徐汇区精神卫生中心住院患者用药现状调查分析

目的调查抗精神病药在精神分裂症患者中的使用现状,以及患者性别、年龄与药物剂量之间关系。为临床合理用药提供帮助。方法对近1年来我中心住院的342例精神分裂症,分裂样精神病患者应用抗精神病药物情况进行调查分析。结果住院患者的用药以氯氮平和氯丙嗪最为常用,分别为29.39%和27.38%。而在药物剂量方面,男性剂量高于女性剂量。男性:25岁以下有效剂量最大,而女性则是46～55岁剂量最大,55岁以上男女患者的有效剂量明显低于其他年龄段的有效剂量。结论氯氮平和氯丙嗪较为有效、安全和价廉,而新型抗精神病药物在临床替代传统药物的速度明显加快,且逐渐趋于单一用药。     

The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity

One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug-induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second-generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT_2A, 5-HT_2C and 5-HT_1A receptors and decreased affinity to D₃ receptors associated with increased prefrontal-striatal FC (p?=?0.0004, r²?=?0.46; p?=?0.004, r²?=?0.33; p?=?0.002, r²?=?0.37; p?=?0.02, r²?=?0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D₂ receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics.     

Antipsychotic drugs stimulate prolactin release

Antipsychotic drugs have been found to markedly stimulate prolactin secretion in male and female rats. The amount of prolactin released was greater in females than in males. Most non-antipsychotic phenothiazines failed to alter prolactin. These results imply that the dopamine receptor that inhibits prolactin release may be similar to the dopamine receptor involved in the action of antipsychotic drugs.     

抗精神病药物对精神分裂症患者血糖的影响

目的：探讨抗精神病药物对精神分裂症患者血糖的影响。方法选取2012年1月—2014年6月重庆市江北区精神卫生中心收治的精神分裂症患者126例,随机分为A组、B组、C组,各42例。A组患者予以氯丙嗪治疗,B组患者予以阿立哌唑治疗,C组患者予以喹硫平治疗。观察3组患者治疗前（入院时）、治疗第4周、第8周、第12周血糖水平及治疗第12周高血糖发生情况。结果治疗前、治疗第4周、第8周、第12周3组患者血糖水平比较,差异无统计学意义（ P>0.05）, A组患者治疗后第12周血糖水平高于治疗前,差异有统计学意义（ P<0.05）;治疗第12周,B、C组患者高血糖发生率低于A组,差异有统计学意义（ P<0.05）,B、C组患者高血糖发生率比较,差异无统计学意义（ P>0.05）。结论氯丙嗪对精神分裂症患者的血糖影响较大,阿立哌唑和喹硫平对精神分裂症患者血糖的影响较小。     

抗精神病药物所致体重增加与多巴胺D2受体基因多态性和治疗效应的关联分析

目的　探讨抗精神病药物 (APS)所致体重增加与多巴胺D2 受体 (DRD2 )基因TaqIA多态性和治疗效应之间有无相关。方法　采用PCR RFLP方法分析 117例首发精神分裂症患者DRD2 基因TaqIA多态性 ,APS(氯丙嗪或利培酮 )单药治疗 10周 ,测定患者治疗前后体重和体重指数 (BMI) ,用阳性和阴性症状量表 (PANSS)评定患者治疗前后精神症状 ,并分析BMI变化值与基因型和PANSS减分率的相关性。结果　治疗后患者平均体重变化 (3 15± 3 47)kg或基础体重的(5 6 9± 6 15 ) % ,体重变化的范围为 - 7kg～ 12kg或 - 7 78%～ 32 43% ;患者年龄和基础BMI明显影响BMI变化值 ,差异有显著性 (P =0 0 3)和非常显著性 (P =0 0 0 0 1) ;A1等位基因和PANSS减分率对BMI变化值的影响差异均无显著性 (P >0 0 5 )。结论　DRD2 基因TaqIA多态性不可能是APS所致精神分裂症体重增加的主要遗传因素 ;体重增加不是APS临床治疗效果的指标。     

