Long-term effectiveness of quetiapine in bipolar disorder in a clinical setting

Objective

To assess quetiapine effectiveness in bipolar disorder (BD) patients in a clinical setting.

Methods

We naturalistically administered open quetiapine to outpatients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form.

Results

96 patients (36 BD I, 50 BD II, 9 BD NOS, 1 Schizoaffective Bipolar Type, mean ± SD age 42.3 ± 13.8 years, 66.7% female) received quetiapine, combined with an average of 2.5 (in 66.7% of patients at least 2) other psychotropic medications and 0.9 non-psychotropic medications, started most often during depressive symptoms (53.1%) or euthymia (37.5%). Mean quetiapine duration and final dose were 385 days and 196 mg/day (50.0% of patients took ≤75 mg/day). Quetiapine was discontinued in 38.5% of trials, after on average 307 days, most often (in 19.8%) due to CNS adverse effects (primarily sedation). In 38.5% of trials quetiapine was continued on average 328 days with no subsequent psychotropic added. In 22.9% quetiapine was continued on average 613 days, but had subsequent psychotropic added after on average 113 days, most often for depressive symptoms. In 67 trials started at Stanford, quetiapine tended to primarily maintain euthymia and relieve depressive symptoms. In 29 trials started prior to Stanford, continuing quetiapine tended to primarily maintain euthymia and relieve mood elevation symptoms. Aside from sedation, quetiapine was generally well tolerated.

Conclusions

In bipolar disorder outpatients quetiapine had a moderate (38.5%, with 385-day mean duration) discontinuation rate, and commonly did not require subsequent additional pharmacotherapy, suggesting effectiveness in a clinical setting.     

拉莫三嗪维持治疗双相障碍躁狂发作的疗效评价

目的评价拉莫三嗪维持治疗双相障碍躁狂发作的疗效。方法将73例维持期双相障碍躁狂发作患者随机分为两组，研究组用拉莫三嗪系统治疗，对照组用碳酸锂系统治疗，共治疗12周，并在入组时和治疗后第4、12、24周末评定蹂狂量表（BRMS）和社会功能缺陷筛查量表（SDSS），分别评估躁狂症状严重程度和社会功能受损情况，副反应量表（TESS）评定不良反应。结果在治疗第4周末及第12周末，研究组BRMS和SDSS评分均较治疗前有显著性降低（P〈0.05），而对照组无显著性变化。治疗第4周末、第12周末及第24周末，研究组的BRMS和SDSS评分均显著低于对照组（P〈0.05）。结论拉莫三嗪对双相障碍躁狂发作的维持期治疗有显著疗效，且可有效改善患者的社会功能。     

Effectiveness of lamotrigine in bipolar disorder in a clinical setting

ObjectiveTo assess lamotrigine effectiveness in bipolar disorder (BD) patients in a clinical setting.MethodOpen lamotrigine was naturalistically administered to outpatients at the Stanford University BD Clinic assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form.ResultsOne hundred and ninety-seven patients (64 BD I, 110 BD II, 21 BD NOS, 2 Schizoaffective Bipolar Type, mean ± SD age 42.2 ± 14.4 years, 62% female) had 200 trials of lamotrigine. Lamotrigine was combined with a mean of 2.1 ± 1.5 other psychotropic medications, most often during euthymia or depressive symptoms. Mean lamotrigine duration was 434 ± 444 days, and mean final dose was 236 ± 132 mg/day without valproate, and 169 ± 137 mg/day with valproate. Lamotrigine was discontinued in only 26.5% of trials at 255 ± 242 days, most often due to inefficacy, and seldom due to adverse effects. In 31.5% of trials lamotrigine was continued 264 ± 375 days with no subsequent psychotropic added. In 42.0% of trials lamotrigine was continued 674 ± 479 days, but had subsequent psychotropic added at 146 ± 150 days, most often for anxiety/insomnia and depressive symptoms. In 145 trials started at Stanford, lamotrigine primarily yielded relief of depressive symptoms or maintained euthymia. In 55 trials in which lamotrigine was started prior to Stanford, lamotrigine primarily maintained euthymia. Lamotrigine was generally well tolerated, with no serious rash, and only 3.5% discontinuing due to benign rash.ConclusionIn a cohort of bipolar disorder outpatients commonly with comorbid conditions, and most often receiving complex combination therapy, lamotrigine had a low (26.5%, with an overall mean duration of treatment of 434 days) discontinuation rate, suggesting effectiveness in BD in a clinical setting.     

