抗精神病药物所致高催乳素血症的遗传因素研究进展

高催乳素血症是抗精神病药物治疗中常见的不良反应，可引起月经紊乱、溢乳、男性乳房女性化、性功能障碍以及乳腺癌等多种临床结局，降低精神分裂症患者服药依从性和生活质量，影响预后。本文对与抗精神病药物所致催乳素升高的遗传因素的研究进展进行综述，旨在为抗精神病药物临床个体化用药和未来临床研究提供参考依据。     

综合干预对非慢性精神分裂症患者预后的影响

单一的抗精神病药物治疗可良好改善精神分裂症患者的阳性症状,但对于影响精神分裂症患者预后和结局的阴性症状和社会功能疗效并不一定理想[1].因此,近年来探索抗精神病药物治疗结合社会技能训练、职业康复等综合干预,是人们正在积极探索对精神分裂症治疗更为有效的一种方法.本研究比较了综合干预与单一抗精神病药物治疗对130例非慢性精神分裂症患者为期2年的效果.     

迟发性运动障碍脑MRI研究进展

迟发性运动障碍(Tardive Dyskinesia,TD)为长期应用抗精神病药后,出现异常不自主运动的综合征[1-2].使用典型抗精神病药治疗10年以上的病例,TD年发生率高达50％,具有明显的致残性和不可逆性[3].随着非典型抗精神病药物的应用,迟发性运动障碍的发生率和流行率似乎相对稳定[4].     

第二代抗精神病药致静坐不能的研究进展

目前第二代抗精神病药物(SGAs)广泛用于各类精神病治疗,与第一代抗精神病药物(FGAs)比较,引起锥体外系副反应(EPSEs)比较少[1],但是SGAs并不是没有EPSEs,通常认为与FGAs有关EPSEs也同样与SGAs有关联.在所有的EPSEs里,本文着重关注静坐不能,一个抗精神病药物和其他一些药物引起的最常见的、致残的药物副反应之一[2].本文对第二代抗精神病药物所致静坐不能的发生率、病理生理学、最新的治疗进展等文献作一综述,以提高对静坐不能的重视.     

精神分裂症患者用药前后甲状腺素催乳素及糖脂代谢水平观察

正精神分裂症是最严重的一种精神疾病,病因不十分明确,患者在思维、情感、行为和感知等多方面存在精神不协调或功能障碍,出现幻听、幻视、兴趣减退现象,易反复发作,加重病情恶化,降低生活质量[1-2]。非典型抗精神病药物是近年来临床上应用较多的一类治疗精神分裂症药物,疗效较好,不良反应少[3]。本文探讨精神分裂症患者应用抗精神分裂药物前后甲状腺素、催乳素及糖脂代谢水平变化,现报道如下。     

抗精神病药物引起高催乳素血症的机制

催乳素(PRL)升高是抗精神病药物常见的不良反应,可以引起性功能障碍、泌乳、月经不调、骨质疏松以及乳腺癌等多种临床结局.本文综述了精神分裂症患者的血清催乳素水平、抗精神病药物对精神分裂症患者血清催乳素水平的影响及机制的探讨,为临床科研以及临床用药提供循证医学依据.     

抗精神病药与高催乳素血症

典型抗精神病药物引起的高催乳素血症曾被认为是抗精神病治疗不可避免的副反应。但大多数非典型抗精神病药物如氯氮平、奥氮平、奎硫平等都不引起明显的催乳素升高。这可能是因为这些非典型抗精神病药物在阻断多巴胺通路中更具特异性，它们不阻断漏斗一结节多巴胺通路。利培酮在治疗中却引起明显的催乳素升高，其原因不明，有研究表明利培酮对垂体前叶的泌乳细胞有直接的作用。     

常见抗精神病药物对儿童青少年患者血清催乳素水平影响的研究进展

高催乳素血症（HPRL）是儿童青少年精神障碍患者使用抗精神病药物的常见不良反应，会影响儿童青少年的正常发育，出现骨质发育障碍、月经失调等临床表现，从而降低患者的生活质量和用药依从性，影响患者的预后，加重社会的经济负担。因此，早期识别和及时干预HPRL具有重要意义。本文对常见抗精神病药物对于儿童青少年精神障碍患者血清催乳素水平的影响、HPRL可能的作用机制和治疗方法进行综述，旨在了解儿童青少年患者催乳素波动的特点和机制，为其个体化治疗提供一定依据。     