Acute and chronic effects of NMDA receptor antagonists in rodents,relevance to negative symptoms of schizophrenia: A translational link to humans

Negative symptoms of schizophrenia remain an unmet clinical need as they are common, persistent, respond poorly to existing treatments and lead to disability. Blunted affect, alogia, asociality, anhedonia and avolition are regarded as key negative symptoms despite DSM-IV-TR specifying a more limited range. The key to development of improved therapies is improved animal models that mimic the human condition in terms of behaviour and pathology and that predict efficacy of novel treatments in patients. Accumulating evidence shows that NMDA receptor (NMDAR) antagonists mimic cognitive deficits of relevance to schizophrenia in animals, along with associated pathological changes. This review examines evidence for the ability of NMDAR antagonists to mimic anhedonia and asociality, two negative symptoms of schizophrenia, in animals. The use of various species, paradigms and treatment regimens are reviewed. We conclude that sub-chronic treatment with NMDAR antagonists, typically PCP, induces social withdrawal in animals but not anhedonia. NMDAR antagonists have further effects in paradigms such as motivational salience that may be useful for mimicking other aspects of negative symptoms but these require further development. Sub-chronic treatment regimens of NMDAR antagonists also have some neurobiological effects of relevance to negative symptoms. It is our view that a sub-chronic treatment regime with NMDAR antagonists, particularly PCP, with animals tested following a wash-out period and in a battery of tests to assess certain behaviours of relevance to negative symptoms and social withdrawal (the animal equivalent of asociality) is valuable. This will enhance our understanding of the psycho and neuropathology of specific negative symptom domains and allow early detection of novel pharmacological targets.     

SR146131, a cholecystokinin-A receptor agonist,antagonizes prepulse inhibition deficits produced by dizocilpine and DOI

Abstract Rationale. Converging evidence has demonstrated that cholecystokinin (CCK) inhibits mesolimbic brain dopamine (DA) function via activation of CCK-A (CCK-1) receptors. These effects of CCK have stimulated interest in the potential use of CCK agonists as antipsychotic drugs. Most research on the antipsychotic-like drug effects of CCK has used CCK or CCK analogues that nonselectively activate both CCK-A and CCK-B (CCK-2) receptors, which may produce opposite effects. SR146131, a CCK-A selective nonpeptide agonist, has recently been developed (Sanofi-Synthelabo). Objective. To determine whether SR146131 exhibits antipsychotic-like qualities in the prepulse inhibition (PPI) paradigm. Methods. We performed experiments to determine whether SR146131 (vehicle, 0.01, 0.1, 1.0 mg/kg) would attenuate PPI deficits induced by amphetamine (2.0 mg/kg), an indirect dopamine agonist, and dizocilpine (0.1 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Since SR146131 demonstrated significant effects on PPI disrupted by the noncompetitive NMDA antagonist, an effect associated with drugs that inhibit serotonin (5HT)2A transmission, we also tested the effects of SR146131 on PPI disruption produced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 0.5 mg/kg), a direct 5HT2A agonist. Results. SR146131 did not significantly affect startle magnitude, baseline PPI, or amphetamine-induced PPI deficits. However, it dose-dependently antagonized dizocilpine and DOI-induced PPI deficits. Conclusions. The lack of an effect of SR146131 on amphetamine-induced disruption of PPI suggests that a selective nonpeptide CCK-A agonist may not produce antipsychotic-like effects on dopamine transmission. However, the unexpected effects of SR146131 on dizocilpine and DOI-induced PPI deficits are consistent with the effects of drugs that inhibit transmission in the 5HT2A receptor system, including atypical antipsychotic drugs. Possible mechanisms underlying these findings are discussed. Electronic Publication     

Metoclopramide: Antipsychotic efficacy of a drug lacking potency in receptor models