拉莫三嗪与丙戊酸钠治疗双相抑郁的对照研究

目的评价拉莫三嗪治疗双相障碍抑郁发作的效果和安全性。方法对107例双相障碍抑郁发作患者采用随机、平行分组、对照的方法分别以拉莫三嗪和丙戊酸钠治疗,疗程8周,以汉密尔顿抑郁量表(HAMD)、临床疗效总评量表(CGI)在治疗前和治疗后第1、2、4、6、8周末评价疗效,同时采用治疗时出现的症状量表(TESS)进行安全性评估,在第1、2、4、6、8周末及需要时用Bech-Rafaelsen躁狂量表(BRMS)评定躁狂症状。结果拉莫三嗪组和丙戊酸钠组比较,两组有效率分别为75.5%和51.9%,治疗第6周和第8周末HAMD总分和减分率差异有统计学意义。治疗组不良反应明显较对照组发生率低。结论拉莫三嗪治疗双相障碍抑郁发作疗效优于丙戊酸钠,且前者不良反应较少,安全性高。     

拉莫三嗪治疗精神分裂症和双相抑郁及重性抑郁症耐受性与敏感性的文献分析

目的 分析拉莫三嗪在精神分裂症、双相抑郁和重性抑郁症急性期治疗中耐受性与敏感性.方法 选择符合急性期、随机双盲、安慰剂对照的关于拉莫三嗪治疗急性期精神分裂症、双相抑郁和重性抑郁症的临床试验进行分析;以不良事件引起治疗终止发生率为拉莫三嗪的耐受性指标,以皮疹和头痛为敏感性指标.分别计算拉莫三嗪(200 mg/d)事件发生率相对于安慰剂事件发生率增加(ARI),以及拉莫三嗪(200 mg/d)治疗相对于安慰剂治疗所致1例不良事件发生前需要治疗的患者数(NNH);显著性检验以95%可信区间(95%CI)表示.结果 (1)难治性精神分裂症4项、双相抑郁4项、难治性双相抑郁1项和重性抑郁症3项临床试验被分析;(2)在难治性精神分裂症、双相抑郁及难治性双相抑郁、重性抑郁症的急性治疗期,与安慰剂比较,拉莫三嗪(200 mg/d)相关不良事件引起治疗终止NNH(95%CI)依次为323(-23～20)、-47(-17～60)、-34(-10～22)和-32(-14～158)例,皮疹依次为133(-51～29)、-46(-18～83)、51(-16～10)和-31(-15～1208)例,头痛依次为-26(-11～61)、-168(-16～19)、-28(-6～9)和53(-24～13)例,差异无统计学意义(95%CI包括0).结论 拉莫三嗪单药或增效治疗精神分裂症、双相抑郁和重性抑郁症具有良好的耐受性与安全性.

Abstract：

Objective To compare the tolerability and sensitivity of lamotrigine in the treatment of schizophrenia, bipolar depression and major depressive disorder (MDD). Methods Data from randomized,double-blind, placebo-controlled trials of lamotrigine adjunctive or monotherapy in the acute treatment of treatment-resistant schizophrenia, bipolar depression, and MDD were used. The discontinuation due to adverse events (DAEs) was used as an index of tolerability. The reported headache and occurrence of rash were used as indexes of sensitivity. Absolute risk increase (ARI) and number needed to harm (NNH) of lamotrigine at dose of 200 mg/d relative to placebo for DAEs, headache, and rash were estimated with 95% confidence interval (CI) to reflect the magnitude of variance. Results Four trials in treatment-resistant schizophrenia, 4 in bipolar depression, 1 in treatment-resistant bipolar depression and 3 in major depressive disorder were analyzed. In the acute treatment of treatment-resistant schizophrenia, bipolar depression or treatment-resistant bipolar depression and major depressive disorder, lamotrigine 200 mg/d did not significantly increase the risk for DAEs [NNH 95% CI respectively as 323(-23 to 20) ,-47(-17 to 60), -34(-10 to 22) and-32(-14 to 158)], rash [NNH 95% CI respectively as 133 (-51 to 29),-46(-18 to 83), 51 (-16 to 10) and -31 (-15 to 1208)] and headache [NNH 95% CI respectively as -26(-11 to 61),-168 (-16 to 19),-28 (-6 to 9) and 53 (-24 to 13)] relative to placebo. Conclusion The available data indicate patients with schizophrenia, bipolar depression and major depressive disorder tolerate lamotrigine 200 mg/d as well as placebo and have a similar sensitivity to lamotrigine as to placebo.     

