Before the last 150 years, the use of the term mania to mean any kind of agitated state and the term childhood to include people up to their early 20s make historical identification of manic-depression in children difficult. Not long after Kraepelin's seminal work was published, similar syndromes were identified in youth, usually adolescents. Interestingly, however, the question of whether preadolescent mania should be broadly or narrowly defined–the so-called bipolar controversy–has been an issue for at least 50 years. Although the question of whether and how a disorder characterized by discrete episodes of mania and depression with periods of relative normality between episodes relates to one characterized by more fluctuating and intense mood lability/dysregulation remains unanswered, the work of researchers in the twenty-first century will be to understand not only symptoms of bipolar disorder but also how it develops and how emotion regulation relates to both the development of bipolar disorder and to other conditions that are characterized by dysregulated emotion.

OBJECTIVE: We examined the influence of age at onset of illness and the delay in time to first treatment on morbidity in adulthood. METHOD: 529 adult outpatients with a mean age of 42 years, who entered our research network from 1996 through 2001 and who were diagnosed with bipolar disorder according to DSM-IV criteria, were rated prospectively on a daily basis with the National Institute of Mental Health-Life Chart Method during naturalistic treatment for up to 4 years. RESULTS: Fifty percent of patients had illness onset in childhood (<13 years of age) or adolescence (13-18 years of age). In year 1 of follow-up, these patients, compared to those with adult onset, showed significantly (P<.05) greater severity of depression and mania, greater number of episodes, more days depressed, more days of ultradian cycling, and fewer days euthymic. After 4 years, the mean severity and duration of depression remained greater and the number of days euthymic fewer in those with childhood compared to adult onset (P<.05). The delays to first treatment correlated inversely with age at onset of illness. Independently, delay to first treatment was associated with more time depressed, greater severity of depression, greater number of episodes, more days of ultradian cycling, and fewer days euthymic (all P<.05). CONCLUSIONS: These data converge with other evidence that onset of bipolar disorder in childhood is common and often associated with extraordinarily long delays to first pharmacologic treatment. Both childhood onset and treatment delay were associated with a persistently more adverse course of illness rated prospectively in adults. These data should help foster efforts to ensure earlier and more effective treatment of bipolar illness in children and adolescents. It is hoped that appropriate early intervention would result in a more benign illness and a better prognosis in adulthood.

篇首： 儿科双相障碍的临床样本率为6%,其发作可致严重残疾、共患物质滥用和学习成绩下降[1].

Clinicians who treat children and adolescents with bipolar disorder desperately need current treatment guidelines. These guidelines were developed by expert consensus and a review of the extant literature about the diagnosis and treatment of pediatric bipolar disorders. The four sections of these guidelines include diagnosis, comorbidity, acute treatment, and maintenance treatment. These guidelines are not intended to serve as an absolute standard of medical or psychological care but rather to serve as clinically useful guidelines for evaluation and treatment that can be used in the care of children and adolescents with bipolar disorder. These guidelines are subject to change as our evidence base increases and practice patterns evolve.

[目的]观察托吡酯治疗双相障碍躁狂发作的临床疗效分析及对安全性进行评价。[方 法]2009年1月~2010年1月期间,62例双相障碍躁狂发作患者随机分为两组,观察组31例采用托吡酯和对照组31例采用碳酸锂,比较治疗前后的临 床疗效、BRMS和CGI-SI评分比较和不良反应的发生情况。[结果]观察组的总有效率为77.4%,对照组的总有效率为83.9%,两组比较差异无统 计学意义（P﹥0.05）。两组治疗后BRMS和CGI-SI评分均较治疗前明显下降,差异有统计学意义（P﹤0.05）。但两组治疗后BRMS和 CGI-SI评分比较,差异无统计学意义（P﹥0.05）。观察组不良反应发生率明显低于对照组（P﹤0.05）。[结论]托吡酯对双相障碍躁狂发作的疗 效治疗的疗效与传统药物相当,能够明显降低患者BRMS和CGI-SI评分,并且不良反应发生率低,值得在临床推广应用。

