Antipsychotic drugs

Antipsychotic use is associated with significant side-effects, most notably movement disorders (tardive dyskinesia) and weight gain. It is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics. Drop-out and symptom relapse rates are similar for both classes of drugs.

Both generations of medication block receptors in the brain's dopamine pathways, but atypical antipsychotics often act on serotonin receptors as well.

The atypical antipsychotics amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side-effects. Atypical antipsychotics have a greater propensity for metabolic adverse effects, weighed against the significantly higher risk of tardive dyskinesia (which can be caused by long-term/high dose administration) and other extrapyramidal symptoms of typical antipsychotics. The higher dopamine D₂ receptor affinity of the typical antipsychotics underlies these latter side-effects. Quetiapine and clozapine are considered the lowest risk agents for precipitating tardive dyskinesia. NICE recommends that the choice of antipsychotic should be an individual one, determined by consideration of the particular profiles of the individual drug and the patient's preferences. Some patients do not respond fully or even partly to treatment.

Typical antipsychotics (first generation drugs, also known as neuroleptics)

Chlorpromazine was the first antipsychotic to be discovered. It is one of the most sedating of the typical antipsychotics and also causes antimuscarinic effects. May be prescribed for managing schizophrenia and other psychoses, mania, short-term adjunctive management of severe anxiety, intractable hiccup, relief of acute symptoms of psychoses and nausea and vomiting of terminal illness (where other drugs have failed or are not available). May be used in children for some behavioural problems. Side-effects include psychomotor agitation, excitement, and violent or dangerously impulsive behaviour.

Benperidol is approved in the UK (and other countries, not in the US) for use in the control of deviant antisocial sexual behaviour (hypersexual behaviour).

Flupentixol is less sedating than chlorpromazine, but with more Parkinson’s effects. It may have an antidepressant effect, but has also been associated with suicidal thoughts. Notable side-effects include sweating, itching and rashes.

Haloperidol is less sedating and causes fewer antimuscarinic side-effects than chlorpromazine, but more neuromuscular effects, especially muscle spasms and restlessness. Haloperidol is contra-indicated alongside fluoxetine (raises haloperidol levels), carbamazepine (lowers haloperidol levels) or lithium (increased risk of toxic effects).

Levomepromazine is more sedating than chlorpromazine, and poses a risk of causing hypotension, particularly in people over 50.

Pericyazine (periciazine) is more sedating than chlorpromazine, and poses a risk of causing hypotension when treatment starts. It is approved in the UK  (and other countries, not in the US) for the management of schizophrenia or other psychoses, and as short-term adjunctive management of severe anxiety, psychomotor agitation, and violent or dangerously impulsive behaviour. Contact skin rashes from handling the tablets may occur.

Perphenazine is less sedating than chlorpromazine, but causes more neuromuscular side-effects, especially muscle spasms, particularly at high doses. It may cause blurred vision.

Pimozide is less sedating than chlorpromazine. It may cause depression. Nocturia is common. Because high doses can cause serious disturbances in heart rhythm, avoid prescribing with other antipsychotics, tricyclic antidepressants, and other drugs which affect the heart. Warn patients to avoid grapefruit juice whilst taking this medication.

Prochlorperazine is less sedating than chlorpromazine, but causes more neuromuscular side-effects, particularly muscle spasms. Contact skin rash may occur from handling tablets.

Promazine is as sedating as chlorpromazine. Contact skin rash may occur from handling tablets.

Sulpiride is less sedating than chlorpromazine and has a different chemotype. Skin pigmentation, and sensitivity to sun are common side-effects. Contact skin rash may occur from handling tablets.

Trifluoperazine is less sedating than chlorpromazine, and is less likely to lower body temperature or blood pressure, and causes fewer antimuscarinic effects than chlorpromazine. Produces neuromuscular side-effects, and restlessness, especially when the dose is over 6mg/day, and it may cause agitation. Trifluoperazine may cause spontaneous ejaculation.

Zuclopenthixol is as sedating as chlorpromazine. It may cause tinnitus, vertigo, drooling and thirst.

Atypical antipsychotics (second generation drugs)

Most of these drugs may be prescribed for the management of schizophrenia, and some of them are also licensed for mania. They may also be used for psychotic episodes in severe depression.

Risperidone and olanzapine in particular should not be used to treat behavioural problems in older dementia patients because of evidence showing that these drugs significantly increase the risk of stroke in these group. The most significant side-effects of atypical antipsychotics are weight gain and associated metabolic effects. Other important side-effects include somnolence, dizziness, neuromuscular symptoms, postural hypotension, which may be associated with fainting or tachycardia in some patients.

