抗精神病药物的临床应用及分析

精神分裂症对人类健康危害较大,目前不断有抗精神病药上市,据药物作用的受体不同可分为典型和非典型抗精神病药.典型抗精神病药主要阻断多巴胺受体D2,非典型抗精神病药的药理特征是5-HT2A和D2受体阻断之比率高[1].本文对两类抗精神病药的临床应用及特点进行总结和分析,为临床更合理的应用抗精神病药物提供参考.     

阿立哌唑与氯氮平治疗精神分裂症时心脏安全性的比较

阿立哌唑为日本大冢制药公司开发的一种高度脂溶性的喹诺啉酮类衍生物,作为多巴胺部分激动剂,其作用机制与已上市的典型及非典型抗精神病药完全不同,它通过对多巴胺D2受体和5-羟色胺5-HTLA受体的部分激动作用以及通过对5-羟色胺5-HT2A受体的拮抗作用而共同起效,为第二代非典型抗精神病药.     

介绍一种新的非典型抗精神病药:阿兰札平

阿兰札平(Olanzapine)是一种新的“非典型”抗精神病药。所谓“非典型”,是与传统的抗精神病药相对而言。传统的抗精神病药,其作用原理是阻断中枢神经系统的多巴胺受体,如氟哌啶醇、氟奋乃静、氯丙嗪等。阻断中脑边缘叶系统的多巴胺受体后,可以起到治疗作用,尤其是治疗精神分裂症,但令人遗憾的是同时也阻断了黑质纹状体系统的多巴胺受     

奥氮平:一种新的非典型神经安定药

奥氮平(olanzapine)是一种新研制的“非典型”神经安定药,或称为非典型抗精神病药。本文将该药与传统的抗精神病药物进行比较和评价。传统的抗精神病药,例如氟哌啶醇、氟奋乃静和氯丙嗪等,其作用原理是阻断中脑边缘区的中枢多巴胺受体。但令人遗憾的是同时也阻断了黑质-纹状体系统的多巴胺受体,可引起锥体外系反应综合征,从而使临床应用受到很大限制。于是,人们开始寻找其他类型的药物,即所谓的非典型的抗精神病药物。以前报道过的非典型抗精神病药物中,氯氮平有较好的作用,其作用原理是既可阻断多巴胺受体,又可阻断5-羟色胺受体。由于氯氮…     

利培酮对受体的拮抗作用和相关不良反应

利培酮为临床广泛应用的非典型抗精神病药，其对多巴胺D2受体、5-HT2受体、α1和α2肾上腺素能受体及组胺H1受体有不同程度的拮抗作用。其阻断多巴胺D：受体引致锥体外系反应和高催乳素血症，阻断5-HT2和组胺H1受体引致体重增加和血糖升高。其他常见不良反应有失眠、焦虑、头痛、头晕、注意力下降、便秘、恶心、呕吐、视物模糊、皮疹、直立性低血压、高血压、心动过速及性功能障碍等。     

新型抗精神病药：哌罗匹隆

哌罗匹隆是一种新型非典型抗精神病药,主要药理机制是5-羟色胺(5-HT)和多巴胺D_2受体拮抗作用。与传统抗精神病药相比,哌罗匹隆对阳性症状、阴性症状和情感症状均有较好疗效,锥体外系不良反应和致催乳素升高作用轻微。哌罗匹隆是一种安全有效的非典型抗精神病药。     

非典型抗精神病药的临床应用及不良反应

目的:对近几年出现的一些非典型抗精神病药物利培酮、奥氮平、奎的平、思普酮、思庭多进行介绍,并讨论这些药物的作用机制,临床应用,不良反应及经济学评价等问题.方法:通过查阅相关文献并进行综述.结果:这类药物的作用机制可能与多巴胺受体(D2)、5-羟色胺受体(5-HT)受体的联合阻断有关,具有用药简单,疗效显著,耐受性及安全性良好等优点,但仍然不可避免地存在一定的不良反应.结论:新一代非典型抗精神病药在改善精神分裂症的阳性,阴性症状以及安全性,耐受性方面明显优于传统抗精神病药,但仍应注意不良反应.     

