Antipsychotics

Synonyms: Neuroleptics or Major tranquillisers.

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

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

Used to quieten disturbed patients, for example in:

• Schizophrenia (adults and children)
• Brain injury
• Bipolar affective disorder (antipsychotics are used in the acute phase, for maintenance during pregnant patients and when rapid cycling present)
• Delirium (acute confusion)
• Anxiety
• Restlessness and agitation in elderly
• Depression with agitation
• Intractable hiccup

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

1. Typical and atypical antipsychotics:
   • Typical: e.g. phenothiazines (chlorpromazine), thioxanthines (flupenthixol), butyrophenones (haloperidol), diphenylbutylpiperidines (pimozide), substituted benzamides (sulpiride)
   • Atypical: e.g. amisulpiride, olanzapine, quetiapine, risperidone and zotepine
2. According to potency:
   • High potency - e.g. haloperidol and fluphenazine
   • Intermediate potency - e.g. loxapine and perphenazine
   • Low potency - e.g. chlorpromazine and thioridazine

• 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.¹
• 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.²

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.

Considerations prior to starting antipsychotics

1. Ensure working diagnosis is correct
2. Mental health team referral has taken place:
   • If there is any risk of harm to self or others then urgent admission is necessary (perhaps under The Mental Capacity Act).
   • If there is likely to be a delay in assessment then consider starting with an atypical antipsychotic, after discussing with a specialist.
3. Baseline parameters:
   • Check pulse rate; consider a 12 lead ECG if tachycardia present
   • Check blood pressure and a lying and standing blood pressure
   • Check temperature
   • Monitor weight
   • Baseline FBC, renal function and liver function tests
4. Choice of drug:
   • 30 - 50 % of schizophrenic patients with positive symptoms are not responsive or only partially responsive to the typical antipsychotics.¹
   • 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 and thioridazine) 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.
   • Atypical antipsychotics are thought to be more selective for dopamine receptors and also exhibit partial inhibition of serotonin receptors. However clinically significant superiority of efficacy has not been definitely shown (except for olanzapine). They are first line in schizophrenia (being particularly good for negative symptoms), and can also be used in mania and bipolar disorder. Their main attraction is fewer side affects namely, less extra-pyramidal side effects. Despite this they can have severe metabolic affects including weight gain.
5. Route of administration:
   • Antipsychotics are available in oral preparations and some are available as depot formulations.
   • Depot injections are given intramuscularly. These include: flupentixol decanoate, fluphenazine decanoate, haloperidol, pipotiazine palmitate, risperidone and zuclopenthixol decanoate. The advantages of depot medication include better compliance; however, it may take 3-6 months to attain steady state levels, therefore they are not useful in the acute phase.
6. 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
7. Multidisciplinary approach with patient and carer education:
   • Once the patient is diagnosed involve family and carers at patients consent.
   • Educate regarding the disorder, management options and local services available e.g. support groups.
   • Warn about driving - patients must stop driving during an acute episode. DVLA will consider relicensing if patient stable on treatment for 3 months and compliant with medication.

Withdrawing or changing antipsychotics

• Antipsychotics should usually continue for one to two years to prevent further relapses.
• Withdraw antipsychotic gradually - never abruptly. Some patients will relapse within a year once antipsychotics are stopped.
• Aim to reduce the dose over 8 weeks.
• At the same time regularly monitor for signs and symptoms that might suggest a relapse.

Patient's 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.

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.
  • Side effects such as, weight gain, Oligomenorrhoea,³ sexual dysfunction and itching - these are a common cause for poor compliance.
  • 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 require cardiac follow-up.⁴
• 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.
• Compliance: Poor compliance is a major reason for patients to have relapses which can lead to severe psychosocial dysfunction. There are a number of reasons for poor compliance, such as, poor insight or side effects.

Caution in the elderly¹

• 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.⁵
• 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.⁶
• Therefore, in elderly patients the starting dose should be small and the dose titrated up slowly.