Amisulpride can be prescribed to control both positive and negative symptoms of schizophrenia. Parkinsonism is a very common side-effect. Insomnia, anxiety, agitation, raised prolactin levels causing milk production, and associated sexual problems are also recognised side-effects.  Amisulpride should be prescribed with caution in patients with kidney problems and in older patients. It should not be used in pregnancy or while breastfeeding.

Aripiprazole does not cause as much weight gain as some of the other atypical antipsychotic drugs. Side-effects commonly include Parkinsonism and sialorrhea. Light-headedness, insomnia, nausea and vomiting, indigestion, headache and lack of energy may also be experienced. Aripiprazole should be prescribed with caution in people with a history of seizures and should not be taken during pregnancy or while breastfeeding. Aripiprazole may take days or weeks to have its full antipsychotic effect. Warn patients to avoid grapefruit juice whilst taking this medication. Aripiprazole interacts with carbamazepine in such a way that the dose of aripiprazole should be doubled if they are given together.

Asenapine is prescribed for managing manic episodes in bipolar disorder, and not for other psychoses. Common side-effects include anxiety and drowsiness as well as weight gain and increased appetite, muscle spasms, extreme restlessness, Parkinsonism, and involuntary movements, dizziness, unusual taste sensations, numb lips and mouth, raised liver enzymes, stiff muscles and fatigue. Asenapine should not be prescribed to patients with severe liver insufficiency, and it is not suitable for patients with dementia.

Clozapine may be prescribed for managing schizophrenia when other antipsychotics are ineffective or unsuitable. Because of the severity of the possible side-effects, the prescribing psychiatrist, the patient and the supplying pharmacist must all be registered with the appropriate Patient Monitoring Service/access system. Side-effects include sedation, sialorrhea, tachycardia, blood pressure changes (high or low), dizziness, headache, and dry mouth. Some of these improve, although tachycardia, sialorrhea and sedation may persist.

Olanzapine may be prescribed for managing schizophrenia, mania (in combination with mood stabilisers) and preventing recurrence in bipolar disorder. Side-effects include Parkinsonism, and metabolic syndrome and weight gain is often very marked. Olanzapine should not be prescribed for dementia patients. It should be used with caution in pregnancy, in men with prostate problems, and in patiebts with paralytic ileus, or liver or kidney problems, or those taking certain types of heart drugs. Carbamazepine lowers the circulating level of olanzapine.

Paliperidone is the active metabolite of risperidone. It therefore shares most of risperidone’s characteristics. A prolonged-release formulation is available which releases steadily over a 24-hour period, stabilising the level of the drug in the blood.  The most common side-effect is headache. The usual side effects of antipsychotics may occur, including Parkinsonism, and other neuromuscular effects, raised prolactin with sexual effects and effects on heart rhythm.

Quetiapine may be prescribed for managing schizophrenia and for manic episodes, either alone or with mood stabilisers. It is especially useful when treating patients with intolerable Parkinson’s symptoms, or symptoms of raised prolactin levels caused by other drugs. Side-effects are similar to those caused by clozapine, but quetiapine is not associated with serious blood disorders. It causes fewer neuromuscular side-effects than the older antipsychotics. 

Risperidone may be prescribed for managing psychotic illnesses and for mania. It is thought to improve both positive and negative symptoms of schizophrenia. It has side-effects similar to chlorpromazine, but neuromuscular side-effects are usually less marked. However, it is more likely to cause Parkinsonism than most other atypical antipsychotics.  Insomnia, agitation, anxiety, headache, weight gain, and nocturnal enuresis are common side-effects. Risperidone should not be prescribed for dementia patients. It should be used with caution in patients with liver or kidney disease, epilepsy or heart disease, as hypotension can occur. It may aggravate Parkinson’s disease. Carbamazepine lowers serum risperidone levels.

Depot injection antipsychotics

Some antipsychotics are available in slow-release formulations, administered by intramuscular injection. Injections are given between once/week and once/month depending on response, severity of condition and drug preparation prescribed.

Typical antipsychotics available in these formulations tend to contain nut oils, and are therefore unsuitable for use in patients with nut allergies.

Depot injections of older antipsychotics may cause more neuromuscular reactions than oral drugs, for example depot flupentixol decanoate causes more neuromuscular side-effects than chlorpromazine (and contains nut oil). Depot zuclopenthixol decanoate may be more suitable for patients who are highly agitated, while flupenthixol decanoate may be more suitable for patients with low mood associated with their condition.

None of the slow-release formulations of depot atypical antipsychotics contain nut oils. Atypical antipsychotics available in slow-release formulations include:

• olanzapine embonate
• paliperidone palmitate
• aripiprazole
• risperidone