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Atypical antipsychotics mechanism of action

Atypical antipsychotics

The term ‘atypical’ is applied to the second generation of antipsychotics owing to their reduced propensity to cause EPSEs. The fi rst of this group was clozapine, which was fi rst synthesised in 1958. After initial launch in the 1970s it was withdrawn because of the recognition of previously unidentifi ed and potentially fatal but rare side effects. It was re-launched with a restricted licence in the UK in 1990, and was followed by other drugs.

Mechanism of action

Like the typical antipsychotics, atypicals reduce positive symptoms through dopamine D2 antagonism in the meso-limbic pathway. They are equally as effective as typical antipsychotics with the possible exception of clozapine, which is a fairly weak D2 antagonist. As a group they may be viewed as dopamine D2 and serotonin 5-HT2A antagonists but in other respects they are quite individual. Clozapine is the most complex, acting as an antagonist at no fewer than seven serotonin and four dopamine receptor subtypes. How these actions combine remains unclear, although evidence shows that it is superior in effi cacy to typical antipsychotics  and helps a proportion of those resistant to conventional treatment. It is suggested that other atypicals may have some benefi cial effect on negative symptoms but the evidence remains rather equivocal.

The hypothesis regarding both effi cacy for negative symptoms and the low incidence of EPSE concerns the atypicals’ serotonin 5-HT2A receptor antagonism. Serotonin has extensive infl uence on dopamine activity but this is not consistent between the dopamine pathways. In the meso-cortical pathway where dopaminergic defi ciency is thought to relate to negative symptoms, 5-HT2A antagonism causes an increase in dopamine activity. In the nigro-striatal pathway serotonin inhibits dopamine release. Antagonism at 5-HT2A enhances dopamine release, allowing for greater competition at D2 receptor sites between the drug and dopamine and so reducing the proportion of D2 antagonised receptors and reducing side effects.

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