碳酸锂联用拉莫三嗪对双相情感障碍快速循环型的疗效研究

目的 探讨碳酸锂联用拉莫三嗪对双相情感障碍快速循环型的疗效。方法 将40例快速循环型患者随机分为实验组和对照组,每组20例。实验组选用碳酸锂联用拉莫三嗪联合治疗,对照组单用碳酸锂治疗,分别于治疗前、治疗第2周、第4周和第6周选用大体评定量表（CGI）和简明精神病评定量表（BPRS）予以评定。结果 实验组在治疗第2周、第4周和第6周CGI评定总有效率分别为27％、48％、76％,显著高于对照组,BPRS评分显著低于对照组。结论 碳酸锂联用拉莫三嗪对双相情感障碍快速循环型具有良好的疗效。     

Jaundice and hepatic enzyme induction during lamotrigine therapy in a bipolar II patient

Lamotrigine is a novel mood stabiliser as well as an anti-epileptic drug that has already been used for the prevention of convulsions. Despite several known side effects, hepatic dysfunction related to the drug has not been widely reported. A few cases have been observed in neurological, especially paediatric patients, but not in psychiatric patients. We report a case of cholestatis which occurred 6 weeks after starting lamotrigine therapy and which resolved after discontinuation, during the acute phase of disease. To the best of our knowledge, this is the first case of lamotrigine associated with cholestasis reported in patients with bipolar disorder.     

Lithium: still a major option in the management of bipolar disorder

Still after more than 50 years, lithium is a major treatment of bipolar disorder, even though it has not been promoted by the pharmaceutical industry over the last decades. In recent years the evidence base on lithium for bipolar disorder has substantially increased due to results from a number of trials. Therefore, a review of this evidence is timely. The efficacy of lithium as an acute treatment and as a maintenance treatment of bipolar disorder was evaluated through a review of the evidence, focusing on modern, randomized, parallel-group designed trials. Additionally, the evidence was sought translated into the proper use of lithium in clinical practice. Lithium's antimanic efficacy has been convincingly demonstrated. However, as blood monitoring due to the risk of toxicity is required and due to an insufficient response in highly agitated patients, lithium monotherapy has a limited place in the acute treatment of severe manic states. For acute bipolar depression, results are conflicting. Recent maintenance trials have added substantially to the documentation of lithium's long-term stabilizing properties in bipolar disorder, and these properties have been demonstrated independently of any acute response to lithium. Finally, it is now beyond doubt that not only does lithium prevent mania, but also depression in bipolar disorder. Lithium is still to be considered a major if not the most important mood- stabilizer, at least for maintaining long-term stability in patients with bipolar disorder. The potential risks of lithium should be weighed up against its benefits and the fact that serious adverse effects are usually avoidable.     

Social anxiety disorder comorbidity in patients with bipolar disorder: a clinical replication

BACKGROUND: The authors investigated frequency, clinical correlates and onset temporal relationship of social anxiety disorder (SAD) in adult patients with a diagnosis of bipolar I disorder. METHODS: Subjects were 189 patients whose diagnoses were assessed by the Structured Clinical Interview for DSM-III-R-Patient Version. RESULTS: Twenty-four patients (12.7%) met DSM-III-R criteria for lifetime SAD; of these, 19 (10.1% of entire sample) had SAD within the last month. Significantly more bipolar patients with comorbid SAD also had substance use disorders compared to those without. On the HSCL-90, levels of interpersonal sensitivity, obsessiveness, phobic anxiety and paranoid ideation were significantly higher in bipolar patients with SAD than in those without. Bipolar patients with comorbid SAD recalled separation anxiety problems (school refusal) more frequently during childhood than those without. Lifetime SAD comorbidity was associated with an earlier age at onset of syndromal bipolar disorder. Pre-existing OCD tended to delay the onset of bipolarity. CONCLUSIONS: Social anxiety disorder comorbidity is not rare among patients with bipolar disorder and is likely to affect age of onset and phenomenology of bipolar disorder. These findings may influence treatment planning and the possibility of discovering a pathophysiological relationship between SAD and bipolarity.     

