Abstract
Atypical antipsychotics represent the great progress in schizophrenia treatment. The mechanisms underlying the unique effectivity and safety of these drugs are to date not sufficiently explained.
This article summarizes the hypothetical mechanisms of atypical antipsychotic action with respect to the neurobiology of schizophrenia. The role of dopamine blockade and modulation is still prevailing when considering treatment models for schizophrenia but the adequate occupancy of D2 receptors seems to be crucial.
Only transient D2 antagonism is sufficient for an antipsychotic effect. Moreover permanent D2 blockade increases the risk for antipsychotic toxicity (extrapyramidal symptoms).
Partial D2 agonism offers a new possibility to maintain optimal blockade and function of D2 receptors. Balancing the presynaptic and the postsynaptic D2 antagonism is another mechanism which can, through increased release of endogenous dopamine in the striatum, protect against the excessive toxic blockade of D2 receptors.
Also, serotonergic modulation offers a beneficial higher striatal dopamine release. The effect on negative and cognitive symptoms would be associated with dopamine release in the prefrontal cortex mediated by combined D2 and 5-HT2A antagonism, partial D2 antagonism or the preferential blockade of inhibitory dopamine autoreceptors.
In the context of the neurodevelopmental disconnection hypothesis of schizophrenia, the atypical antipsychotics (in contrast to classical) induce neuronal plasticity and synaptic remodelation not only in the striatum, but also in other brain areas such as the prefrontal cortex and hippocampus. This mechanism would normalize glutamatergic dysfunction and structural abnormalities and affects the core pathophysiological substrates for schizophrenia