also cause anticholinergic side effects, hypotension and sedation.

extrapyramidal side effectsExtrapyramidal side effects are more likely to be associated with typical antipsychotics and include dystonia, Parkinsonian side effects, akathisia and tardive dyskinesia.

Dystonias usually have an abrupt onset and appear within the first few days of treatment or a dose increase. Young men are at most risk, especially if they have not been prescribed antipsychotics previously. Antimuscarinics can be used for prevention or treatment.

Parkinsonian side effects include stiffness, tremor, shuffling gait, akinesia, drooling and an expressionless, mask-like face. They ▶

Antipsychotics are used to treat schizophrenia, mania and behavioural problems

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CPD Zone update

affect about 30 per cent of those on chronic treatment. They are more common in elderly women, occurring within the first few months of treatment and can be effectively treated with oral antimuscarinics. They tend to disappear after around three months of treatment, when the antimuscarinic can be discontinued.

Akathisia involves motor restlessness and subjective feelings of inner restlessness which can be very distressing. Patients rock from foot to foot and pace, or move their feet restlessly while sitting. It often occurs within the first few weeks of treatment and does not normally respond to, or may even be exacerbated by, antimuscarinics.

With tardive dyskinesia, patients have abnormal movements, especially of the mouth and tongue, including facial grimacing, choreo-athetoid-like movements (ceaseless, rapid, jerky movements) of the fingers and toes, and slow, writhing movements of the trunk. They increase when the patient is aroused and are absent during sleep. Risk factors include being elderly, being female, having an affective disorder and the summative antipsychotic dose. Tardive dyskinesia can be irreversible, so it is important to prevent it occurring. Antimuscarinics should not be used, because they often worsen the condition. These symptoms can also occur in patients with untreated schizophrenia.

hormonal side effectsHormonal side effects include galactorrhoea (milk production), gynaecomastia (breast growth), both of which can occur in men and women, reduced libido in both sexes, sexual dysfunction in men and menstrual abnormalities. There is also a possible increased risk of osteoporosis, cardiovascular disease and breast cancer in the long term.

Because many of the hormonal effects of antipsychotics are caused by raised prolactin, serum levels should be measured routinely and, if found to be elevated or if symptoms are reported, a reduced dose should be considered. Switching to a prolactin-sparing atypical may help. Otherwise, the addition of aripiprazole or a dopamine agonist may be effective.4 Sexual dysfunction in males can be successfully treated with sildenafil or similar.

Anticholinergic side effectsThese include dry mouth, blurred vision, constipation, difficulty in micturition, confusion, cognitive difficulties and precipitation of glaucoma, all of which can be particularly problematic in the elderly.

Cardiovascular side effectsOrthostatic hypotension due to alpha-1 adrenergic blockade is common. Electrocardiogram (ECG) changes, such as prolongation of the QT interval can also occur, particularly when high doses are prescribed.

Patients taking haloperidol are required to have an ECG before starting treatment, and the Royal College of Psychiatrists advises ECG monitoring when maximum doses of antipsychotics are exceeded.

haematological disordersAgranulocytosis and neutropenia are rare, potentially fatal, side effects occurring with some of the older antipsychotics but more commonly with clozapine, which requires special monitoring. A full blood count should be obtained in patients who show an unusually high incidence of infections. Such disorders are reversible if the offending agent is withdrawn promptly.

Other side effectsPhotosensitivity, urticaria, contact and exfoliative dermatitis and cholestatic jaundice have been reported with chlorpromazine. High doses of antipsychotics or rapid dose increases can cause seizures. Hypothermia, exacerbated by sedation, is a risk for the elderly treated with typicals. Weight gain can occur, due to reduced activity and increased appetite as well as concurrent effects at multiple receptors.

Neuroleptic malignant syndrome (NMS) is rare, but the mortality rate in untreated ▶ patients can be as high as 20 per cent. Onset may be acute or insidious and the course fluctuating; it is more commonly associated with typicals but is not unknown with atypicals (see Box 2, below).

Atypical antipsychotics cause fewer extrapyramidal side effects than typicals, but some are associated with significant weight gain, dyslipidaemia, glucose intolerance and hyperprolactinaemia, with the consequent associated health risks during long-term use. In addition, at higher doses, some so-called atypicals, such as risperidone and amisulpride, are associated with extrapyramidal side effects and elevated prolactin levels. These should more accurately be called “partial atypicals”.

interactionsSedative antipsychotics potentiate other sedatives. They also increase the plasma levels of some antidepressants and antiepileptics through inhibition of metabolism. Some selective serotonin reuptake inhibitors slow the metabolism of haloperidol, risperidone, aripiprazole and clozapine, leading to raised plasma levels and potential toxicity.

The effect of antihypertensives may be enhanced by antipsychotics that block alpha-1 adrenergic receptors. Several antipsychotics are known to prolong the QT interval and should not be prescribed with medicines that have a similar effect. Clozapine should not be prescribed with agents that depress the bone marrow, such as carbamazepine and co-trimoxazole.

Inhaled hydrocarbons as a result of smoking

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Box 1. Tips for community pharmacists

● Poor adherence is the greatest barrier to good outcomes in both schizophrenia8 and bipolar disorder.9 ● Long-acting injectables and orodipsersible formulations are available; patients and carers should be aware of these.● Information concerning relative side-effect profiles facilitates choice and also promotes good adherence.● Liaison with community nurses and community mental health teams can assist seamless care, as can signposting to local support groups.● Patients should be encouraged to have a healthy lifestyle and accept opportunities for regular physical health checks.● Patients, especially those on clozapine, should be encouraged to contact their doctor if they experience persistent flu-like symptoms.● It is helpful to inform patients complaining of hormonal side effects that these can be managed and they should talk to their doctor about them.● It is important to be aware of the significant interactions involving antipsychotics, especially the effects of smoking cessation and changes in caffeine intake.● The use of antipsychotics in BPSD is discouraged, and should only be used in the short term with close monitoring.