Many studies have supported the role of protein kinase C (PKC) inhibitors in the physiopathology and treatment of bipolar disorder in adults. Tamoxifen is one of the drugs with the effect of PKC inhibition. This study aimed to determine the effect of tamoxifen on the rate of improvement mania symptoms in the sample of children and adolescents with acute mania. In this randomized, placebo-controlled clinical trial study, registered in www.irct.ir with the code of IRCT201410126418N3, overall 44 patients with bipolar disorder with acute manic episode were randomly assigned into treatment and control groups. The serum levels of lithium and tamoxifen among the participants in the treatment groups were 0.8 -1.1 mg and 20-40 mg per day respectively. Serum level of lithium among participants in the control group was similar. The main comparisons were made based on the Young Mania Rating Scale (YMRS) and Children Depression Inventory (CDI) scores of the participants at baseline and at the end of each study week. The pharmacological side effects of serum level of lithium were examined weekly. Analysis of Covariance(ANCOVA) test was used for the statistical analysis. There was no difference in the baseline score of YMRS and CDI in the treatment and control groups while a statistical significant difference (P < 0.05) in these scores was found between and within the groups. The addition of tamoxifen to lithium causes a significant difference in reducing the symptoms of mania and depression in the treatment group compared to the control group.

目的： 探讨儿童情感性精神障碍首次确诊困难的原因。　方法： 对４ 例患儿的临床表现、病程特点进行综合分析。　结果： 曾诊断为其他精神疾病的患儿更正诊断为儿童情感性精神障碍。　结论： 儿童情感性精神障碍首次确诊困难的原因可能与儿童期情感特点、情感表达手段、精神病学界的成见及其本身症状多变、难以与儿童期其它精神障碍鉴别有关。

Abstract Bipolar disorder is a serious condition that adversely affects social, emotional, academic, and family functioning in children and adolescents with the disorder. Despite the severity of this illness, there is very little data to guide treatment decisions in the management of bipolar disorder in youth. The majority of information available about pharmacological treatments for bipolar disorder in children and adolescents relies upon open studies, case series, and case reports. In this article, data on medications for the treatment of bipolar disorder in children and adolescents are presented and clinical recommendations are discussed.

Bipolar disorder is a complex illness, and no single agent has been proven in randomized, placebo-controlled trials to effectively prevent and/or control all aspects of the illness-acute mania, rapid cycling, and breakthrough depression. However, for the most important issue, prophylaxis of episodes, lithium has more evidence of efficacy than any other agent. Like lithium, typical antipsychotics, carbamazepine, divalproex, and the atypical antipsychotic olanzapine are effective in the treatment of mania. Carbamazepine, divalproex, and olanzapine seem effective in preventing manic episodes but, like lithium, are less effective in preventing depression. Few trials have been conducted in the more difficult-to-treat characteristics of bipolar disorder, specifically, rapid cycling and break-through depression. For patients with rapid cycling, carbamazepine or divalproex therapy may improve symptoms, but only lamotrigine has been shown to reduce cycling, mostly in the bipolar II group, in a randomized, placebo-controlled study. For the treatment of depressive episodes, lithium and olanzapine have shown modest efficacy in controlled trials, and among the mood stabilizers, lamotrigine has the most robust effect. Because manic symptoms may respond best to one agent and depressive symptoms to another, combination therapy may be the optimal treatment for many patients with bipolar disorder. For example, lithium augmentation may improve overall response rates to treatment with carbamazepine or divalproex, and the lithium-lamotrigine combination should provide effective prevention of both mania and depression. Also, each mood stabilizer may be given at lower doses when given in combination, resulting in a reduced side effect burden and improved compliance.

This small-scale pilot study was performed to grossly document safety and any evidence of efficacy of in . Ten patients hospitalized for were given open-label monotherapy for up to 28 days. The mean Young Mania Rating Scale (YMRS) score decreased from 32 (range, 26-40) at baseline to 22 (range, 2-40) at the end of the study. Five patients exhibited evidence of moderate to marked improvement, three subjects had at least a 50% reduction in YMRS scores, and the other two patients experienced an improvement of 25% to 49% on the YMRS. The preliminary findings of this small series suggest that may be effective in . Double-blind controlled trials are now needed to further investigate the efficacy and safety of in .

