双相障碍患者DNA甲基化水平分析

目的 探讨双相障碍患者全血样本基因组DNA甲基化水平的改变.方法 采用Illumina公司人类450K甲基化芯片分析10例双相障碍患者和5名健康对照样本全血基因组DNA甲基化水平.采用R软件minfi包进行数据预处理,应用R软件IMA包筛选样本分组间的甲基化位点.采用GCBI在线分析软件对差异候选基因进行Gene ontology、Pathway分析.结果 双相障碍患者和对照组相比,SLC6A3、ARNTL、MAGI2、FAM111A、ZNF578、FAM196A基因甲基化率明显上调,SMPD1、ZEB2、KCNQ5、FAM41C、RGS18基因甲基化率明显下调.结论 双相障碍与DNA甲基化水平改变有关.     

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.     

Memantine: New prospective in bipolar disorder treatment

We review preclinical and clinical evidences strongly suggesting that memantine, an old drug currently approved for Alzheimer's dementia, is an effective treatment for acute mania and for the prevention of manic/hypomanic and depressive recurrences of manicdepressive illness. Lithium remains the first line for the treatment and prophylaxis of bipolar disorders, but currently available treatment alternatives for lithium resistant patients are of limited and/or questionable efficacy. Thus, research and development of more effective mood stabilizer drugs is a leading challenge for modern psychopharmacology. We have demonstrated that 21 d administration of imipramine causes a behavioural syndrome similar to a cycle of bipolar disorder, i.e., a mania followed by a depression, in rats. Indeed, such treatment causes a behavioural supersensitivity to dopamine D2 receptor agonists associated with an increase sexual activity and aggressivity(mania). The dopamine receptor sensitization is followed, after imipramine discontinuation, by an opposite phenomenon(dopamine receptor desensitization) and an increased immobility time(depression) in the forced swimming test of depression. Memantine blocks the development of the supersensitivity and the ensuing desensitization associated with the depressive like behavior. On the basis of these observations we have suggested the use of memantine in the treatment of mania and in the prophylaxis of bipolar disorders. To test this hypothesis we performed several naturalistic studies that showed an acute antimanic effect and a long-lasting and progressive mood-stabilizing action(at least 3 years), without clinically relevant side effects. To confirm the observations of our naturalistic trials we are now performing a randomized controlled clinical trial. Finally we described the studies reporting the efficacy of memantine in maniclike symptoms occurring in psychiatric disorders other than bipolar. Limitations: A randomized controlled clinical trial is needed to confirm our naturalistic observations.Conclusion: We believe that this review presents enough pharmacological and clinical information to consider the administration of memantine in the treatment of bipolar disorders that no respond to standard mood stabilizers.     

Increased neurotrophin-3 in drug-free subjects with bipolar disorder during manic and depressive episodes

Bipolar disorder (BD) has been increasingly associated with abnormalities in neuroplasticity. Previous studies demonstrated that neurotrophin-3 (NT-3) plays a role in the pathophysiology of mood disorders. The influence of medication in these studies has been considered a limitation. Thus, studies with drug-free vs. medicated patients are necessary to evaluate the role of medication in serum NT-3 levels. About 10 manic and 10 depressive drug-free, and 10 manic and 10 depressive medicated patients with BD type I were matched with 20 controls for sex and age. Patients were assessed using SCID-I, YMRS and HDRS. Serum NT-3 levels in drug-free and medicated patients is increased when compared with controls (2.51 ± 0.59, 2.56 ± 0.44 and 1.97 ± 0.33, respectively, p < 0.001 for drug-free/medicated vs. control). Serum NT-3 levels do not differ between medicated and drug-free patients. When analyzing patients according to mood states, serum NT-3 levels are increased in both manic and depressive episodes, as compared with controls (2.47 ± 0.43, 2.60 ± 0.59 and 1.97 ± 0.33, respectively, p < 0.001 for manic/depressive patients vs. controls). There is no difference in serum BDNF between manic and depressive patients. Results suggest that increased serum NT-3 levels in BD are likely to be associated with the pathophysiology of manic and depressive symptoms.     

Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients

Bipolar disorder (BD) has been associated with abnormalities in neuroplasticity and previous studies suggest an important role for BDNF in the pathophysiology of BD. The confounding effect of the use of medication in these studies has been considered a limitation. Thus, studies with both drug-free and medicated patients are necessary to assess the role of medication in serum BDNF levels. Twenty-two manic and depressed drug-free and 22 medicated BD type I patients were matched to 22 controls according to sex and age in a cross-sectional study. BDNF serum levels were assessed using sandwich-ELISA. Serum BDNF levels in drug-free (0.23 ± 0.09), and medicated (0.29 ± 0.19) BD patients were decreased when compared to controls (0.40 ± 0.12) - drug-free/medicated vs. control p < 0.001. The BDNF levels did not differ between medicated and drug-free BD patients. When analyzing patients according to mood states, serum BDNF levels were lower in BD patients during both manic (0.28 ± 0.11) and depressive episodes (0.22 ± 0.17), as compared with healthy controls (0.40 ± 0.12) - manic/depressed patients vs. controls p < 0.001. Results suggest that the association of lower serum BDNF and BD mood episodes is kept even in medicated patients, which strengthens the notion that BDNF serum levels may be considered a biomarker of mood episodes in BD.     

双相障碍不同首选用药间处方方式、不良反应、经济负担、依从性比较

目的比较首选心境稳定剂和首选抗精神病药治疗的双相障碍患者处方方式、不良反应、经济负担及药物治疗依从性等。方法对河北省11个地市39家精神卫生机构中接受心境稳定剂或抗精神病药治疗的240例双相障碍患者,采用自制调查问卷、临床总体印象病情严重程度量表(clinical global impressions scale-severity of illness,CGI-SI)、不良反应量表(treatment emergent symptom scale,TESS)、药物依从性评定量表(medication adherence rating scale,MARS)进行社会人口学、疾病临床特征、处方方式(联合用药情况)、精神类药物花费、不良反应及治疗依从性等方面的调查。结果首选抗精神病药治疗者(抗精神病药组)152例(63.3%),首选心境稳定剂治疗者(心境稳定剂组)88例(36.7%)。抗精神病药组与心境稳定剂组相比,住院患者构成比(90.1%vs.76.1%)、伴有精神病性症状患者构成比(27.0%vs.11.4%)、不良反应发生率(46.1%vs.31.8%)、精神类药物日花费(中位数12.00元vs.8.37元)和总花费(中位数344.61元vs.144.64元)均较高(P0.05)。但两组间药物处方方式、不良反应严重程度、MARS总分无统计学差异(P0.05)。结论河北省双相障碍患者以首选抗精神病药治疗为主,但首选抗精神病药并未减少之后的联合用药,且不良反应发生率及药物经济负担均明显高于首选心境稳定剂治疗者,所以心境稳定剂仍应作为双相障碍主要首选用药。     

Refractoriness in bipolar disorder: definitions and evidence-based treatment

Defining refractoriness in bipolar disorder is complex and should concern and include either every phase and pole or the disorder as a whole. The data on the treatment of refractory bipolar patients are sparse. Combination and add-on studies suggest that in acutely manic patients partial responders to lithium, valproate, or carbamazepine, a good strategy would be to add haloperidol, risperidone, olanzapine, quetiapine, or aripiprazole. Adding oxcarbazepine to lithium is also a choice. There are no reliable data concerning the treatment of refractory bipolar depressives and also there is no compelling data for the maintenance treatment of refractory patients. It seems that patients stabilized on combination treatment might do worse if shifted from combination. Conclusively there are only limited and sometimes confusing data on the treatment of refractory bipolar patients. Further focused research is necessary on this group of patients.     

有冲动攻击行为的双相情感障碍患者与基因甲基化的研究新进展

双相情感障碍(Bipolar Disorder,BD)是以反复发作的躁狂和抑郁为主要临床表现的一种重型精神障碍,具有高患病率,高复发率,高致残率(联合国卫生组织将其列为十大致残疾病),高死亡率(其中25%~50%的患者自杀未遂,11%~19%的患者自杀身亡)等特点.     