第二代抗精神病药治疗时代的氯氮平

氯氮平一直被作为第2代抗精神病药的原型有着“神话”般的历史.Hippius[1 ]将氯氮平的发现描述为是一个“矛盾、不幸和幸运的事件( paradoxes,luck and unfortunate incidents)”.矛盾之一:氯氮平是一个非常老的药,20世纪60年代中期,奥地利和德国医生首先开始研究氯氮平,认为它是非常有潜力的抗精神病药,该药于20世纪70年代早期在很多国家上市.但氯氮平又是最新的抗精神病药之一.氯氮平第2次重新上市是由美国医生开发,而且作为第2代抗精神病药的原型,现在仍然被认为是将来治疗精神分裂症的一个先驱者[2-3].矛盾之二:一些药理学家指出,氯氮平所表现出的效果不像是抗精神病药,它的抗精神病效果不同于第1代抗精神病药,没有锥体外系不良反应(EPS)风险;也有药理学家认为,氯氮平突破了对第1代抗精神病药的药理作用假设,是新型药物的代表[4-5].矛盾之三:从立体结构看,氯氮平更像抗抑郁药,最初氯氮平也确实是作为抗抑郁药进行开发(其结构与抗抑郁药米帕明的原型相似),同期开发的7种结构类似的药物都有抗抑郁效果,只有氯氮平在实验和临床治疗中表现出抗精神病效果[1].     

抗精神病药与高催乳素血症

典型抗精神病药物引起的高催乳素血症曾被认为是抗精神病治疗不可避免的副反应。但大多数非典型抗精神病药物如氯氮平、奥氮平、奎硫平等都不引起明显的催乳素升高。这可能是因为这些非典型抗精神病药物在阻断多巴胺通路中更具特异性 ,它们不阻断漏斗—结节多巴胺通路。利培酮在治疗中却引起明显的催乳素升高 ,其原因不明 ,有研究表明利培酮对垂体前叶的泌乳细胞有直接的作用     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.     

The influence of comorbid depression on seizure severity

PURPOSE: To determine the relation between depressive symptoms and seizure severity among people with epilepsy. METHODS: A postal questionnaire was used to survey a nationwide community sample about seizures and depression. The Seizure Severity Questionnaire (SSQ) assessed the severity and bothersomeness of seizure components. The Centers for Epidemiological Studies-Depression scale categorized levels of depression. RESULTS: Respondents categorized as having current severe (SEV, n = 166), mild-moderate (MOD, n = 74), or no depression (NO, n = 443) differed significantly in SSQ scores (all p < 0.0001). People with SEV or MOD reported significantly worse problems than did those with NO depression for overall seizure recovery (mean, 5.3, 4.9, 4.5, respectively); overall severity (5.0, 4.5, 4.2); and overall seizure bother (5.3, 4.8, 4.4) (all p < 0.005). Cognitive, emotional, and physical aspects of seizure recovery also were rated worse among people with SEV than with NO depression (all p < 0.05). Symptoms of depression were significantly correlated with higher levels of all components of generalized tonic-clonic seizure severity (r = 0.33-0.48; all p < 0.0001), and partial seizures (r = 0.31-0.38; all p < 0.01). CONCLUSIONS: Clinically depressed people with epilepsy reported higher levels of perceived severity and bother from seizures, as well as greater problems with overall seizure recovery than did nondepressed people experiencing similar types of seizures. The pervasive influence of depressive symptoms on reports of seizure activity suggests that people with epilepsy should be screened for depression. These data highlight the importance of detecting and treating depression among people with epilepsy.     

Une phénoménologie de la dépendance à l'alcool. Une expérience primordiale de la « nostrité »

The phenomenological approach to alcoholism interestingly focuses on specific dynamics of interpersonal relationships displaying the founding of the Self from a primary “us” and its original basis in the human feast. Priorities for treatment intervention recommend to involve social setting and relationships of the patients, reaching their active participation to a motivational and long term group treatment, underlying the specific therapeutic effect of world exchanges. Biopsychosocial determination of alcoholism could be primarily based on components of interpersonal relationships. Regarding social background, drinking is one of the most famous supports for the achievement of the feast, a founding marker of present time. Taking an existential point of view, the feast appears as the heart of mankind because it presents a primary “us”, a plural state which indicates the beginning and founding of the Self from the others. During the feast, we regularly have to reach our Self from the “us” while avoiding two main dangers, drunkenness, an increase in the dizziness of upright verticality, and addiction, an opposite vertical surrender to alcohol and falling into in the alcoholic relapse, both situations imply a spatial domination and the disappearance of others. Treatment programs of alcohol addicts need to integrate the necessity of reaching the existential basic trust from the support of a group to the appropriation of the community which can be defined as an original “usness”.