Abstract BACKGROUND: A series of open studies suggests that topiramate has efficacy in bipolar disorder. To further investigate the potential value of topiramate as an antimanic agent, we conducted an open trial in 11 manic patients. METHOD: Eleven patients with bipolar I disorder with an acute manic episode (DSM-IV) were treated with a mood stabilizer and/or antipsychotics in sufficient and fixed doses. All had a Young Mania Rating Scale (YMRS) score of at least 24 (mean +/- SD = 33.5+/-8.1). Topiramate was added after stable plasma levels of concomitant mood stabilizers had been reached and was titrated within 1 week to a final dose in the range of 25 to 200 mg/day, depending on clinical efficacy and tolerability. Topiramate was discontinued after 10 days, while concomitant medication remained unchanged. After 5 days, topiramate was reintroduced at similar or increased dosages for another 7 days. Patients were assessed with the YMRS; the Clinical Global Impressions scale version for bipolar patients; and the 21-item Hamilton Rating Scale for Depression. RESULTS: Seven of the 11 patients initially showed a good antimanic response with > 50% reduction in YMRS score. One patient showed psychotic features following rapid increase in topiramate dosage and dropped out on day 10. After discontinuation of topiramate, 7 of the remaining 10 patients worsened (increase of > or = 25% in YMRS score), 2 remained stable, and 1 discontinued follow-up after good recovery. After reintroducing topiramate, all patients improved again within a week, with 8 of 9 meeting the responder criterion of > or = 50% YMRS score reduction when comparing baseline values with those of day 22. With the exception of the patient who developed psychosis, topiramate was well tolerated. Concomitant medication did not interfere with plasma levels of drug, except for carbamazepine level in 1 patient. CONCLUSION: The antimanic response among patients in this study appears reproducibly linked to the addition of topiramate.

目的了解国内儿童应用托吡酯的不良反应(ADR)发生情况及其相关因素。方法计算机检索中国知网 (CNKI)文献数据库,收集国内关于抗癫痫药物托吡酯用于儿童的临床研究文献,由2位研究者采用统一的资料提取表格,提取纳入文献中ADR病例的原患疾 病,托吡酯用药剂量,ADR 病例的性别及年龄,ADR出现时间、类型、处理及转归等资料。对儿童应用托吡酯导致的 ADR 及其相关因素采用 SPSS 16.0统计学软件进行数据分析。结果经文献检索,最终符合本研究纳入标准的关于儿童托吡酯 ADR的研究文献共计22篇,关于托吡酯疗效的研究文献共计110篇,共计纳入13011例患儿,其中2771例发生ADR,ADR发生率为21.3%。 关于托吡酯 ADR 的研究中,55.1%的 ADR 涉及神经及精神系统(泌汗障碍、影响自主神经功能等),34.5%涉及内分泌系统(影响骨代谢及生长发育等)；关于托吡酯疗效的研究文献报道的 ADR中,35.2%涉及神经及精神系统(出汗减少、记忆力下降、注意力不集中、头昏等),27.1%涉及消化系统(食欲下降、胃肠道反应 等),19.5%为全身反应(体质量下降、发热等)。99.6%的儿童应用托吡酯发生的 ADR的严重程度为Ⅲ~Ⅳ级,多数在降低托吡酯剂量或停药后症状减轻。结论本研究纳入的132篇关于儿童应用托吡酯发生 ADR的研究文献中,均未提示重大 ADR发生,但由于受到研究设计和样本量局限,同时,纳入本研究的关于 ADR的文献,均存在关键信息不完整、研究报告质量欠佳等情况,因此建议进一步对儿童应用托吡酯开展上市后循证再研究及再评价,以确保临床用药安全。儿童 应用托吡酯治疗导致的 ADR及药物安全性问题,有待以后高质量、大样本、多中心的随机对照研究进一步证实。