Metabolic syndrome in subjects with bipolar disorder and major depressive disorder in a current depressive episode: Population-based study: Metabolic syndrome in current depressive episode

ObjectiveTo assess the differences in the prevalence of the metabolic syndrome (MetS) and their components in young adults with bipolar disorder (BD) and major depressive disorder (MDD) in a current depressive episode.MethodsThis was a cross-sectional study with young adults aged 24–30 years old. Depressive episode (bipolar or unipolar) was assessed using the Mini International Neuropsychiatric Interview – Plus version (MINI Plus). The MetS was assessed using the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III).ResultsThe sample included 972 subjects with a mean age of 25.81 (±2.17) years. Both BD and MDD patients showed higher prevalence of MetS compared to the population sample (BD = 46.9%, MDD = 35.1%, population = 22.1%, p < 0.001). Higher levels of glucose, total cholesterol and LDL cholesterol, Body Mass Index, low levels of HDL cholesterol, and a higher prevalence of abdominal obesity were observed in both BD and MDD individuals with current depressive episode compared to the general population. Moreover, there was a significant difference on BMI values in the case of BD and MDD subjects (p = 0.016).ConclusionMetabolic components were significantly associated with the presence of depressive symptoms, independently of the diagnosis.     

Neurodevelopmental basis of bipolar disorder: a critical appraisal

Neurodevelopmental factors have been implicated in the pathophysiology of mental disorders. However, the evidence regarding their role in bipolar disorder is controversial. We reviewed the pertinent literature searching for evidence regarding a neurodevelopmental origin of bipolar disorder. Findings from clinical, epidemiological, neuroimaging, and post-mortem studies are discussed, as well as the implications of the available data for a better understanding of the mechanisms involved in the genesis of bipolar disorder. While some evidence exists for developmental risk factors in bipolar disorder, further research is needed to determine the precise extent of their contribution to pathogenesis. The timing and course of such developmentally mediated neurobiological alterations also need to be determined. Of particular importance for further study is the possibility that bipolar disorder may be mediated by an abnormal maturation of brain structures involved in affect regulation.     

Effects of comorbid anxiety disorders on the course of bipolar disorder-I

Abstract

Background and aims: Although comorbid anxiety disorders (AD) are quite frequent in bipolar disorders (BD), data on how this comorbidity affects BD are limited. In the present study, we aimed to investigate the frequency of comorbid AD in Turkish patients with bipolar disorder-I (BD-I) and the effects of comorbid AD on the course of BD-I. Methods: 114 patients with BD-I were included in the study. All patients were diagnosed by a psychiatrist. The patients were divided into two groups as BD-I patients with lifetime comorbid AD (BDI-CAD) or those without comorbid AD (BDI). Results: 37 (32.46%) patients had one or more comorbid lifetime AD. The numbers of admissions to the outpatient clinic within calendar year 2013 (P = 0.014), the number of lifetime mood episodes (P = 0.019) and the duration of BD (P = 0.007) were higher in the BDI-CAD group compared with the BDI group. There was a strong relationship between the duration of the disorder and the number of episodes (r = 0.583, P < 0.001). Partial correlation analyses showed that the number of admission to the outpatient clinic correlated significantly with the frequency of episodes (P = 0.007, r = 0.282). Conclusion: We found that the patients with BDI-CAD use the healthcare system more frequently than the BDI patients. This suggests that AD comorbidity may have a negative influence on the course of BD-I and it is a factor that should be considered in the clinical follow-up.     

Monotherapy treatment of bipolar disorder with levetiracetam

Bipolar patients with early-onset, comorbid substance abuse, rapid cycling, and mixed episodes are difficult to treat and frequently require rational polypharmacy. When polypharmacy is unsuccessful, the clinician must consider the off-label use of newer psychotropics. Levetiracetam is a novel anticonvulsant with antikindling, inhibitory, and neuroprotective properties that is effective in an animal model of mania. This case report describes a patient with treatment-resistant rapid cycling bipolar disorder who failed 15 psychotropics, individually or in various combinations (maximum of 6), but ultimately responded to levetiracetam monotherapy and remained without bipolar features during 1 year of maintenance treatment, excluding 1 week during which the patient was medicine noncompliant. Further, methylphenidate used to treat comorbid attention deficit disorder did not precipitate manic features. Levetiracetam should be further studied for its potential use in the treatment of bipolar disorders.     

