19.02.7 Atypical Antipsychotics (Second Generation)

Atypical antipsychotics are very different chemicals to typical antipsychotics, with different receptor binding profiles. The prototype of this group was clozapine, which ameliorates the positive symptoms of schizophrenia, and some are quite effective on the negative and cognitive symptoms as well. Clozapine has proven most effective, however it is not first line therapy owing to its liability to cause agranulocytosis, myocarditis and cardiomyopathy in vulnerable individuals. It is reserved for individuals who fail to respond to other drugs, with close monitoring.

Most atypical antipsychotics are dopamine D2 receptor antagonists. These drugs occupy 40-60% of D2 receptors at therapeutic doses. Many of the atypical antipsychotics have high affinity for 5-HT2 receptors.  It is considered that the ratio of D2:5-HT2 receptor occupancy provides additional therapeutic features of atypical antipsychotics, and reduces their liability to cause motor and endocrine side effects, thus making them more tolerable, which improves compliance. Clozapine and olanzapine, currently the most effective antipsychotics, also show high affinity for dopamine D4 receptors.

Whilst atypical antipsychotics produce fewer side effects than the typical antipsychotics, their use has lead to the emergence of another insidious side effect, metabolic syndrome. These drugs can cause weight gain, hyperglycaemia and elevated triglycerides, which increase risk of obesity, cardiovascular disease and diabetes mellitus. Thus, although these drugs appear to be an improvement on the typical antipsychotics, they do not escape limitations.