Summary: Purpose: This study was undertaken to evaluate the effects of topiramate (TPM) on excitatory amino acid-evoked currents. Methods: Kainate and N -methyl-D-aspartate (NMDA) were applied to cultured rat hippocampal neurons by using a concentration-clamp apparatus to selectively activate the AMPA (ot-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)/ kainate and NMDA receptor subtypes, respectively. The evoked membrane currents were recorded by using perforated-patch whole-cell voltage-clamp techniques. Results: TPM partially blocked kainate-evoked currents with an early-onset reversible phase (phase I) and a late-onset phase (phase II) that occurred after a 10- to 20-min delay and did not reverse during a 2-h washout period. Application of dibutyryl cyclic adenosine monophosphate (cAMP; 2 m M ) during washout after phase II block enhanced reversal, with the kainate current amplitude being restored by =50%. Phase II but not phase I block was prevented by prior application of okadaic acid (1 M), a broad-spectrum phosphatase inhibitor, suggesting that phase II block may be mediated through interactions with intracellular intermediaries that alter the phosphorylation state of kainate-activated channels. Topiramate at 100 M blocked kainate-evoked currents by 90% during phase II, but had no effect on NMDA-evoked currents. The median inhibitory concentration (IC 50 ) values for phase I and II block of kainate currents were 1.6 and 4.8 M, respectively, which are within the range of free serum levels of TPM in patients. Conclusions: The specific blockade of the kainate-induced excitatory conductance is consistent with the ability of TPM to reduce neuronal excitability and could contribute to the anticonvulsant efficacy of this drug.

Topiramate (TOP) is a novel drug with multiple mechanisms of action used in the treatment of . Measurements of cerebral were obtained in six controls using 1H MRS at baseline and at 3 and 6 hours following the administration of 3 mg/kg of TOP. Brain concentrations rose by 72% at 3 hours and by 64% at 6 hours compared with baseline (p < 0.004). This study demonstrates that TOP significantly increases cerebral concentrations in healthy individuals.

目的 观察癫痫患者服用托吡酯后血糖、胰岛素、胰岛素抵抗指数等变化,评估托吡酯对于抗癫痫治疗的临床意义及局限性.方法 回顾性分析2014-06-2016-05我院神经内科门诊及住院的78例癫痫患者临床资料,随机分成2组,托吡酯组40例给予托吡酯治疗,丙戊酸钠组38例给予常规的丙戊酸钠治疗,分别于治疗前和治疗后3个月、6个月检测2组糖代谢指标差异及不良反应发生情况.结果 2组治疗后体质量、胰岛素、IR、瘦素及脂联素比较差异有统计学意义(P<0.05).托吡酯不良反应发生率为12.5%,显著低于丙戊酸钠组的23.7%,差异有统计学意义(P<0.05). 结论 (1)癫痫患者葡萄糖代谢存在异常,抗癫痫药物对癫痫患者糖代谢存在影响;(2)托吡酯与丙戌酸钠均会导致癫痫患者糖代谢指标出现不同程度的下降或升高,故两种药物是否可作为理想药物尚待进一步研究,建议临床合理选用抗癫痫药物,尽可能减少药物不良反应.

目的 为探讨碳酸锂与托吡酯治疗躁狂症的疗效及安全性.方法 采用随机双盲、对照研究,对符合入组标准的96例躁狂症患者单一服用碳酸锂、托吡酯治疗.并在入组前和入组后1、2、4周进行血、尿、肝功能检查、心电 图、血压、体重的检查及BRMS、CGI、TESS量表评定,疗程最终为4周.结果 托吡酯有效率80.85%,碳酸锂有效率87.76%,二者无明显差异(P＜0.05),托吡酯组BRMS、CGI-SI评分疗后4周极显著低于治疗前 (P＜0.01),且与碳酸锂组无明显差异(P＞0.05),在第2周时BRMS评分显著低于治疗前(P＜0.05),第2周就有明显的疗效,托吡酯的平 均治疗剂量为(261.35±52.38mg);碳酸锂组在副反应方面特别是消化系统、神经系统高于托吡酯组,有显著差异(P＜0.05或 P＜0.01),而托吡酯组体重下降明显多于碳酸锂组(P＜0.01).结论 托吡酯在第2周就见效,疗效与碳酸锂相当,不良反应少,安全、有效,因有降低体重的作用,易为大多数女患者所接受.