抑郁症还是双相障碍？

1 病史简介 患者,男,34岁,工人,已婚。因反复烦躁不安、情绪低落发作19年,于2011年5月26日第1次住我院。患者于1992年读初中二年级时与同学打架后,对老师的处理方式不满,渐出现不愿意读书,眠差,情绪不稳定,烦躁,之后出现情绪低落,注意力不易集中,记忆力下降,兴趣减退,自1992年起休学。     

The effect of temperament on the treatment adherence of bipolar disorder type I

Background and aims: Treatment adherence is one of the most important factors that may determine treatment response in patients with bipolar disorders (BD). Many factors have been described to be associated with treatment adherence in BD. Temperament that can influence the course of BD will have an impact on treatment adherence. The aim of this study is to investigate temperament effect on treatment adherence in euthymic patients with BD-I. Methods: Eighty patients with BD-I participated in the study. A psychiatrist used the Structured Clinical Interview for DSM-IV Axis-I Disorders to determine the diagnosis and co-morbidities. Hamilton Depression and Young Mania Rating Scale were used to detect the remission. We used the Temperament Evaluation of Memphis, Pisa, Paris, San Diego Autoquestionnaire and the 4-item Morisky Medication Adherence Scale to evaluate temperament and treatment adherence, respectively. The study group was divided into two groups as “treatment adherent” and “treatment non-adherent”. Results: The cyclothymic and anxious temperament scores of the treatment non-adherent patients with BD-I were significantly higher than those of the treatment adherent group (p < 0.001, p = 0.006, respectively). Multiple linear regression analysis determined that cyclothymic temperament predicted treatment non-adherence (p = 0.009). Conclusion: It should be kept in mind that BD-I patients with cyclothymic temperament may be treatment non-adherent and future studies should explore whether temperament characteristics deteriorate BD-I course by disrupting treatment adherence.     

Add-on memantine to valproate treatment increased HDL-C in bipolar II disorder

Memantine is a noncompetitive NMDA receptor antagonist. As an augmenting agent, it has an antidepressant-like and mood-stabilizing effect. Memantine also reduces binge eating episodes and weight. We investigated whether memantine added on to valproate (VPA) is more effective than VPA alone for treating BP-II depression and improving the patient's metabolic profile. This was a randomized, double-blind, controlled study. BP-II patients undergoing regular VPA treatments were randomly assigned to one of two groups: VPA plus either add-on [1] memantine (5 mg/day) (n = 62) or [2] placebo (n = 73) for 12 weeks. The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) were used to evaluate clinical response. Height, weight, fasting serum glucose, fasting total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides were followed regularly. Multiple linear regressions with generalized estimating equation methods were used to analyze the effects of memantine on clinical performance. There were no significant differences in pre- and post-treatment YMRS and HDRS scores between the VPA + memantine and VPA + placebo groups. Although there were no significant differences in the pre- and post-treatment values of most metabolic indices between the two groups, there was a significant increase of HDL-C (p = 0.009) in the VPA + memantine group compared with the VPA + placebo group. This increase remained significant even after controlling for body mass index (BMI) (p = 0.020). We conclude that add-on memantine plus VPA treatment of BP-II depression increases the blood level of HDL-C even in the absence of change in affective symptoms.     

双相障碍共病强迫症的研究进展

双相障碍(BD)共病强迫症(OCD)在临床中越来越常见.尽管国内外有许多关于BD共病OCD的文献报道,但是关于神经生物学和治疗方面的研究较少[1],对于临床医生来说,治疗BD共病OCD的患者是一个挑战,因为稳定情绪和抗强迫的治疗应该共同进行.然而BD共病OCD的患者对于药物治疗的反应较差,作为OCD一线治疗药物的5-羟色胺再摄取抑制剂(SSRI)在治疗中可以诱导BD中的躁狂/混合情绪状态发作,药物联合治疗和心理治疗的效果也不理想,所以在目前还没有比较理想的治疗方法 [2-3].     

Differential prevalence and demographic and clinical correlates of second-generation antipsychotic use in bipolar I versus bipolar II disorder

AimsTo assess second-generation antipsychotic (SGA) use, demographics, and clinical correlates in patients with bipolar I disorder (BDI) versus bipolar II disorder (BDII).MethodsStanford Bipolar Disorder (BD) Clinic outpatients enrolled during 2000–2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Current SGA use, demographics, and clinical correlates were assessed for BDI versus BDII.ResultsAmong 503 BD outpatients, in BDI versus BDII, SGA use was more than twice as common (44.0% versus 21.2%), and doses were approximately twice as high. BDI patients taking (N = 107) versus not taking (N = 136) SGAs less often had current full time employment and college degree; and more often had lifetime psychiatric hospitalization, current depression, and current complex pharmacotherapy, and had a higher mean current Clinical Global Impression for Bipolar Version Overall Severity score, and these persisted significantly after covarying for employment and education. Prior psychiatric hospitalization was the most robust correlate of SGA use in BDI patients. In contrast, these demographic and clinical correlates of SGA use were not statistically significant among patients with BDII, although BDII (but not BDI) patients taking (N = 55) versus not taking (N = 205) SGAs were more likely to have current mood stabilizer use (67.3% versus 51.7%).LimitationsAmerican tertiary bipolar disorder clinic referral sample, cross-sectional design.ConclusionsCurrent SGA use was robustly associated with prior psychiatric hospitalization in BDI and to a more limited extent with current mood stabilizer use in BDII. SGA use associations with other unfavorable illness characteristics in BDI were less robust.     

