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。     

氯氮平治疗精神分裂症及血药浓度研究

目的：探讨氯氮平治疗的适宜剂量及血药浓度与临床效应的关系。方法：氯氮平治疗精神分裂症６周共６２例（１５０ｍｇ／ｄ组２１例,３００ｍｇ／ｄ组２０例,４５０ｍｇ／ｄ组２１例）。用阳性和阴性症状量表（ＰＡＮＳＳ）和副反应量表（ＴＥＳＳ）评定疗效及副反应。在治疗第２、４、６周末晨服药前测血药浓度。结果：３种剂量组间有效率、ＰＡＮＳＳ减分值、ＴＥＳＳ增分值均无显著差异（Ｐ〉０．０５）,不同时段ＰＡＮＳＳ分值改变也无明显差异,提示３组间不仅疗效相当且起效快慢也无明显差异。完成血药浓度测定者４２例,有效血浓度低于以往研究推荐的３５０～４５０μｇ／Ｌ。提示氯氮平血浓度治疗窗尚有较大探讨余地。结论：在一定范围内低剂量氯氮平能取得与高剂量同样的疗效,对临床工作中避免盲目大剂量用药有指导意义,同时也有助于人们对氯氮平血浓度治疗窗有新     

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.     

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.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Special Pharmacokinetic Considerations in Children

Summary: Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.