Toll-like receptor expression and function in type I bipolar disorder

Bipolar disorder (BD) has been associated with immune imbalance and low-grade inflammation. The underlying mechanisms remain largely obscure but may involve changes in cell signaling. Toll-like receptors (TLRs) are widely expressed by immune cells. Specific binding of TLRs to pathogen- or danger-associated signals leads to inflammatory responses. Here, we analyzed the frequencies of TLR-1, TLR-2, TLR-4, TLR-5 and TLR-6 in monocytes, regulatory T cells (Tregs) and activated T cells from type I BD euthymic patients and healthy controls (HCs). Monocytes were stimulated in vitro with specific TLR agonists (flagellin, LPS, LTA, BLP and PGN) and immunophenotyped. Cytokines (IL-8, IL-1beta, IL-6, IL-10, TNF-alpha and IL-12p70) were assessed with cytometric bead arrays. At baseline, increased percentages of TLR-1+ and TLR-2+ monocytes and reduced expression of TLR-5 were observed in BD. Following stimulation, the percentage of TLR-1+, TLR-2+, and TLR-6+ monocytes was higher in BD subjects than in HCs. Increased levels of IL-8, IL-12p70 and TNF were observed following stimulation with TLR-1, TLR-2 and TLR-6 agonists, suggesting increased signaling via these receptors in BD. In contrast to HCs, BD patients exhibited no changes in TLR-5 expression following stimulation. The percentage of TLR-2+ Treg cells as well as activated T cells expressing both TLR-2 and TLR-5 increased in BD patients. Given the importance of TLRs in triggering immune responses, our data indicate a role for these receptors in the low-grade inflammatory profile documented in BD.     

High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder.

BACKGROUND: Previously, we found an increased prevalence of thyroid autoantibodies in patients with bipolar disorder. In the present study, we investigated other signs of immune activation in bipolar patients, in particular an activation of the T cell system. METHODS: Fluorescence activated cell scanning (FACS) analysis was performed on lymphocytes of 64 outpatients with DSM-IV bipolar disorder using the T cell marker CD3 in combination with the activation markers MHC-class II, CD25, CD69 or CD71. In 34 patients, these assays were repeated after an interval of 2 years. In addition, T cell activation was determined by measuring serum soluble IL-2 receptor (sIL-2R) in 172 bipolar outpatients. Outcomes were compared with a healthy control group. RESULTS: Significantly higher numbers of circulating activated T cells and raised sIL-2R levels were found in euthymic, manic, and depressed bipolar patients when compared with healthy controls. In general, these abnormalities were stable over time. Manic patients showed significantly higher levels of sIL-2R in comparison with depressed patients. CONCLUSION: The T cell system was found to be activated in both symptomatic and euthymic patients with bipolar disorder. The pathophysiological significance of these findings remains to be explored.     

甲状腺功能水平与双相情感障碍相关性的对照研究

目的 探索甲状腺功能与双相情感障碍的相关性.方法 以符合美国精神疾病分类与诊断标准第4版修订本(DSM-Ⅳ-TR)的双相情感障碍诊断标准的患者59例为研究对象,并选取41名健康人作为对照,应用酶联免疫吸附法(ELISA)分别测定所有研究对象的血清甲状腺激素水平,包括TT3、FT3、TT4、FT4及TSH.选用HAMD、HAMA及Bech-Rafaelsen躁狂量表评估患者组临床症状.结果 双相躁狂组中TT4、FT4水平明显高于对照组,FT3水平明显高于抑郁组,差异有统计学意义(P<0.01).双相抑郁组中TT3、FT3水平明显低于对照组,FT4水平则明显高于对照组,差异有统计学意义(P<0.01).按性别分层比较,女性双相躁狂组FT4水平与对照组相比明显升高,差异有统计学意义(P<0.05);女性双相抑郁组TT3明显低于对照组或双相躁狂组,FT4明显高于对照组,FT3则明显低于对照组,差异均有统计学意义(P<0.05),而男性躁狂组中仅TT4水平显著高于对照组(P<0.05).在双相抑郁患者中,HAMD总分与FT4呈负相关(r=-0.34,P=0.03).结论 双相情感障碍患者的甲状腺功能存在一定的改变,不同临床相甲状腺功能改变亦不相同,且这种变化以女性患者明显.     

Thyroglobulin antibodies and risk of readmission at one year in subjects with bipolar disorder

Thyroid autoimmunity has been proposed as an endophenotype for Bipolar Disorder (BD), although its relationship with clinical outcomes remains unclear. We aimed to determine whether thyroid autoimmune status (thyroperoxidase antibodies [TPO-Abs] and thyroglobulin antibodies [TG-Abs]) in BD is associated with a greater risk for readmission at one year. We studied 77 inpatients with BD admitted for an index manic or mixed episode. Serum thyroid antibodies (TPO-Abs and TG-Abs) were determined at admission. We compared the readmission risk at 1 year, based on patients? thyroid autoimmunity profile using survival analyses. Cox regression was used to control covariates. TG-Abs+ but not TPO-Abs+ was associated with a lower risk of relapse. The Kaplan–Meier mean estimated survival times were 341.6 days (CI95% 316.4–366.8) for the TG-Abs+ group and 261.9 days (CI95%: 221.8 to 302.0) for the TG-Abs− group. Cox proportional hazards regression indicated that subjects with TG-Abs+ were 3.7 (1/OR=1/0.27) times less likely to get admitted during the follow-up period than those with TG-Abs−. Our study suggests that an autoimmune biomarker in patients with BD (i.e., the presence of TG-Abs) is associated with a lower risk of psychiatric readmission after an index hospitalization for a manic or mixed episode.     