Metoclopramide is a substituted benzamide derivative, structurally similar to procainamide and sulpiride. In behavioral, biochemical, and neuroendocrine tests it displays classic neuroleptic dopamine (DA) antagonist properties; in contrast to other DA antagonists, it lacks potency in currently used DA receptor models. In clinical studies using low doses or dubious measures, it was considered not to be efficacious as an antipsychotic. We now find that it indeed has a clinical profile similar to known neuroleptics when used in a dose range predicted from animal models. The findings raise questions regarding the validity and universality of several predictive models, as well as hypotheses purporting to explain molecular mechanisms of action of neuroleptic agents. The drug's inactivity in receptor models suggests that an as yet unidentified DA receptor subpopulation may be important as the mediator of many DA dependent neurobiologic phenomena.     

抗精神病药物对女性精神病患者血清催乳素的影响研究

目的分析抗精神病药物对女性精神病患者血清催乳素的影响。方法选取2007年11月—2012年11月治疗的女性精神类疾病患者100例,分为A组、B组、C组和D组,分别使用利培酮、舒必利、齐拉西酮和奥氮平治疗,比较4组患者用药后1、3、6个月血清催乳素的变化情况,并出现的溢乳和月经异常情况。结果治疗后1、3、6个月4组患者的血清催乳素水平均出现升高,A组和B组升高显著(P<0.05),C组和D组升高不明显(P>0.05);A组和B组出现溢乳以及月经异常现象的比率较之C组和D组相对更高(P<0.05)。结论部分抗精神病药物对女性精神病患者的血清催乳素具有较明显的影响,并直接对女性身体功能产生不良作用,临床应慎重选用合理的抗精神病药物。     

抗精神病药物对精神分裂症患者血糖、血脂影响的研究

目的探讨不同抗精神病药物对精神分裂症患者血糖、血脂的影响。方法选择首患精神分裂症患者286人,单一用不同抗精神病药物治疗。于治疗前及治疗8周后测定血糖、血脂。结果用抗精神药物患者8周后血糖值比未用抗精神药物患者血糖值增加非常显著(P<0.01);除氯氮平外其他药物治疗8周前后血脂值无显著变化(P>0.05)。结论多数抗精神病药物均有增加患者血糖的风险,氯氮平短期有增加血糖及血脂的风险,选择抗精神病药物要慎重。     

Effects of competitive and non-competitiveN-methyl-d-aspartate (NMDA) antagonists in squirrel monkeys trained to discriminated-CPPene (SDZ EAA 494) from vehicle

Drug discrimination studies have proven useful for comparing and contrasting the behavioral effects of site-selectiveN-methyl-d-aspartate (NMDA) antagonists. This study examined the effects of competitive and non-competitive NMDA antagonists in squirrel monkeys trained to discriminate 1 mg/kgd-CPPene [d-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid; SDZ EAA 494] from vehicle in a two-lever drug discrimination procedure. Results show thatd-CPPene and several other competitive NMDA antagonists (NPC 17742, CGS 19755, and CGP 37849) completely substituted ford-CPPene in a dose-dependent manner. In contrast, phencyclidine (PCP) and ketamine produced only partial substitution at doses that severely suppressed response rates. These results are consistent with results of earlier studies with rats and monkeys showing differences in the discriminative stimulus effects of competitive and PCP-like non-competitive NMDA antagonists. The data support the predictions (1) thatd-CPPene and the other competitive NMDA antagonists tested would have similar subjective effects in humans and (2) that some differences would be found in the subjective effects of competitive NMDA antagonists and PCP-like non-competitive antagonists.     

