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  • CNS Drugs 2006; 20 (5): 389-409REVIEW ARTICLE 1172-7047/06/0005-0389/$39.95/0 2006 Adis Data Information BV. All rights reserved.

    Mechanism of Action of AtypicalAntipsychotic Drugs and theNeurobiology of SchizophreniaJiri Horacek,1,2,3 Vera Bubenikova-Valesova,1 Milan Kopecek,1,2 Tomas Palenicek,1,2,3Colleen Dockery,1,2 Pavel Mohr1,2 and Cyril Hoschl1,2,3

    1 Prague Psychiatric Centre, Prague, Czech Republic2 Centre of Neuropsychiatric Studies, Prague, Czech Republic3 3rd Medical Faculty of Charles University, Prague, Czech Republic

    ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3891. Classification of Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3912. Clinical Effect of Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3913. Mechanisms of Action of the Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

    3.1 Dopaminergic Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3933.1.1 Dopamine D2 Receptor Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3933.1.2 D1 Receptor Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3933.1.3 D4 Receptor Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3943.1.4 Blockade of D2/D3 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3943.1.5 Rapid Dissociation from D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3943.1.6 Partial Agonism of D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

    3.2 Serotonergic Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3953.2.1 Serotonin 5-HT2A Receptor Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3953.2.2 5-HT2C Receptor Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3963.2.3 Agonism of 5-HT1A Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

    3.3 Combined Modulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3973.3.1 Blockade of 5-HT2A and D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3973.3.2 Blockade of 5-HT2C and D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3983.3.3 Agonism of 5-HT1A and Blockade of D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3993.3.4 D2 Antagonism and Interaction with Muscarinic Receptors . . . . . . . . . . . . . . . . . . . . . . . . . 3993.3.5 Blockade of -Adrenergic and D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400

    4. The Neurobiology of Schizophrenia and the Effects of Atypical Antipsychotics . . . . . . . . . . . . . . . . . 4004.1 Neuroplastic Effect of Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

    5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

    Atypical antipsychotics have greatly enhanced the treatment of schizophrenia.AbstractThe mechanisms underlying the effectiveness and adverse effects of these drugsare, to date, not sufficiently explained. This article summarises the hypotheticalmechanisms of action of atypical antipsychotics with respect to the neurobiologyof schizophrenia.

  • 390 Horacek et al.

    When considering treatment models for schizophrenia, the role of dopaminereceptor blockade and modulation remains dominant. The optimal occupancy ofdopamine D2 receptors seems to be crucial to balancing efficacy and adverseeffects transient D2 receptor antagonism (such as that attained with, for example,quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, whilepermanent D2 receptor antagonism (as is caused by conventional antipsychotics)increases the risk of adverse effects such as extrapyramidal symptoms. Partial D2receptor agonism (induced by aripiprazole) offers the possibility of maintainingoptimal blockade and function of D2 receptors. Balancing presynaptic and post-synaptic D2 receptor antagonism (e.g. induced by amisulpride) is another mecha-nism 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 striataldopamine release. Effects on the negative and cognitive symptoms of schizophre-nia relate to dopamine release in the prefrontal cortex; this can be modulated bycombined D2 and serotonin 5-HT2A receptor antagonism (e.g. by olanzapine andrisperidone), partial D2 receptor antagonism or the preferential blockade ofinhibitory dopamine autoreceptors.

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

    The development of antipsychotics represents effect only compensates for this deficit at a sympto-one of the most important successes of applied matologic level, remains unanswered.neuroscience. In most patients, antipsychotic drugs Newer (atypical) antipsychotic drugs offer notbring a significant improvement in psychotic symp-

    only a better therapeutic tool but, because of theirtoms and better health and quality of life. However,

    stratified effect on the finer dimensions of psychoticwhile antipsychotic drugs provide a basic therapeu-symptoms, they also provide deeper insight into thetic tool for the treatment of schizophrenia and otherpathophysiology of schizophrenia itself. While thepsychotic conditions, their effectiveness is associat-majority of models explaining the effects of antipsy-ed with a series of unresolved questions. It is not

    clear, for example, which neurobiological mecha- chotic drugs indicate that these drugs modulate vari-nism (beyond dopamine D2 receptor antagonism) is ous monoaminergic systems, novel theories ofthe final therapeutic target responsible for the bene- schizophrenic pathophysiology are predominantlyficial effect on distorted information processing in focused on different levels of cortical and cortico-schizophrenia and for subsequent elimination or re-

    subcortical disconnection. This article surveys con-duction of psychotic symptoms. Also, the principaltemporary concepts and hypotheses of the effects ofquestion of whether the effectiveness of antipsy-antipsychotic drugs and the neurobiological basis ofchotic drugs represents a causal intervention intoschizophrenia with respect to the integration of thesethe pathophysiological chain of events leading toaspects.psychotic information processing or whether their

    2006 Adis Data Information BV. All rights reserved. CNS Drugs 2006; 20 (5)

  • Mechanism of Atypical Antipsychotics 391

    1. Classification of positive symptoms and the superiority of atypicalsAtypical Antipsychotics on negative and affective symptoms, cognitive dys-

    function and aggression.[5] Furthermore, during theThe original classification of antipsychotics ac- course of illness, atypical antipsychotics are associ-

    cording to their chemical structure (phenothiazines, ated with the following benefits:[2,4]thioxanthenes, butyrophenones, perathiepines and

    higher rate of responders;diphenylpiperidines) and prevailing sedative or efficiency in patients with refractory disease;antipsychotic (incisiveness) potential is still relevant lower risk of suicides;for the conventional (typical) antipsychotic agents. better functional capacity;The classification of atypical antipsychotics is improved quality of life;linked essentially to their pharmacodynamic proper-

    ties, which reflect their affinities for specific recep- favourable pharmacoeconomic profile.tors. Atypical antipsychotics with a high selectivity They also have a more favourable adverse effectfor serotonin 5-HT2A receptors and dopamine D2 profile, being associated with a lower risk of EPSreceptors (and also 1-adrenoceptors) are called se- and tardive dyskinesias, hyperprolactinaemia, mor-rotonin-dopamine antagonists (SDA). Drugs show- phological changes in the CNS and noncompliance,ing an affinity for 5-HT2A, D2 and receptors of other as well as better overall tolerability.[5] However,systems (cholinergic, histaminergic, 5-HT1A, 5- atypical antipsychotics, as a class, are associatedHT2C and others) are designated as multi-acting with their own unique adverse effects; their meta-receptor-targeted antipsychotics (MARTA).[1] bolic adverse effects, for example, are currently ofDrugs that preferentially block D2 and D3 subtypes great interest to clinicians.[6]of the

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