Ask your questions on mental healthApril is mental health month in Update – and our expert is on hand to answer your queries. From SSRIs to antipsychotics, submit your questions now via chris.chapman@ubm.com

induces the metabolism of both clozapine and olanzapine, reducing plasma levels by up to 70 per cent. Stopping smoking can, therefore, result in reduced metabolism and increased plasma levels and toxicity.5 Caffeine, as a potent enzyme inhibitor, has the opposite effect, and changes in caffeine intake can significantly affect plasma levels of clozapine and olanzapine, requiring dosage adjustment.5

guideline recommendationsNice recommends olanzapine, quetiapine or risperidone for acute mania and olanzapine as prophylaxis in bipolar disorder but these guidelines are under review.6 In schizophrenia, Nice recognises that there is little to choose between antipsychotic efficacy7 and states ▶

22 Chemist+Druggist 13.04.2013

CPD Zone update

1. Typical antipsychotics are less like to cause extrapyramidal side effects than atypical antipsychotics. True or false?2. Antipsychotics cause extrapyramidal side effects because they block D2 receptors in the basal ganglia. True or false?3. Dystonias caused by antipsychotics usually have an abrupt onset and appear within the first few days of treatment. True or false?4. Tardive dyskinesia caused by antipsychotics can be irreversible. True or false?5. Antimuscarinics are commonly used to relieve symptoms of tardive dyskinesia. True or false?6. Hormonal side effects of antipsychotics include galactorrhoea and gynaecomastia in both men and women. True or false?

7. Patients taking clozapine should have regular blood tests for agranulocytosis. True or false?8. High doses of antipsychotics or rapid dose increases can cause seizures. True or false?9. Changes in caffeine intake can significantly affect plasma levels of risperidone and aripiprazole. True or false?10. Nice recommends olanzapine, quetiapine or ripseridone for the treatment of acute mania. True or false?

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that choice should be based on side-effect profiles. Physical health monitoring and a healthy lifestyle are advised, because such patients are at increased risk of cardiovascular mortality and this is exacerbated by antipsychotics.

Tips for your CPD entry on antipsychotics Reflect Which antipsychotics are licensed for use in children and adolescents? What are the symptoms of tardive dyskinesia? Why do some antipsychotics raise prolactin levels? how does stopping smoking affect some antipsychotics?

Plan this article contains information for pharmacists about the use, mode of action, side effects and interactions of antipsychotics. the pharmacist’s role in helping patients taking these medicines to manage their treatment is also discussed.

Act read the article and the suggested reading (below), then take the 5 minute test (left). update and update Plus subscribers can then access their answers and a pre-filled CPD logsheet.

Find out more information about antipsychotic drugs from the BNF section 4.2.1 Antipsychotic drugs.read the information leaflet for patients about antipsychotics on the royal College of Psychiatrists website http://tinyurl.com/antipsychotic1Find out if there are any support groups for mental health patients in your area.read the mur tips for typical and atypical antipsychotics on the C+D websitehttp://tinyurl.com/antipsychotic2http://tinyurl.com/antipsychotic3

Evaluate Are you now confident in your knowledge of antipsychotics? Are you familiar with and could you spot their side effects? Could you give advice to patients about managing their medication?

references1. Cowen P, Harrison P, Burns T. The Shorter Oxford Textbook of Psychiatry, Sixth Edition 2012. Oxford University Press ISBN 978-0=19=960561-3.2. Summary of product characteristics. Risperdal – www.medicines.org.uk. 3. Summary of product characteristics. Abilify – www.medicines.org.uk.4. Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines, 11th Edition. 2011 Informa Healthcare.5. Jose de Leon.Psychopharmacology: atypical antipsychotic dosing: the effect of smoking and caffeine psychiatric services 2004; doi: 10.1176/appi.ps.55.5.491– www.ps.psychiatryonline.org/article.aspx?articleid=885596. National Institute for Health and Clinical Excellence. Bipolar disorder: The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. CG38 Nice: 2006 – www.nice.org.uk.7. National Institute for Health and Clinical Excellence. Schizophrenia: Core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. CG82 Nice: 2009 – www.nice.org.uk8. Feetam C L, Roberts H. Medicine-taking

behaviour in Schizophrenia Parts 1 & 2. Progress in Neurology and Psychiatry; Volume 14;4:15-18. 2010 – www.progressnp.com9. Feetam C L Bipolar depression: a therapeutic challenge? Progress in Neurology and Psychiatry: Volume 15;6:21-25. 2011 – www.progressnp.com

5 minute test

Box 2. Signs and symptoms of neuroleptic malignant syndrome

● Sweating● Fever/hyperthermia● Hypertension● Autonomic instability (fluctuating blood pressure)● Tachycardia● Incontinence● Urinary retention● Bowel obstruction● Muscular rigidity (which may be confined to head and neck)● Confusion● Agitation● Altered consciousness● Raised creatinine phosphokinase (>1,000IU/L) ● Leukocytosis

13.04.2013 Chemist+Druggist 23

CPD Zone update

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