Recent advances in novel atypical antipsychotic agents: potential therapeutic agents for the treatment of schizophrenia

There are now numerous drugs in advanced stages of clinical testing as potential antipsychotics. The major focus of development of antipsychotics is serotonin (5-HT)_2A antagonism, based on the hypothesis that this property is a critical facet of the pharmacology of clozapine and risperidone. These drugs have been found to exhibit relatively potent 5-HT_2A antagonism compared to their dopamine D₂ antagonistic effects. A large number of other antipsychotics with a similar 5-HT_2A/D₂ profile have been identified. In general, these compounds have minimal cataleptic effects at doses that block dopamine receptor agonist-induced behaviour, and have highly selective effects on mesolimbic dopamine neurones. Because they differ in relative potency as antagonists of a variety of other key receptors (e.g., D₁, D₂, D₃, D₄, D₅, 5-HT_2A, 5-HT_2C, 5-HT₆, 5-HT₇, M₁ and α₁-adrenoceptors), it is likely that these compounds will have significantly different side effects and efficacy profiles (multi-acting receptor targeted agents [MARTA]). Some may be effective in treating negative symptoms and improving cognitive dysfunction. The potential usefulness of N-methyl-D-aspartate (NMDA) receptor agonists for schizophrenia is limited by possible epileptogenic or neurotoxic side effects. In this respect, ligands at strychnine-insensitive glycine binding sites of the NMDA receptor ion channel complex and metabotropic glutamate receptors (mGluR) are expected to have relatively few side effects. A novel sigma₁ receptor antagonist appears to be of particular interest based upon its ability to block the behavioural effects of phencyclidine (PCP). The close relationship between some neuropeptides, such as cholecystokinin and neurotensin, and dopaminergic systems in the brain is sufficient to sustain interest in these apart from the tantalising possibility of mediation by a neuropeptide system of some of the psychopharmacology of schizophrenia.     

Perceptions and prescribing considerations among US psychiatrists regarding drug–drug interactions associated with oral atypical antipsychotics

Abstract

Objective:

Contemporary literature has demonstrated the potential for drug–drug interactions (DDIs) with oral atypical antipsychotic (OAA) agents. However, less is known about psychiatrists’ perceptions about DDIs when prescribing OAAs. This study addresses this gap by surveying US psychiatrists about their perceptions of DDI when prescribing a new OAA.     

抗精神病药物主观耐受性障碍和服药依从性研究现状分析

近年来精神分裂症患者服用抗精神病药物引起的主观耐受性障碍与服药依从性的关系日益受到重视,本文对精神分裂症患者服用抗精神病药物主观耐受性障碍和服药依从性方面发生情况和相关研究现状进行综述,并在此基础上对未来的研究方向提出新的思考。     

抗精神病药物联合小剂量丙戊酸镁治疗精神分裂症攻击行为的临床分析

目的 研究和探讨抗精神病药物联合小剂量丙戊酸镁治疗精神分裂症患者攻击行为的临床效果和应用价值.方法 选择本院2014年11月至2015年11月收治的具有精神分裂症攻击行为的患者180例,随机分为对照组(使用抗精神药物利培酮治疗,90例)和观察组(使用利培酮联合丙戊酸镁治疗,90例),对比和分析两组临床治疗效果和应用价值.结果 治疗前,对照组阳性与阴性症状(75.6±5.6)分,外显攻击行为(7.5±0.9)分,观察组阳性与阴性症状(75.7±7.2)分,外显攻击行为(7.4±0.8)分;治疗后,对照组阳性与阴性症状(62.5±7.6)分,外显攻击行为(4.9±0.8)分,观察组阳性与阴性症状(51.2±7.9)分,外显攻击行为(2.9±1.1)分;治疗后,两组评分指标均好于治疗前,观察组评分指标明显优于对照组,差异具有统计学意义(P＜0.05).观察组不良反应发生率24.44％;对照组22.22％,差异无统计学意义(P＞0.05).结论 抗精神病药物联合小剂量丙戊酸镁药物治疗精神分裂症攻击行为临床效果佳,能够明显降低抗精神病药物带来的临床不适反应,具有推广价值.     