托吡酯联合舍曲林治疗双相抑郁急性发作的对照研究

目的 评价与拉莫三嗪联合舍曲林治疗双相抑郁急性发作相比,托吡酯联合舍曲林治疗双相抑郁的疗效及安全性.方法 将符合CCMD -3双相抑郁诊断标准的68例患者随机进入拉莫三嗪联合舍曲林组(研究组)或托吡酯联合舍曲林组(对照组)接受治疗,最终研究组有30例和对照组有34例完成治疗,分别在治疗前和1、2、4、6、8周末评定HAMD、HAMA、TESS总分.结果 两组间HAMD、HAMA评分在第4、6周末具有统计学意义(P＜0.01,P＜0.05).两组内各阶段末HAMD、HAMA评分具有统计学意义(P＜0.01),提示托吡酯联合组与拉莫三嗪联合组对双相抑郁急性发作有效.两组TESS不良反应在第2、4周末差异具有统计学意义(P＜0.01).结论 托吡酯联合舍曲林治疗双相抑郁在疗效方面,有效且起效时间快;在安全性方面,托吡酯联合舍曲林治疗双相抑郁时不良反应较早出现,但经过持续坚持观察治疗后,在不良反应方面与拉莫三嗪联合舍曲林治疗双相抑郁的不良反应相当.     

Development of a computerized assessment of clinician adherence to a treatment guideline for patients with bipolar disorder

The adoption of treatment guidelines for complex psychiatric illness is increasing. Treatment decisions in psychiatry depend on a number of variables, including severity of symptoms, past treatment history, patient preferences, medication tolerability, and clinical response. While patient outcomes may be improved by the use of treatment guidelines, there is no agreed upon standard by which to assess the degree to which clinician behavior corresponds to those recommendations. This report presents a method to assess clinician adherence to the complex multidimensional treatment guideline for bipolar disorder utilized in the Texas Medication Algorithm Project. The steps involved in the development of this system are presented, including the reliance on standardized documentation, defining core variables of interest, selecting criteria for operationalization of those variables, and computerization of the assessment of adherence. The computerized assessment represents an improvement over other assessment methods, which have relied on laborious and costly chart reviews to extract clinical information and to analyze provider behavior. However, it is limited by the specificity of decisions that guided the adherence scoring process. Preliminary findings using this system with 2035 clinical visits conducted for the bipolar disorder module of TMAP Phase 3 are presented. These data indicate that this system of guideline adherence monitoring is feasible.     

Creativity in familial bipolar disorder

Studies have demonstrated relationships between creativity and bipolar disorder (BD) in individuals, and suggested familial transmission of both creativity and BD. However, to date, there have been no studies specifically examining creativity in offspring of bipolar parents and clarifying mechanisms of intergenerational transmission of creativity. We compared creativity in bipolar parents and their offspring with BD and bipolar offspring with attention-deficit/hyperactivity disorder (ADHD) with healthy control adults and their children. 40 adults with BD, 20 bipolar offspring with BD, 20 bipolar offspring with ADHD, and 18 healthy control parents and their healthy control children completed the Barron–Welsh Art Scale (BWAS), an objective measure of creativity. Adults with BD compared to controls scored significantly (120%) higher on the BWAS Dislike subscale, and non-significantly (32%) higher on the BWAS Total scale. Mean BWAS Dislike subscale scores were also significantly higher in offspring with BD (107% higher) and offspring with ADHD (91% higher) than in healthy control children. Compared to healthy control children, offspring with BD had 67% higher and offspring with ADHD had 40% higher BWAS Total scores, but these differences failed to reach statistical significance when adjusted for age. In the bipolar offspring with BD, BWAS Total scores were negatively correlated with duration of illness. The results of this study support an association between BD and creativity and contribute to a better understanding of possible mechanisms of transmission of creativity in families with genetic susceptibility for BD. This is the first study to show that children with and at high risk for BD have higher creativity than healthy control children. The finding in children and in adults was related to an enhanced ability to experience and express dislike of simple and symmetric images. This could reflect increased access to negative affect, which could yield both benefits with respect to providing affective energy for creative achievement, but also yield liabilities with respect to quality of interpersonal relationships or susceptibility to depression.