From pharmacological profiles to clinical outcomes.

The reformulated dopamine hypothesis of schizophrenia postulates that over-activity of dopaminergic neurones in limbic areas of the brain is responsible for the positive symptoms of the illness. At the same time, dopaminergic under-activity in the frontal cortex is thought to underlie the negative symptoms and cognitive impairment. In addition, it has emerged that classical dopaminergic D2 receptors comprise a family of several different subtypes of which D2 is widely distributed, whereas D3 and D4 are concentrated in limbic and cortical areas. Amisulpride selectively blocks D2 and D3 receptors but with preference for the latter. Amisulpride also has preferential activity at presynaptic rather than postsynaptic receptors. It was predicted therefore that amisulpride would alleviate both the under-activity in the frontal cortex and the over-activity in the limbic system. Amisulpride is also virtually free of activity at receptors for other neurotransmitters. This unique pharmacology is consistent with the therapeutic profile of amisulpride, which has been clearly demonstrated to control both the positive and negative symptoms of schizophrenia with equal efficacy as well as being well tolerated.