Dopaminergic agents including 3-PPP and its enantiomers on medial septal self-stimulation

The effects of several dopamine agonists were determined on medial septal self-stimulation in rats and compared with selected dopamine antagonists and with the psychostimulants, d-amphetamine and nomifensine. Apomorphine, 3-PPP, TL-99, N,N-dipropyl-5,6-ADTN and N,N-dipropyl-6,7-ADTN inhibited self-stimulation at dose ranges selective for the dopamine autoreceptor as indicated by biochemical studies. Haloperidol and molindone produced dose-related inhibition but sulpiride increased self-stimulation. D-amphetamine and nomifensine also increased responding. The agonist-induced inhibition differed from neuroleptic-induced inhibition of self-stimulation. Both (+) and (-) 3-PPP inhibited responding by a similar amount over the dose range 0.25-1.0 mg/kg. At higher doses, (-) 3-PPP further decreased responding whereas the effects of (+) 3-PPP plateaued at approximately 55% of controls. These studies show that dopamine agonists, like neuroleptics, inhibit medial septal self-stimulation. This effect appears to be mediated via autoreceptor activation. Differences between neuroleptic- and agonist-induced inhibition and the 3-PPP stereoisomer data accord with the hypothesis that behavioural inhibitory effects caused by autoreceptor activation are less severe than those caused by dopamine postsynaptic blockade.     

Effects of classical and novel agents in a MPTP-induced reversible model of Parkinson's disease

A modified primate model of Parkinson's disease was developed to assess the effectiveness of various agents that act via dopamine, acetylcholine, serotonin or glutamate systems. Using a MPTP dosing regimen a reversible parkinsonian-like syndrome was produced in the marmoset. An obvious advantage of such a protocol is that it allows multiple drug studies to be undertaken in animals, without the need for prolonged anti-parkinsonian therapy to maintain their health. Results show that dopamine D2 agonists (bromocriptine, quinpirole, N,N-dipropyl,A,5,6-DTN, (+)3PPP and PHNO), anti-muscarinics (atropine, scopolamine and benztropine), in addition tol-DOPA and nomifensine, all reduced the bradykinesia induced by MPTP. The D1 agonist SKF-38393 and the partial dopamine agonist (–)3PPP were both ineffective. Finally, agents with potential therapeutic use in Parkinson's disease were also tested. However, a glutamate antagonist (MK801) and three serotonin antagonists (ritanserin, ketanserin and ICI 170,809) were all unable to alter the MPTP effects, at the doses used in our study.     

Polymorphisms in dopamine receptors: what do they tell us?

Many genetic studies have focussed on dopamine receptors and their relationship to neuropsychiatric disease. Schizophrenia, bipolar disorder, and substance abuse have been the most studied, but no conclusive linkage or association has been found. The possible influence of dopamine receptor variants on drug response has not received as much attention. While there is some evidence that polymorphisms and mutations in dopamine receptors can alter functional activity and pharmacological profiles, no conclusive data link these gene variants to drug response or disease. The lack of unequivocal findings may be related, in part, to the subtle changes in receptor pharmacology that these polymorphisms and mutations mediate. These subtle effects may be obscured by the influence of genes controlling drug metabolism and kinetics. Further insight into the pharmacogenetics of dopamine receptors may require not just more studies, but novel approaches to the study of complex genetic traits and diseases.     

The "two-headed" latent inhibition model of schizophrenia: modeling positive and negative symptoms and their treatment

