Atypical Antipsychotics Part I: Pharmacology, Pharmacokinetics, and Efficacy

Markowitz, John S.; Brown, Candace; Moore, Thea R.

doi:10.1345/aph.17215

Cited by 191 publications

(113 citation statements)

References 63 publications

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“…Such an expansive review is, however, beyond the scope of this paper; thus, the reader is referred to other sources. 1,5,152 In general, although the proportion of patients who improve and the magnitude of therapeutic effects vary greatly, SGAs appear to be at least as effective for psychotic symptoms as FGAs (for reviews, see Markowitz et al 153 and Remington and Kapur 154 ). However, there has been considerable debate with regard to the clinical superiority of SGAs over FGAs.…”

Section: Second-generation Antipsychotic Agentsmentioning

confidence: 99%

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

et al. 2004

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The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

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Section: Second-generation Antipsychotic Agentsmentioning

confidence: 99%

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

et al. 2004

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“…It is a substrate for the cytochrome P450 1A2 (CYP 1A2) and for the UDP-glucuronosyltransferase 1A4 (UGT 1A4) 9 and has no active metabolites. 10,11 Risperidone, another drug in this class, has a different side effect profile. Weight gain is less pronounced than with olanzapine, 12 but it is much more likely to increase prolactin.…”

Section: Introductionmentioning

confidence: 99%

“…It is a substrate for the cytochrome P450 2D6 and 3A (CYP 2D6 and CYP 3A) 13 and has an active metabolite, 9-hydroxyrisperidone, with a comparable receptor affinity profile. 10,11 Study of the AAP pharmacological feature, which is responsible for the development of pre-diabetic complications in vulnerable populations, has principally centered around weight gain caused by these medications. Histamine 1 (H 1 ) and serotonin 2C (5HT 2C ) receptor antagonism were among the most important pharmacologic mechanisms discussed.…”

Section: Introductionmentioning

confidence: 99%

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

et al. 2007

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Atypical antipsychotics induce pre-diabetic symptoms in some but not all patients, characterized most notably by elevated weight. The side effect profiles of the various drugs in the class differ, however, raising the possibility of drug-specific mechanisms for similar side effects. We used physiogenomic analysis, an approach previously employed to study the genetics of drug and diet response, to discover and compare genetic associations with weight profiles observed in patients treated with olanzapine and risperidone as an approach to unraveling contrasting mechanistic features of both drugs. A total of 29 single nucleotide polymorphisms (SNPs) were selected from 13 candidate genes relevant to two potential pharmacological axes of psychotropic-related weight profiles, appetite peptides and peripheral lipid homeostasis. We applied physiogenomic analysis to a cross-section of 67 and 101 patients being treated with olanzapine and risperidone, respectively, and assessed genetic associations with the weight profiles. Weight profiles in patients treated with olanzapine were significantly associated with SNPs in the genes for apolipoprotein E, apolipoprotein A4 and scavenger receptor class B, member 1. Weight profiles in patients treated with risperidone were significantly associated with SNPs in the genes for leptin receptor, neuropeptide Y receptor Y5 and paraoxonase 1. These results are consistent with contrasting mechanisms for the weight profile of patients treated with these drugs. Genes associated with olanzapine weight profiles may be related to peripheral lipid homeostatic axes, whereas those associated with risperidone's may be related to brain appetite peptide regulation. Future physiogenomic studies will include neurotransmitter receptor SNPs and validation in independent samples.

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“…Originally, the term was used to describe effective antipsychotic agents associated with a minimal risk of causing EPS. 2,3 However, as described in reviews by Markowitz et al 2 and Goldstein, 4 a broader definition of atypicality is used today. In addition to a reduced risk of EPS, other elements thought to contribute to atypicality include the following: transient elevation in prolactin levels, efficacy in treating both positive and negative symptoms of schizophrenia, a mechanism of action that involves serotonin (5-HT)-2A and -2C antagonism and/or mesolimbic specificity over nigrostriatal dopamine neurons, and efficacy in treatmentresistant schizophrenia.…”

Section: Definition Of Atypicalitymentioning

confidence: 99%

“…In addition to a reduced risk of EPS, other elements thought to contribute to atypicality include the following: transient elevation in prolactin levels, efficacy in treating both positive and negative symptoms of schizophrenia, a mechanism of action that involves serotonin (5-HT)-2A and -2C antagonism and/or mesolimbic specificity over nigrostriatal dopamine neurons, and efficacy in treatmentresistant schizophrenia. 2,4 At times, various combinations of these descriptions have served to define atypicality.…”

Section: Definition Of Atypicalitymentioning

confidence: 99%

Atypicality of Atypical Antipsychotics

Farah¹

2005

Prim. Care Companion CNS Disord.

112

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Objective: To review the current definition of atypicality, discuss the unique features of each atypical antipsychotic, and determine whether the available drugs in this class really meet the classical definition of atypicality.Data Sources: A PubMed search was conducted to identify literature on the subject of this review, supported by additional articles based on the author's clinical knowledge and experience.Study Selection and Data Extraction: Relevant references were extracted and summarized in order to meet the objective of the article.Data Synthesis: Atypical antipsychotics are considered a major advance over conventional antipsychotics, primarily because they offer effective treatment alternatives that are relatively free of extrapyramidal symptoms. In fact, the term atypicality was originally used to describe antipsychotic agents with a minimal risk of causing extrapyramidal symptoms. However, over the years the definition has been modified such that there is currently no consensus on a true definition of atypicality for these agents. Each of the atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) commercially available in the United States is unique in terms of its pharmacologic profile, differing with respect to receptor-binding affinity, mechanism of action, and adverse events. Of the available atypical antipsychotics, clozapine and quetiapine have shown the lowest propensity to cause extrapyramidal symptoms. Although the risk of extrapyramidal symptoms is lower with risperidone and olanzapine than with conventional antipsychotics, risk increases with dose escalation. Data for ziprasidone indicate that the risk of extrapyramidal symptoms may be similar to that of risperidone and olanzapine. There is a concern of akathisia with aripiprazole; however, more experience with this agent is needed before definitive conclusions are made.Conclusion: If the definition of "atypical" antipsychotic is considered to be freedom from extrapyramidal symptoms, then, based on a comprehensive review of available data and clinical experience, clozapine and quetiapine appear to be the only true atypicals.( Prim Care Companion J Clin Psychiatry 2005;7:268-274)

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Atypical Antipsychotics Part I: Pharmacology, Pharmacokinetics, and Efficacy

Abstract: Data from controlled trials on efficacy and extrapyramidal side effects support risperidone or olanzapine as first-line agents for the treatment of schizophrenia. Pharmacologic and pharmacokinetic factors do not distinguish between agents sufficiently for drug selection.

Cited by 191 publications

References 63 publications

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

Atypicality of Atypical Antipsychotics

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