Objective: To evaluate the efficacy and tolerability of topiramate monotherapy in adults with acute manic or mixed episodes of bipolar I disorder. Methods: In four trials, adults hospitalized with acute mania, a diagnosis of bipolar I disorder, history of 0909061 previous manic or mixed episodes, and 09090620 Young Mania Rating Scale (YMRS) score were randomized to double-blind treatment with topiramate (target doses: 200, 400, or 600 mg/day) or placebo; two trials included an active comparator (lithium, 1500 mg/day). The core study duration in all trials was 3 weeks; three trials also had 9-week double-blind extensions. The primary efficacy variable was mean change from baseline in YMRS in the core 3-week study. Results: Changes in YMRS score during 3 weeks were not significantly different for topiramate versus placebo (mean YMRS reductions, 0908085.1 to 0908088.4). Mean YMRS reductions in lithium-treated groups were significantly greater (p 0909¤ 0.001 versus placebo and topiramate). A similar pattern was observed after 12 weeks of double-blind treatment in studies with double-blind extensions. Paresthesia, appetite decrease, dry mouth, and weight loss were more frequently associated with topiramate than with placebo. Conclusions: These studies do not support the efficacy of topiramate as monotherapy in acute mania or mixed episodes in adults with bipolar I disorder. Topiramate was not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression. Lithium was confirmed as an effective therapy in this population.

Objective: Anticonvulsant agents such as carbamazepine and valproate are alternatives to lithium in treating subjects with bipolar disorder. Topiramate (Topamax03), a new antiepileptic agent, is a candidate drug for bipolar disorder. We evaluated topiramate as adjunctive treatment for bipolar patients. Methods: Eighteen patients with DSM-IV bipolar I disorder [mania (n=12), hypomania (n=1), mixed episode (n=5), and rapid cycling (n=6)], and two subjects with schizoaffective disorder61–61bipolar type, resistant to current mood-stabilizer treatment were initiated on topiramate, 25 mg/day, increasing by 25–50 mg every 3–7 days to a target dose between 100 and 300 mg/day, as other medications were held constant for 5 weeks. The Young Mania Rating Scale (Y-MRS), Hamilton Depression Rating Scale (Ham-D), and Clinical Global Impression-Bipolar Version Scale (CGI-BP) were used to rate subjects weekly. Results: By 5 weeks, 12 (60%) subjects were responders, i.e., 50% reduction in the Y-MRS scores and a CGI of ‘much’ or ‘very much improved’. Three subjects were ‘minimally improved’, four showed no change, and one was ‘minimally worse’. Six subjects had parasthesia, three experienced fatigue, and two had ‘word-finding’ difficulties; in all cases, side effects were transient. All patients lost weight with a mean of 9.4 lb in 5 weeks, and a significant reduction in body mass index (BMI) occurred too. Conclusions: Topiramate appears to have efficacy for the manic and mixed phases of bipolar illness. Other preliminary data suggest antidepressant efficacy too. Among obese bipolar subjects, the weight loss potential of topiramate may be beneficial. If controlled trials confirm these initial results, topiramate may be a significant addition to the available treatments for bipolar disorder.

目的探索精神分裂症患者服用奥氮平肥胖的治疗和预防方法。方法通过性别、年龄、生活习惯等多维度,结合相关量表综合评估奥氮平与肥胖的关系。结果研究组治疗第4、8、12周末体重、BMI、腰围、臀围变化值均明显低于对照组同期的变化,差异具有统计学意义(P0.05);治疗第12周末WHR变化值与对照组比较差异有统计学意义(P0.05)。结论托吡酯能有效地减轻奥氮平所致的体重增加,托吡酯可作为奥氮平的辅助用药,两药合用安全性及耐受性良好。

目的探讨托吡酯辅助治疗氯氮平所致糖脂代谢紊乱的疗效和安全性。方法将72例稳定服用治疗剂量或维持剂量的氯氮平患者,随机分为两组,一组合并托吡酯治疗(研究组),另一组单用氯氮平治疗(对照组)。观察治疗6个月,定期测体重、腰围、血糖、血脂、UKU不良反应量表。对研究组与对照组的临床资料进行比较。结果 6个月末两组的血糖水平有统计学意义(t=-2.54,P0.05),甘油三酯和总胆固醇两组相比有统计学差异(t=-2.15,-2.54;P0.05)。两组不良反应的比较经t检验差异无统计学意义(t=1.463,P0.05)。结论托吡酯辅助治疗氯氮平所致糖脂代谢紊乱疗效好、安全性高。