精神分裂症患者氯氮平维持治疗的治疗依从性、剂量及浓度研究

目的 探讨精神分裂症患者氯氮平维持治疗的治疗依从性、剂量及浓度与预防复发／恶化的关系。方法 对经氯氮平治疗后疗效达到明显好转而出院的102例精神分裂症患者随访1年。每月评定简明精神病评定量表（BPRS）,采用BPRS的核心条目（4、7、11、12和15）判定是否复发／恶化;每日评定服药依从性;每2个月采集出血。结果 复发／恶化率为32．4％（33／102）。复发／恶化者的服药依从性明显低于未复发者（P＜0．001）。经运筹特性曲线分析得出,未复发者氯氮平维持治疗的最佳有效剂量为137．5mg/d（灵敏度为100．0％,特异度为93．9％）,氯氮平最低有效血清浓度为132．0μg/L（灵敏度为100．0％,特异8度为93．9％）;氯氮平＋去甲氯氮平最低血清浓度为201．0μg/L（灵敏度为98．6％,特异度为97．0％）。结论 对于经氯氮平治疗后疗效达到明显好转以上的精神分裂症患者,维持治疗时需提高服药依从性。氯氮平维持治疗的剂量应不低于137．5mg/d,氯氮平或氯氮平＋去甲氯氮平的血清浓度应分别不低于132．0μg/L和201．0μg/L.     

氯氮平的浓效关系

目的 探索氯氮平治疗4周时血药浓度与疗效的关系。方法 给39例精神分裂症病人服用氯氮平,从治疗第13天晚到第28天晚剂量固定不变。结果 4周血药浓度与4周PSNSS总分减分率无相关性(γ=0.0780,df=38,P>0.05),4周氯氮平血浓度在200～375μg/L之间的显效率(12/31)比此范围外的(0/8)显著为高(P=0.036085<0.05)。结论 4周氯氮平血浓度在200～375μg/L之间为有效浓度。     

氯丙嗪和氯氮平对血清催乳素和生长素的影响

目的：探讨精神分裂症患者用氯丙嗪和氯氮平治疗前后血清催乳素（ＰＲＬ）、生长素（ＧＨ）的变化及其与临床疗效的关系。方法：采用固定剂量的氯丙嗪和氯氮平治疗首发精神分裂症患者５６例,疗程８周;在治疗前后评定简明精神病评定量表（ＢＰＲＳ）,并用放射免疫法测定治疗前后血清中ＰＲＬ和ＧＨ浓度,以２０例健康者为对照。结果：氯丙嗪组及氯氮平组基础ＰＲＬ水平皆较正常对照组显著为高。用氯丙嗪治疗后ＰＲＬ水平显著升高,且与ＢＰＲＳ减分值显著相关;用氯氮平治疗后ＰＲＬ水平变化不明显,且与ＢＰＲＳ减分值无显著相关。两组ＧＨ基础水平相仿;治疗后两组ＧＨ水平皆显著下降,但与ＢＰＲＳ减分值无显著相关。结论：支持精神分裂症多巴胺（ＤＡ）功能亢进假说,精神分裂症患者可能有中枢５－羟色胺（５－ＨＴ）功能障碍。     

氯氮平存在治疗窗

本文用氯氮平固定剂量(300mg/日);台疗20例精神分裂症病人,结果发现第4周临床疗效与氯氮平血药浓度相关,中浓度疗效最好;血浓度增高,疗效反而下降。提示氯氯平血药浓度在0.98～1.82μmol/L为适宜血药浓度。     

精神分裂症血浆S100B蛋白测定及临床意义探讨

目的探讨精神分裂症急性期血浆S100B蛋白水平及临床意义。方法用ELISA法检测血浆S100B蛋白含量。应用阳性和阴性症状量表（PANSS）评定精神症状。结果精神分裂症60例急性期血浆S100B蛋白水平（0．063±0．054μg／1）显著高于对照组（0．019±0．009μg／1，P〈0．001）；治疗6周后血浆S100B蛋白水平（0．079±0．093μg／L）与治疗前（0．063±0．054μg／L）差异不显著（P〉0．05）；治疗后血浆S100B持续增高者PANSS阴性症状评分较高。结论S100B持续增高与精神分裂症阴性症状相关。S100B绝对浓度可作为阴性症状发生的预测因子。     

精神分裂症患者脑源性营养因子与临床特征的关系

目的：探讨精神分裂症患者脑源性营养因子（BDNF）与临床特征的相关性。方法：符合美国精神障碍诊断与统计手册第4版（DSM-IV）诊断标准的精神分裂症患者173例,并选择年龄、性别相匹配的健康居民作为对照,以阳性和阴性症状量表（PANSS）评估精神症状,用酶联免疫吸附法检测血清BDNF水平。结果：患者组血清BDNF水平（9．8±1．9）μg／L显著低于正常对照组（11．8±2．5）μg／L,（t=-7．6．v=322,P〈0．01）;女性患者血清BDNF水平（10．4±2．1）μg／L显著高于男性组（9．6±1．8）μg／L,（t=2．3,v=154,P〈0．05）;氯氮平治疗的患者BDNF（10．1±1．6）μg／L显著高于利醅酮治疗者（8．9±2．6）μg／L,（F=3．1,v=2．P〈0．05）;患者BDNF水平与年龄、总病程、PANSS量表中阴性症状分呈显著负相关（r=-0．2,-0．16,-0．14,P〈0．05）,结论：精神分裂症患者血清BDNF水平显著下降;BDNF存在着性别差异,年龄越大、病程越长、阴性症状越重BDNF越低,接受氯氮平治疗患者BDNF高于利酪酮组.     

