These are also called neuroleptics or major tranquillisers. They are indicated in schizophrenia, mania and psychotic depression and may be useful for short-term sedation in aggression or agitation. Their antipsychotic effect may take several weeks to develop. Antipsychotics also have important prophylactic effect in schizophrenia. Generally, because of their long half-lives a single dose may be prescribed. Antipsychotics are divided into "typical" and "atypical".

Typical Antipsychotics

These drugs have been in use for around 5 decades and their introduction was a major advance in the treatment of schizophrenia.

Mechanism of action

The therapeutic effect of typical antipsychotics depends on their ability to block dopamine D2 receptors. Indeed the clinical dose of these drugs correlated highly with their affinity for these receptors. This is a major argument in favour of the "dopamine hypothesis" of schizophrenia. Some of these drugs are available in depot form that can be administered to patients by intramuscular injection every 1-4 weeks. This is a great advantage in-patients with poor compliance.

Cautions

Cardiovascular and cerebrovascular disease, parkinsonism, epilepsy, pregnancy and breast feeding, renal and hepatic impairment, prostatism, glaucoma.

Adverse effects

Pharmacologically they are similar to TCAs without significant monoamine re-uptake blockade (and so they are not antidepressant) but with dopamine antagonism (so that they are antipsychotic). As a general rule therefore their side effects are similar to TCAs. However they have important additional extrapyramidal effects (EPS) due to the dopamine antagonism in the basal ganglia:

• An immediate effect may be acute dystonia often of jaw, neck or external ocular muscles.

 

• After days or weeks of treatment; parkinsonism with the classical triad of akinesia, rigidity and tremor may manifest. Both of these earlier effects respond to antimuscarinic drugs (e.g. procyclidine, orphenadrine).

 

• Akathisia, a subjective restlessness of the legs often leading to pacing, may appear within weeks of starting treatment but does not respond to antimuscarinics.

 

• Tardive dyskinesia, appears later, after at least several months. It manifests in involuntary, choreiform movements mainly of mouth and face but sometimes also limbs and trunk. The condition is often irreversible despite neuroleptic withdrawal.

 

• Dopamine blockade in hypothalamus also leads to hyperprolactinaemia with gynaecomastia, galactorrhoea and amenorrhoea.

Other adverse effects include:

• Neuroleptic Malignant Syndrome (NMS): A rare but potentially fatal syndrome of rigidity, hyperpyrexia and clouding of consciousness. Serum creatinine phosphokinase levels are elevated. There is a higher risk in hot weather or pyrexial patients.

 

• Blood dyscrasias, hepatitis, skin rashes and photosensitivity Interactions: Increased effect of other hypotensives or sedatives.

 

Examples

These drugs may be usefully grouped according to adverse effective profile: ·

• Sedation +++; anticholinergic ++; Extrapyramidal ++
  Chlorpromazine; an aliphatic phenothiazine also a potent alpha adrenergic antagonist causing marked hypotension.

 

• Sedation ++; anticholinergic +++; extrapyramidal +
  Thioridazine; a piperidine phenothiazine. The intrinsic anticholinergic activity of these drugs limits their extrapyramidal effects by the same mechanisms that anticholinergic medication is effective in Parkinson's disease. However thioridazine has a high risk of leading to ECG changes and in the future this may severely limit its use.

 

• Sedation +; anticholinergic +; extrapyramidal +++
  Trifluoperazine; a piperazine phenothiazine
  Haloperidol; a butyrophenone
  Flupenthixol decanoate; Fluphenazine decanoate; depot preparations
  

Atypical Antipsychotics

In recent years there has been the development of several new antipsychotics. These have often been referred to as "atypical". A confusing aspect is that the word "atypical" has developed two different meanings. Some people use it to refer to drugs that have a low incidence of extrapyramidal side effects (EPS). However others use it to refer to a slightly different pharmacology of some drugs that includes a lower potency at blocking D2 receptors but also a high potency at blocking 5-HT2 receptors. Such drugs are 'modelled' on clozapine (see below) and have led to hypothesises that the ratio between D2 and 5-HT2 receptor blockade is important in the treatment of schizophrenia. All these drugs tend to be better tolerated than typical antipsychotics. However they are considerably more expensive. There is an ongoing debate about whether they should be prescribed "first line" or reserved for patients who fail to respond or do not tolerate typical antipsychotics.

Sulpiride

Substituted benzamide that is a 'clean' dopamine antagonist therefore without many of the side effects of typical antipsychotics. In addition it has low affinity for basal ganglia dopamine receptors and therefore cause less EPS (hence it's classification by some people as atypical).

Should be avoided in renal impairment. Less sedating than some typical antipsychotics, though still can be used for acute psychosis

Clozapine

Mixed 5-HT2/D2 antagonist. The only drug that has been conclusively shown to have higher efficacy than typical antipsychotics in regard to treatment resistant schizophrenic patients. Also some evidence that it is able to treat 'negative' symptoms. However it is associated with potentially fatal agranulocytosis. As a result it is only indicated in schizophrenia which has not responded to other antipsychotics. In addition patients MUST have regular (initially weekly) blood counts performed before being prescribed the medication.

Other adverse events include marked sedation, hypersalivation, anticholinergic effects, but less EPS than typical antipsychotics.

Risperidone, Olanzapine, Quetiapine

All different but they have varying degrees of 5-HT2/D2 antagonism which is believed to produce their therapeutic benefit. It remains unclear whether they have advantages over typical with regard to efficacy in the same way that clozapine does. They may have some efficacy with regard to negative symptoms.

All are associated with marked weight gain but less EPS compared to typical antipsychotics.

• Risperidone can cause EPS at higher doses. Can also cause anticholinergic effects and hyperprolactinaemia. Given once or twice a day.
• Olanzapine is reasonably sedative and so of use in agitated patients. It is contraindicated in glaucoma and should be used with caution in myeloproliferative disease.
• Quetiapine needs to be administered twice a day.

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