Antipsychotics serotonin antagonism

Antipsychotic medications antagonize dopamine, which is believed to contribute to the antipsychotic effect of these medications. The atypical antipsychotics have other physiological properties as well, some of which appear to relate to antagonism of the serotonin type 2 (5-HT2) receptor, which may modify dopamine activity in a regionally specific manner. Dual 5-HT2 receptor-dopamine type 2 (D2) receptor antagonism is believed to account, at least in part, for the superior efficacy and more favorable side-effect profile of atypical antipsychotics. 

There is also preliminary data that risperidone, an atypical antipsychotic that antagonizes multiple receptor types including dopamine receptors and serotonin receptors, may affect certain ERP components. A study of chronic risperidone delivery via subcutaneous implants reported increased P20 amplitude but no effects on the N40 component. Risperidone in this study was unable to block the amphetamine-induced decreases in the P20 component, but attenuated amphetamine-induced reduction of the N40 (Siegel et al., 2004). 

Ziprasidone is an atypical antipsychotic in clinical use for both schizophrenia and bipolar disorder (see footnote 1). It has a high affinity for dopamine, serotonin, and alpha-adrenergic receptors and a moderate affinity for histamine receptors. The exact mechanism of action of ziprasidone is unknown. However it has been presumed that its antipsychotic activity is mediated primarily by antagonism at dopamine receptors, specifically D2. Serotonin antagonism may also play a role in the effectiveness of ziprasidone. Antagonism at histaminic and alpha adrenergic receptors are likely responsible for some of the side effects of ziprasidone, such as sedation and orthostasis. The worldwide sales of ziprasidone are expected to be 1 billion in 2009. 

Fuller RW, Snoddy HD. Neuroendocrine evidence for antagonism of serotonin and dopamine receptors by olanzapine (LY170053), an antipsychotic drug candidate. Res Commun Chem Pathol Pharm 1992 77 87-93. 

Table 12.1 is a scorecard indicating the neuromodulatory systems with which some of the major psychoactive drug classes interact. The table indicates that no one drug does it all, and that most are either 5HT-NE enhancers or DA-ACh blockers. Exceptions to the rule do not necessarily prove it. And in the case of the atypical antipsychotics, it is the antagonism to serotonin which may be critical to efficacy. 

Consistent with the role of both serotonin and dopamine in OCD, some OCD patients benefit from treatment with the new serotonin-dopamine antagonists (also known as atypical antipsychotics), especially when there is inadequate response to an SSRI. On the other hand, other patients have no therapeutic response to these new agents, and the condition of still others is even worsened by these drugs. The atypical antipsychotics and serotonin dopamine antagonism are discussed in Chapter 11. 

II. Atypical antipsychotic drugs Serotonin-dopamine antagonism and what several antipsychotic drugs have in common... 

Atypical Antipsychotic Drugs Serotonin-Dopamine Antagonism and What Several Antipsychotic Drugs Have in Common... 

Serotonin 2A antagonism not only reverses dopamine 2 antagonism but causes a net increase in dopamine activity in the mesocortical dopamine pathway, where the balance between serotonin and dopamine is different from that in the nigrostriatal dopamine pathway. That is, unlike the nigrostriatal dopamine pathway, in which dopamine 2 receptors predominate, there is a preponderance of serotonin 2A receptors over dopamine 2 receptors in many parts of the cerebral cortex. Thus, in the mesocortical dopamine pathway, atypical antipsychotics with SDA properties have a more profound effect in blocking densely populated cortical serotonin 2A receptors, thereby increasing DA release, than in blocking thinly populated cortical D2 recep-... 

Serotonin 2A antagonism fortunately fails to reverse D2 antagonism in the mesolimbic system. If serotonin 2A antagonism reverses, at least in part, the effects of D2 antagonism in several dopamine pathways, then why does it not reverse the antipsychotic actions of D2 blockade in the mesolimbic dopamine pathway Evidently, the antagonism by serotonin of the effects of dopamine in this pathway is not robust enough to cause the reversal of D2 receptors by atypical antipsychotics or to mitigate the actions of atypical antipsychotics on positive symptoms of psychosis. 

Although it is not yet clear why the various atypical antipsychotics differ from each other, the answer is most likely to be found in the pharmacologic properties, other than serotonin 2A dopamine—2 antagonism, that they do not share in common. Although some of these properties are still unknown, many of them are known (and are shown in Figure 11—34 and in the individual icons for the various atypical antipsychotics discussed later in this chapter). Of the 17 pharmacologic properties detailed in these icons, some undoubtedly mediate side effects, and others may mediate additional therapeutic actions mentioned here. This raises the question Are atypical antipsychotics with multiple therapeutic mechanisms better than those with fewer therapeutic mechanisms (see Fig. 11-35) This theme of multiple pharma-... 

On the dopamine side of the equation, one of the most promising agents in late clinical development is aripiprazole, theoretically a presynaptic D2 autoreceptor agonist. This compound is postulated to exert its antipsychotic actions in a manner far different from serotonin-dopamine antagonism that is, it may shut off the presynaptic dopamine terminal and stop dopamine release in the mesolimbic dopamine pathway by stimulating presynaptic D2 receptors. The agents Cl-1007 and DAB-... 

Stahl, S.M., and Shayegan, D. (2000) New discoveries in the development of antipsychotics with novel mechanisms of action beyond the atypical antipsychotics with serotonin dopamine antagonism. In Atypical antipsychotics (MDT), Ellenbroek, B.A. and Cools, A.R. (Eds.). Boston, Birkhauser. 

To review the importance of serotonin 2A antagonism to the atypical clinical properties of atypical antipsychotics. 

The pharmacological property which all atypical antipsychotics share is serotonin dopamine antagonism. True or False. 

Which pharmacologic properties in addition to serotonin 2A/dopamine 2 antagonism characterize one or more atypical antipsychotics ... 

Compared to other atypical antipsychotics with potent serotonin 2A antagonism, amisulpride may have more extrapyramidal symptoms and prolactin elevation, but may still be classified as an atypical antipsychotic, particularly at low doses... 

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