氯氮平引起反常高血压

氯氮平系一种非典型抗精神病药，对应用经典制剂耐受的精神分裂症治疗有效。因它有广倍受体亲和力（α-肾上腺素，多巴胺-D1、D2、D3、D4，组胺、毒章碱及5-羟色胺）而被广泛应用。该药不良反应包括镇静、流诞、低血压和粒细胞缺乏。本文报道1例氯氮平治疗期间出现反常高血压患者。一名男性32岁患者，符合DSM一见一R慢性瓦解型精神分裂症诊断标准，特征表现有听幻觉，妄想、思维障碍、瓦解及阴性症状。以往治疗包括大剂量的传统抗精神病药和ECT，均无效。氯氮平始用剂量为25mg，睡前服用，在体位性血压和WBC计数被监测之下，增至400mg…     

氨磺必利的药理学进展与临床应用评价

氨磺必利作为目前精神病治疗的常用非典型抗精神药物,其能够选择性作用多巴胺D2受体以及 D3受体。相对于传统所用抗精神病药物而言,氨磺必利具有明显显著的优势,且不良反应少,应用于精神分裂症阳性以及阴性症状的临床治疗中效果显著。为加深对氨磺必利的认识,本次研究笔者就氨磺必利的药理学进展以及临床应用进行详细地阐述。     

Cariprazine有望用于治疗急性躁狂症

Forest Laboratories和Gedeon Richter公司开发的Cariprazine[RGH188]（I）是一种口服新型非典型抗精神病药，对多巴胺D3、多巴胺D2和5-羟色胺2B受体有拮抗作用，对治疗双极性障碍患者的躁狂发作显示有肯定效果。     

Can antipsychotic drugs be classified by their effects on a particular group of dopamine neurons in the brain?

During the four decades that research has been carried out on antipsychotic drugs, a variety of methods have been used to study the effects of these compounds on dopamine neurotransmission. An important issue in this research was to find an explanation for the difference between "typical" and "atypical" antipsychotic drugs. The hypothesis that the beneficial properties and the motor side effects of antipsychotic drugs result from their effects on different groups of dopamine neurons has received considerable attention. Numerous researchers have tried to discover regiospecific actions of antipsychotic drugs in mesolimbic and in mesocortical dopamine neurons. An overview of these research attempts is presented here. Electrophysiological studies showed a selective action of atypical antipsychotic drugs on A10 dopamine neurons. It was found that chronic treatment with these compounds induced a preferential depolarisation block of the A10 neurons that project to the mesolimbic areas. The model represents certain clinical features of antipsychotic drug use and offers a possible explanation for the lack of extrapyramidal side effects of atypical antipsychotic drugs. Dopamine neurons projecting from A10 to the frontal cortex are also considered as a possible site of action of atypical antipsychotic drugs. Microdialysis studies have shown that certain atypical antipsychotic drugs selectively enhance the release of dopamine in the prefrontal cortex when compared with typical antipsychotic drugs. The finding that repeated treatment with antipsychotic drugs increased dopamine D(2) receptor binding in the frontal cortex confirms the significance of this brain area. These properties might indeed explain certain beneficial effects of atypical antipsychotic drugs such as improvement of cognitive dysfunction. However the effects of typical and atypical antipsychotic drugs in the frontal cortex could not be fully differentiated, which illustrates the difficulty of localising clinical effects of antipsychotic drugs in terms of regional dopamine neurons. Recently new insights into the mechanism of action of typical and atypical antipsychotic drugs have been published. Clinical positron emission tomography (PET) studies have indicated that a moderate dopamine D(2) receptor occupancy, probably combined with a high dissociation rate, might provide the optimal clinical conditions for an antipsychotic drug, without inducing extrapyramidal side effects. Moreover the efficacy of benzamides as atypical antipsychotic drugs suggests that low to moderate dopamine D(2) blockade is probably the most important-if not the only-criterion that determines "atypicality". Interestingly these new insights are based on PET studies of the human basal ganglia and not on the comparison of different brain areas. Apparently, according to this concept an ideal antipsychotic drug need not to act on a particular type of dopamine neurons, as it is the moderate dopamine D(2) receptor occupancy that determines the desirable clinical effects. It is concluded that both beneficial actions and side effects, of antipsychotic drugs might be dose dependently localised in A9 as well as A10 dopamine neurons.     

Atypical antipsychotic drugs and tardive dyskinesia: relevance of D2 receptor affinity

Evidence suggests atypical antipsychotic treatment is associated with a lower incidence of tardive dyskinesia (TD) than typical antipsychotic drugs, and is a potential antidyskinetic treatment. We present the case of a middle-aged woman never previously exposed to antipsychotic treatment who developed TD after 6 months of olanzapine monotherapy. Substitution of quetiapine for olanzapine alleviated her TD symptoms. The case demonstrates that atypical antipsychotic drugs have different effects in relation to TD. Potential psychopharmacological mechanisms explaining these differences are discussed, highlighting the importance of D2 receptor occupancy by atypical antipsychotic drugs for TD.     

