Antipsychotics, second-generation (atypical)

Key examples

• Quetiapine
• Olanzapine
• Risperidone
• Clozapine

 

Common indications

1. Urgent treatment of severe psychomotor agitation leading to dangerous or violent behaviour, or to calm such patients to permit assessment.
2. Schizophrenia, particularly when extrapyramidal side effects have complicated the use of first-generation (typical) antipsychotics, or when negative symptoms are prominent.
3. Bipolar disorder, particularly in acute episodes of mania or hypomania.

 

Mechanisms of action

• Antipsychotic drugs block post-synaptic dopamine D2 receptors. There are three main dopaminergic pathways in the central nervous system. The mesolimbic/mesocortical pathway runs between the midbrain and the limbic system/frontal cortex. D2 blockade in this pathway is probably the main determinant of antipsychotic effect, but this is incompletely understood. The nigrostriatal pathway connects the substantia nigra with the corpus striatum of the basal ganglia. The tuberohypophyseal pathway connects the hypothalamus with the pituitary gland. 
• Features that distinguish second-generation antipsychotics from first-generation agents are improved efficacy in ‘treatment-resistant’ schizophrenia (particularly true of clozapine) and against negative symptoms, and a lower risk of extrapyramidal symptoms. 
• Possible mechanisms for these differences include a higher affinity for other receptors (particularly 5-HT2A receptors), and a characteristic of ‘looser’ binding to the D2 receptors (in the case of clozapine and quetiapine).

 

Important adverse effects

• Most antipsychotics cause some degree of sedation. 
• Blocking dopamine in the nigrostriatal pathway may produce movement abnormalities called extrapyramidal effects. These are more common with first-generation antipsychotics, where they are discussed more fully. 
• Metabolic disturbance, including weight gain, diabetes mellitus and lipid changes, is a common problem with second-generation antipsychotics. 
• Antipsychotics can prolong the QT interval and thus cause arrhythmias. 
• Risperidone has particular effects on dopaminergic transmission in the tuberohypophyseal pathway, which regulates secretion of prolactin. This can cause breast symptoms (in both women and men) and sexual dysfunction. 
• Clozapine causes a severe deficiency of neutrophils (agranulocytosis) in about 1 of patients, and rarely causes myocarditis.

 

Warnings

• Antipsychotics should be used with caution in patients with cardiovascular disease.
• Clozapine must not be used in patients with severe heart disease or a history of neutropenia.

 

Important interactions

• Sedation may be more pronounced when used with other sedating drugs. 
• They should not be combined with other dopamine-blocking antiemetics and drugs that prolong the QT interval (e.g. amiodarone, quinine, macrolides, selective serotonin reuptake inhibitors).