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Mechanism of Action of Atypical Antipsychotic Drugs and the Neurobiology of Schizophrenia

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Abstract

Atypical antipsychotics have greatly enhanced the treatment of schizophrenia. The mechanisms underlying the effectiveness and adverse effects of these drugs are, to date, not sufficiently explained. This article summarises the hypothetical mechanisms of action of atypical antipsychotics with respect to the neurobiology of schizophrenia.

When considering treatment models for schizophrenia, the role of dopamine receptor blockade and modulation remains dominant. The optimal occupancy of dopamine D2 receptors seems to be crucial to balancing efficacy and adverse effects — transient D2 receptor antagonism (such as that attained with, for example, quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, while permanent D2 receptor antagonism (as is caused by conventional antipsychotics) increases the risk of adverse effects such as extrapyramidal symptoms. Partial D2 receptor agonism (induced by aripiprazole) offers the possibility of maintaining optimal blockade and function of D2 receptors. Balancing presynaptic and postsynaptic D2 receptor antagonism (e.g. induced by amisulpride) is another mechanism that can, through increased release of endogenous dopamine in the striatum, protect against excessive blockade of D2 receptors.

Serotonergic modulation is associated with a beneficial increase in striatal dopamine release. Effects on the negative and cognitive symptoms of schizophrenia relate to dopamine release in the prefrontal cortex; this can be modulated by combined D2 and serotonin 5-HT2A receptor antagonism (e.g. by olanzapine and risperidone), partial D2 receptor antagonism or the preferential blockade of inhibitory dopamine autoreceptors.

In the context of the neurodevelopmental disconnection hypothesis of schizophrenia, atypical antipsychotics (in contrast to conventional antipsychotics) induce neuronal plasticity and synaptic remodelling, not only in the striatum but also in other brain areas such as the prefrontal cortex and hippocampus. This mechanism may normalise glutamatergic dysfunction and structural abnormalities and affect the core pathophysiological substrates for schizophrenia.

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Acknowledgements

Preparation of this review and our work reviewed in the article was supported by grant NF/7578 – 3 from MZ CR and the research project 1M0517 MSMT CR. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Prague Psychiatric Centre, Ùstavni 91, Prague 8, 181 00, Czech Republic

    Jiri Horacek, Vera Bubenikova-Valesova, Milan Kopecek, Tomas Palenicek, Colleen Dockery, Pavel Mohr & Cyril Höschl

  2. Centre of Neuropsychiatric Studies, Prague, Czech Republic

    Jiri Horacek, Milan Kopecek, Tomas Palenicek, Colleen Dockery, Pavel Mohr & Cyril Höschl

  3. 3rd Medical Faculty of Charles University, Prague, Czech Republic

    Jiri Horacek, Tomas Palenicek & Cyril Höschl

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  1. Jiri Horacek
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  2. Vera Bubenikova-Valesova
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Correspondence to Jiri Horacek.

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Horacek, J., Bubenikova-Valesova, V., Kopecek, M. et al. Mechanism of Action of Atypical Antipsychotic Drugs and the Neurobiology of Schizophrenia. CNS Drugs 20, 389–409 (2006). https://doi.org/10.2165/00023210-200620050-00004

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