Rationale Latent inhibition (LI), namely, poorer performance on a learning task involving a previously pre-exposed non-reinforced stimulus, is disrupted in the rat by the dopamine (DA) releaser amphetamine which produces and exacerbates psychotic (positive) symptoms, and this is reversed by treatment with typical and atypical antipsychotic drugs (APDs) which on their own potentiate LI. These phenomena are paralleled by disrupted LI in normal amphetamine-treated humans, in high schizotypal humans, and in schizophrenia patients in the acute stages of the disorder, as well as by potentiated LI in normal humans treated with APDs. Consequently, disrupted LI is considered to provide an animal model of positive symptoms of schizophrenia with face, construct and predictive validity. Objectives To review most of the rodent data on the neural substrates of LI as well as on the effects of APDs on this phenomenon with an attempt to interpret and integrate these data within the framework of the switching model of LI; to show that there are two distinct LI models, disrupted and abnormally persistent LI; to relate these findings to the clinical condition. Results The nucleus accumbens (NAC) and its DA innervation form a crucial component of the neural circuitry of LI, and are involved at the conditioning stage. There is a clear functional differentiation between the NAC shell and core subregions whereby damage to the shell disrupts LI and damage to the core renders LI abnormally persistent under conditions that disrupt LI in normal rats. The effects of shell and core lesions parallel those produced by lesions to the major sources of input to the NAC: entorhinal cortex lesion, like shell lesion, disrupts LI, whereas hippocampal lesion, like core lesion, produces persistent LI with changes in context, and basolateral amygdala (BLA) lesion, like core lesion, produces persistent LI with extended conditioning. Systemically induced blockade of glutamatergic as well as DA transmission produce persistent LI via effects exerted at the conditioning stage, whereas enhancement of DA transmission disrupts LI via effects at the conditioning stage. Serotonergic manipulations can disrupt or potentiate LI via effects at the pre-exposure stage. Both typical and atypical APDs potentiate LI via effects at conditioning whereas atypical APDs in addition disrupt LI via effects at pre-exposure. Schizophrenia patients can exhibit disrupted or normal LI as a function of the state of the disorder (acute versus chronic), as well as persistent LI. Conclusions Different drug and lesion manipulations produce two poles of abnormality in LI, namely, disrupted LI under conditions which lead to LI in normal rats, and abnormally persistent LI under conditions which disrupt it in normal rats. Disrupted and persistent LI are differentially responsive to APDs, with the former reversed by both typical and atypical APDs and the latter selectively reversed by atypical APDs. It is suggested that this "two-headed LI model" mimics two extremes of deficient cognitive switching seen in schizophrenia, excessive and retarded switching between associations, mediated by dysfunction of different brain circuitries, and can serve to model positive symptoms of schizophrenia and typical antipsychotic action, as well as negative symptoms of schizophrenia and atypical antipsychotic action.     

Effects of AMPA receptor antagonists on dopamine-mediated behaviors in mice

 Current data indicate that dopaminergic and glutamatergic neurotransmitter systems interact. The role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor subtypes in modulating dopamine neurotransmission, however, remains unclear. The noncompetitive AMPA antagonists, GYKI 52466 (5–40 mg/kg) and LY300164 (1–6 mg/ kg), and the competitive AMPA antagonists, LY326325 (5–80 mg/kg) and NBQX (10–80 mg/kg), were compared to the dopamine antagonist, haloperidol (0.03– 1.0 mg/kg), for their ability to inhibit dopamine-mediated behaviors after IP administration in mice. The behavioral paradigms included amphetamine- or dizocilpine-induced hyperactivity, amphetamine-induced stereotyped sniffing, and apomorphine-induced climbing and stereotyped sniffing. All four AMPA antagonists and haloperidol attenuated amphetamine- and dizocilpine-induced hyperactivity and decreased spontaneous locomotion. Haloperidol and GYKI 52466 were more potent against amphetamine than against dizocilpine. In contrast, LY326325 was more potent against dizocilpine than against amphetamine. The hyperactivity decreases by LY300164 and NBQX were most likely due to non-specific effects on motor behavior. The AMPA antagonists and haloperidol also attenuated amphetamine- induced stereotypy. Unlike haloperidol, however, GYKI 52466, LY300164, and NBQX failed to attenuate apomorphine-induced climbing and stereotyped sniffing. LY326325, on the other hand, attenuated apomorphine-induced stereotypy, but not climbing. These results indicate that AMPA receptor antagonists can attenuate the behavioral effects of drugs, such as amphetamine and dizocilpine, that increase dopamine neurotransmission. However, the behavioral effects of the direct dopamine agonist apomorphine are not consistently attenuated by AMPA antagonists. The competitive AMPA receptor antagonist LY326325 appears to have a profile distinct from both haloperidol and the other AMPA antagonists tested. Received: 23 December 1996/Final version: 8 September 1997