On the prevalence of bipolar disorder in epilepsy

Although mood disorders represent a frequent psychiatric comorbidity in epilepsy, data on bipolar disorder (BD) are still limited, and the role of possible specific confounding variables (seizures and antiepileptic drug therapy) has never been considered. Data for 143 adult outpatients with epilepsy assessed with the Mini International Neuropsychiatric Interview Plus Version 5.0.0 using the Epilepsy Addendum for Psychiatric Assessment, the Mood Disorder Questionnaire, and the Interictal Dysphoric Disorder Inventory revealed that 11.8% had the Diagnostic and Statistical Manual of Mental Disorders-based diagnosis of BD, only 1.4% of whom could be considered as having “pure” BD, because in all other cases BD symptoms were related to phenotype copies of BD such as interictal dysphoric disorder of epilepsy, postictal manic or hypomanic states, and preictal dysphoria.     

DNA methylation, the early-life social environment and behavioral disorders

One of the outstanding questions in behavioral disorders is untangling the complex relationship between nurture and nature. Although epidemiological data provide evidence that there is an interaction between genetics (nature) and the social and physical environments (nurture) in a spectrum of behavioral disorders, the main open question remains the mechanism. Emerging data support the hypothesis that DNA methylation, a covalent modification of the DNA molecule that is a component of its chemical structure, serves as an interface between the dynamic environment and the fixed genome. We propose that modulation of DNA methylation in response to environmental cues early in life serves as a mechanism of life-long genome adaptation. Under certain contexts, this adaptation can turn maladaptive resulting in behavioral disorders. This hypothesis has important implications on understanding, predicting, preventing, and treating behavioral disorders including autism that will be discussed.     

State of the art: treatment of bipolar disorders

Bipolar disorders are lifelong lasting affective disorders, with an episodic course of the illness in most cases. The lifetime prevalence is around 2-5%, the illness usually appears in early adulthood and causes significant impairment in psychosocial functioning. This is a selective review focusing on recent developments and issues of interest in the psychopharmacological treatment of bipolar disorders. It is based primarily on the results of adequately powered, randomised, controlled trials (RCTs). These studies were systematically retrieved by means of a Medline search. The past 10 years have led to a broadening of the psychopharmacological treatment options for bipolar disorders. The proof of efficacy for the combination of fluoxetine/olanzapine as well as quetiapine in the acute treatment of bipolar I depression were important steps. While lithium remains the gold standard in the maintenance treatment of bipolar disorders, valproate, olanzapine, lamotrigine, aripiprazole, and quetiapine have been shown efficacious for this indication, with quetiapine possessing the broadest approval status of all drugs for the different treatment phases of this illness. Despite this progress there remains a huge demand regarding new compounds for nearly every area in the psychopharmacological treatment of bipolar disorders. In addition new methodological approaches regarding the proof of effectiveness in clinical practice are urgently needed.     

双相障碍患者代谢综合征风险研究

目的 调查双相障碍患者长期治疗中代谢综合征的风险发生率及分析可能的相关因素.方法 采用横断面研究.以单用心境稳定剂或联用抗精神病药连续6月以上的门诊双相障碍患者为调查对象.采用统一问卷及实验室检测.代谢综合征诊断标准采用2004年中华医学会糖尿病分会代谢综合征标准.结果 共入组128例,双相障碍患者中代谢综合征的发生率为36.7%(47例).药物类别及用药时间与代谢综合征的发病风险有关(回归系数B值分别为-0.614,-0.797;P值分别为0.028,0.001).结论 与普通人群相比,双相障碍患者有较高的代谢综合征发病风险.用药时间越长代谢综合征的发生风险越高.联用抗精神病药能增加代谢综合征的发生率.临床上应注意监测代谢指标及对代谢异常进行干预.     

A review of DNA methylation in depression

As one of the most common psychiatric disorders, depression has been a major public health problem. Growing evidence suggests that epigenetic modification is essential in biological processes of depression. Recently, DNA methylation has been regarded as a potential link between environment and depression. In this review, we reviewed current studies of the association between DNA methylation and depression. The association between DNA methylation of seven genes, including BDNF, SLC6A4, NR3C1, 5-HTR (1A, 2A, and 3A), FKBP5, MAO-A and OXTR, and depression were reviewed in this study. Most studies showed BDNF and NR3C1 gene methylation levels were correlated with depression while the connection of SLC6A4 and depression was conflicting. Although evidence provided insights to epigenetic processes in depression, the findings were inconsistent. Therefore, longitudinal studies in animal models and in patients with depression are needed to further investigate the diagnostic predictive value of DNA methylation reliably.