氯氮平治疗精神分裂症临床疗效与血浓度研究

目的 探讨氯氮平治疗精神分裂症的临床效应与剂量、血药浓度、的关系。方法 用不同剂量氯氮平治疗精神分裂症64例(A组200mg／日，22例，B组400mg／日，24例；C组600mg／日，18例)，用简明精神症状评定量表(BPRS)和临床总体印象量表(CGI)及副反应量表(TESS)评定疗效及副反应，并测定治疗第2、4、8周末晨服药前的稳态血浓度，共观察8周。结果 (1)三组比较总有效率，BPRS总减分率，TESS增分值均有显差异(P＜0．05)；(2)氯氮平血浓度与剂量呈正相关；(3)血浓度与结束时BPRS评分之间呈负相关(P＜0．05)；(4)高剂量组副反应明显大于低剂量组(P＜0．05)；(5)血浓度与TESS评分之间的关系尚不能确定(P＞0．05)。结论 推荐单用氯氮平治疗精神分裂症的稳态血药浓度为400μg／L左右。     

精神分裂症帕罗西汀激发试验及其与疗效的关系

目的探讨精神分裂症中枢5-羟色胺（5－HT）、多巴胺（DA）功能,以及非典型、典型抗精神病药对它们的影响。方法采用随机、双盲法应用固定剂量利培酮6mg/d、氟哌啶醇20mg／d治疗78例精神分裂症患者,共12周。治疗前后测定皮质醇、催乳素对帕罗西汀激发试验的反应,并以18名正常人为对照组。结果治疗前患者组基础皮质醇[（106±41）μg/L]、皮质醇对帕罗西汀激发试验的反应（曲线下面积AUC为717±229）高于对照组[（73±25）μg／L及AUC585±163],而基础催乳素[（5±7）μg/L]低于对照组[（9±5）μg／L]、催乳素对帕罗西汀激发试验的应答比对照组呈降低趋势（AUC49±41对68±43,P＞0．05）。治疗后,两组患者的催乳素基础值比治疗前均增高（P均＜0.05）;两组之间帕罗西汀介导的催乳素反应差异无显著性。治疗后,两组皮质醇的基础值[（74±32）μg/L及（82±27）μg/L]均较治疗前降低,其中利培酮治疗后降低更为明显。利培酮治疗后皮质醇对帕罗西汀激发试验的反应（AUC518±213）降低,并与对照组差异无显著性,而氟哌啶醇组皮质醇反应与治疗前差异光显著性（P＞0．05）。结论精神分裂症患者治疗前可能有中枢DA功能亢进和5－HT功能增高。利培酮治疗使患者原来过高的中枢5－HT功能接近正常,而氟哌啶醇     

不同剂量氯氮平治疗精神分裂症的血药浓度与临床效应的关系

目的研究氯氮平不同剂量时稳态血药浓度与临床效应的关系。方法以氯氮平治疗１７６例精神分裂症患者，其中采用高剂量（５００ｍｇ／ｄ）治疗８２例和低剂量（２００ｍｇ／ｄ）治疗９４例。疗效和不良反应分别用简明精神病评定量表（ＢＰＲＳ）和副反应量表（ＴＥＳＳ）进行评定，并测定治疗第１，２，４，６周的稳态血药浓度。结果高、低剂量组间的ＢＰＲＳ减分率和有效率差异无显著性（Ｐ＞０．０５）。高剂量组ＴＥＳＳ增分值虽高于低剂量组，但差异无显著性。ＢＰＲＳ减分率和ＴＥＳＳ总分与血药浓度未发现显著性相关，但血浓度＞３００μｇ／Ｌ时疗效提高，＞６００μｇ／Ｌ时不良反应加重。结论提示稳态血药浓度３００μｇ／Ｌ为起效的阈浓度。氯氮平的血浓度监测对指导个体化合理用药具有临床意义。     

氯丙嗪及氯氮平对小鼠生殖细胞的诱变效应

用氯丙嗪１０ｍｇ／ｋｇ，５ｍｇ／ｋｇ，２．５ｍｇ／ｋｇ氯氮平６．６７ｍｇ／ｋｇ，３．３３ｍｇ／ｋｇ，１．６７ｍｇ／ｋｇ分别对小鼠生殖细胞进行亚急性毒性实验，结果显示，连续给药５天后第１周，两药各剂量组的精子头部畸形率均明显高于阴性对照组，且氯丙嗪的作用强于氯氮平，连续给５天后第４周，两药各剂量组的精子头部畸形率与阴性对照组无差异，表示停药４周后氯丙嗪及氯氮平时精子的致畸作用己基本消除。睾丸细胞染色     

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.     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

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.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

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.     

Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.     

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.