Possible dose–side effect relationship of antipsychotic drugs: relevance to cognitive function in schizophrenia

Management of adverse events is a major concern of clinicians who use antipsychotic drugs. The incidence of motor side effects is dose dependent. Atypical antipsychotic drugs are less likely to induce neurologic side effects compared with typical (conventional) antipsychotics, such as haloperidol. Some recent, large-scale studies have shown that the incidence of metabolic side effects often associated with atypical agents does not differ among typical and atypical antipsychotics. Cognitive function, such as verbal learning memory, working memory, executive function, verbal fluency and attention/information processing, is the most influential determinant of outcome in patients with schizophrenia. Atypical antipsychotic drugs have been shown to be more efficacious in treating cognitive disturbances of schizophrenia compared with typical antipsychotic drugs. Serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes, such as the 5-HT_1A receptor, are considered to mediate the ability of antipsychotic drugs to enhance cognition. On the other hand, treatment with some atypical agents, such as risperidone, may deteriorate working memory in some people with early-stage schizophrenia. The paradoxical side effects of these antipsychotic drugs in terms of cognition may be attributable to dose, duration of treatment and type of cognitive domain. Further research will add to the worldwide endeavor to develop more effective psychotropic drugs accompanied with minimal side effects, for the improvement of cognition, adherence and long-term outcome in patients with schizophrenia or other major psychiatric illnesses.     

Dopamine and serotonin receptor binding and antipsychotic efficacy.

The relationship between clinically effective antipsychotic drug dosage and binding affinity to cloned dopamine (DA) and serotonin receptor subtypes was analyzed in an effort to elucidate the contribution of individual receptor subtypes to medication response. Clinically effective dose and binding affinity to D(2) DA receptor were modestly correlated for typical antipsychotic medications (r=0.54, p=0.046), but surprisingly were not correlated for atypical antipsychotics (r=0.41, p=0.31). For typical antipsychotics, a more robust inverse relationship was observed between medication dose and 5-HT(2C) affinity (r=-0.68, p=0.021). The strongest correlation for typical antipsychotics was observed between drug dosage and 5-HT(2C)/D(2) binding affinity ratio (r=-0.81, p=0.003). For atypical antipsychotics, no significant correlations were identified between medication dosage and 5-HT(2C), 5-HT(2A), 5-HT(2C)/D(2), or 5-HT(2A)/D(2) receptor-binding affinities. In contrast, atypical antipsychotic medication dosage was highly correlated with the ratios of D(2) (5-HT(2A)/5-HT(1A)) (r=0.80, p=0.031), and D(2) (5-HT(2C)/5-HT(1A)) (r=0.78, p=0.038) binding affinities. These observations demonstrate an interaction between D(2) and 5-HT(2C) receptor effects contributing to positive symptom response for typical antipsychotic medications, suggesting that signaling through 5-HT(2C) receptors interacts with and improves antipsychotic effects achieved via D(2) receptor blockade. This analysis also demonstrates that, in contrast to typical antipsychotics, therapeutic effects of atypical antipsychotic medications are determined by opposing interactions among three different domains: (1) increasing D(2) DA receptor-binding affinity enhances antipsychotic potency. (2) Increasing 5-HT(2C) and 5-HT(2A) receptor-binding affinities also facilitate antipsychotic efficacy. (3) Increasing 5-HT(1A) receptor-binding affinity, in contrast, reduces antipsychotic efficacy.     

D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs

The affinities of 13 atypical and 12 typical antipsychotic drugs for the cloned rat D₄ dopamine receptor and the D₄/D₂ ratios were examined. Of the atypical antipsychotic drugs tested, only clozapine, risperidone, olanzapine, zotepine and tiospirone had affinities less than 20 nM. In fact, many atypical antipsychotic drugs had relatively low affinities for the cloned rat D₄ receptor, with Ki values greater than 100 nM (Seroquel, fluperlapine, tenilapine, FG5803 and melperone). Additionally, several typical antipsychotic drugs had high affinities for the cloned rat D₄ receptor, with K_is less than 20 nM (loxapine, chlorpromazine, fluphenazine, mesoridazine, thioridazine and trifluoroperazine). The ratios of D₂/D₄ affinities did not differentiate between these two types of antipsychotic drugs. Thus, D₄ dopamine receptor affinity, used as a single measure, does not distinguish between the group of typical and atypical antipsychotic drugs analyzed.     

Inverse agonist properties of atypical antipsychotic drugs

Mechanisms of action of several atypical antipsychotic drugs have been examined at the D(2) dopamine receptor expressed in CHO cells. The drugs tested were found to exhibit inverse agonist activity at the D(2) dopamine receptor based on their effects to potentiate forskolin-stimulated cyclic AMP (cAMP) accumulation. Each of the antipsychotic drugs tested (clozapine, olanzapine, quetiapine and risperidone) increased cAMP accumulation to the same extent. The increase in cAMP was also similar to that seen with typical antipsychotic drugs. Inverse agonism at the D(2) dopamine receptor seems, therefore, to be a property common to all classes of antipsychotic drugs. The effect of sodium ions on the binding of the drugs to the receptor was also assessed. Each of the atypical antipsychotic drugs tested here bound with higher affinity in the absence of sodium ions. Previous studies have shown that some antipsychotic drugs are insensitive to sodium ions and some bind with higher affinity in the presence of sodium ions. Given that all of these antipsychotic drugs are inverse agonists, it may be concluded that this sodium ion sensitivity is unrelated to mechanisms of inverse agonism.     

Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies

Background  Drug discrimination is an increasingly valuable behavioral assay for the preclinical development of antipsychotic drugs. The majority of studies have used the atypical antipsychotic clozapine because it displays robust discriminative stimulus properties and is the “prototypical” or “gold standard” atypical antipsychotic against which other antipsychotics will undoubtedly be compared for many years. Objectives  Pharmacological mechanisms mediating the discriminative stimulus properties of antipsychotics used as training drugs and the usefulness of drug discrimination for distinguishing typical and atypical antipsychotics were reviewed. Results  Clozapine appears to have a compound cue involving antagonism of two or more receptors. While muscarinic receptor antagonism is a prominent factor for mediation of clozapine’s cue in rats with a 5.0-mg/kg training dose, there are differences in clozapine’s cue with a low training dose and in pigeons and mice. With a low training dose, clozapine has consistently produced full or partial generalization to atypical but not to typical antipsychotics. Although not evaluated as extensively, the atypical antipsychotics quetiapine and ziprasidone also appear to generalize to atypical but not typical antipsychotics. This has not been the case for other antipsychotic drugs (olanzapine, chlorpromazine, haloperidol) used as training drugs. Conclusions  There are important differences in discriminative stimulus properties both between and within atypical and typical antipsychotics and across species. While low-dose clozapine discrimination in rats appears to provide a more sensitive behavioral assay for distinguishing atypical from typical antipsychotics, the extent to which clozapine’s discriminative stimulus properties are predictive of its antipsychotic effects remains to be determined.     

Mechanisms of action of atypical antipsychotic drugs: a critical analysis

Various criteria used to define atypical antipsychotic drugs include: 1) decrease, or absence, of the capacity to cause acute extrapyramidal motor side effects (acute EPSE) and tardive dyskinesia (TD); 2) increased therapeutic efficacy reflected by improvement in positive, negative, or cognitive symptoms; 3) and a decrease, or absence, of the capacity to increase prolactin levels. The pharmacologic basis of atypical antipsychotic drug activity has been the target of intensive study since the significance of clozapine was first appreciated. Three notions have been utilized conceptually to explain the distinction between atypical versus typical antipsychotic drugs: 1) dose-response separation between particular pharmacologic functions; 2) anatomic specificity of particular pharmacologic activities; 3) neurotransmitter receptor interactions and pharmacodynamics. These conceptual bases are not mutually exclusive, and the demonstration of limbic versus extrapyramidal motor functional selectivity is apparent within each arbitrary theoretical base. This review discusses salient distinctions predominantly between prototypic atypical and typical antipsychotic drugs such as clozapine and haloperidol, respectively. In addition, areas of common function between atypical and typical antipsychotic drug action may also be crucial to our identification of pathophysiological foci of the different dimensions of schizophrenia, including positive symptoms, negative symptoms, and neurocognitive deficits.This study was supported by the Mental Health Clinical Research Center for the Study of Schizophrenia (USPHS MH-41960)     

Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects

Interaction of the antipsychotic drugs with dopamine receptors of the D2, D3, or D4 subclasses is thought to be important for their mechanisms of action. Consideration of carefully defined affinities of the drugs for these three receptors suggests that occupancy of the D4 subclass is not mandatory for achieving antipsychotic effects, but actions at D2 or D3 receptors may be important. A major difference between typical and atypical antipsychotic drugs is in the production of extrapyramidal side effects by the typical drugs. Production of extrapyramidal side effects by typical drugs seems to be due to the use of the drugs at doses where striatal D2 receptor occupancy exceeds approximately 80%. Use of these drugs at doses that do not produce this level of receptor blockade enables them to be used therapeutically without producing these side effects. The antipsychotic drugs have been shown to act as inverse agonists at D2 and D3 dopamine receptors, and this property may be important for the antipsychotic effects of the drugs. It is suggested that the property of inverse agonism leads to a receptor up-regulation upon prolonged treatment, and this alters the properties of dopamine synapses. Several variants of the dopamine receptors exist with different DNA sequences and in some cases different amino acid sequences. These variants may have different properties that alter the effects of dopamine and the antipsychotic drugs. The determination of such variants in patients may help in the prediction of drug responsiveness.     

Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study

RATIONALE: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. OBJECTIVES: To test the hypothesis that olanzapine, a novel atypical antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. METHODS: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenz amide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving typical antipsychotic drugs (n=12) and clozapine (n=10). RESULTS: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with typical antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all antipsychotic drugs studied. CONCLUSIONS: The atypical antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their atypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of atypical antipsychotic drugs.