单双相抑郁障碍患者应对方式的比较

目的 比较双相抑郁障碍与复发性抑郁障碍患者的应对方式,并评估应对方式与两种疾病的关联.方法 采用横断面的病例对照设计,共入组双相抑郁障碍患者144例,复发性抑郁障碍患者189例,健康对照123例,应用特质应对方式问卷(TCSQ)评估被试的应对方式.结果 与对照组比较,两患者组消极应对方式得分较高,积极应对方式得分较低,差异均有统计学意义(P<0.01);与复发抑郁障碍患者相比,双相抑郁障碍组积极应对方式较高(P<0.01).同种疾病中,非缓解期的患者较缓解期患者消极应对方式得分更高,积极应对方式得分更低.Logistic回归分析结果显示,在控制了年龄和疾病状态的影响后,积极应对方式仍是患双相障碍的危险因素(OR=1.064,95%CI=1.026~1.102),该模型对双相障碍的预测准确率为64.3%.结论 与复发抑郁障碍患者相比,双相抑郁障碍患者多采用较为积极的应对方式;采用较为积极的应对方式的抑郁障碍患者,发展成双相障碍的可能性较大.     

双相障碍患者童年期行为问题的临床研究

目的探讨双相障碍(BPD)患者在儿童早期的行为特征及其与注意缺陷多动障碍(ADHD)的关系。方法使用美国精神障碍诊断与统计手册第4版中ADHD诊断标准、Achenbach儿童行为量表(CBCL)对64例BPD患者(BPD组)儿童期的行为进行诊断和评估,并与64例内科疾病患者(对照组)进行对照。结果(1)BPD组有12例(19%)童年期符合ADHD诊断标准,高于对照组(2例,3%；χ~2=8.020,P=0.005)。(2)BPD组中,有无精神病家族史的患者童年期发生ADHD者分别为4例(25%)和8例(17%),差异无统计学意义(P＞0.05)。(3)BPD组中有无ADHD者的发病年龄分别为(18±4)岁和(20±5)岁,差异无统计学意义(P＞0.05)。(4)童年期CBCL得分,BPD组的退缩、焦虑/抑郁、思维问题、违纪行为、攻击性行为、内化性问题、外化性问题、行为问题总分均高于对照组(P＜0.01)；BPD组中有ADHD病史组(12例,19%)的注意问题、攻击性行为、外化性问题、行为问题总分高于无ADHD病史组(52例,81%；P＜0.05和P＜0.01)。结论BPD患者在童年期有更高的ADHD发生率和较多的行为问题；有ADHD病史者童年期可能存在更多的注意力受损和外化性问题。     

共病边缘型人格障碍的双相情感障碍患者认知功能状况

背景 双相情感障碍与边缘型人格障碍（BPD）共病率高,共病患者认知功能受损更严重。目的 探讨是否共病BPD的双相情感障碍患者认知功能的差异,为临床诊疗提供参考。方法 采用简单随机抽样,选取2021年4月-2022年4月在河北医科大学第一医院治疗的共病BPD的双相情感障碍患者60例（共病组）,其中双相抑郁患者33例,双相躁狂患者27例。同时选取双相情感障碍患者60例（未共病组）,其中双相抑郁35例,双相躁狂25例。采用中文版神经心理状态测验（RBANS）和Stroop色词测验评估患者的认知功能。结果 共病组RBANS中的即刻记忆、视觉广度、言语功能和总评分均低于未共病组,差异均有统计学意义（t=-2.356、-2.138、-3.306、-2.729,P<0.05或0.01）,Stroop色词测验中的单字时间、单色时间、双字时间和双色时间均长于未共病组,差异均有统计学意义（t=4.808、3.341、5.249、5.167,P均<0.01）。共病BPD的双相抑郁患者RBANS中的即刻记忆、视觉广度、言语功能和总评分均低于未共病BPD的双相抑郁患者（t=-2.446、-2.407、-2.231、-2.078,P均<0.05）,Stroop色词测验中的单字时间、单色时间、双字时间和双色时间均长于未共病组（t=3.652、3.035、4.406、5.016,P均<0.01）。共病组双相躁狂患者RBANS中的言语功能和总评分均高于未共病组（t=-2.777、-2.347,P<0.05或0.01）,Stroop色词测验中的单字时间、单色时间、双字时间和双色时间均长于未共病组（t=3.600、2.658、2.943、4.337,P<0.05或0.01）。结论 相较于未共病BPD的双相情感障碍患者,共病BPD的双相情感障碍患者认知功能受损更严重。     

应用轻躁狂检测清单甄别抑郁症中可能存在的双相障碍

目的 通过轻躁狂检测清单(HCL-32)测评结果甄别抑郁症中可能存在的双相障碍.方法 对128例抑郁症患者应用软双相建议性诊断标准进行诊断,并比较软双相与非软双相抑郁症患者HCL-32的差异.结果 (1)128例抑郁症患者中,HCL-32评分0～19(5.7±4.7)分;(2)是否软双相抑郁者分别为15例和113例,HCL-32评分分别为[(9.4±6.7)分vs(5.2±4.2)分,t=3.40,P=0.001],是否宽松软双相抑郁者HCL-32评分分别为[(7.8±5.6)分vs(4.3±3.4)分,t=4.34,P=0.000],有无双相障碍家族史者HCL-32评分分别为[(9.2±6.8)分vs(5.4±4.4)分,t=2.39,P=0.018],有无躁狂转相史者HCL-32评分分别为[(8.6±7.3)分vs(5.3±4.3)分,t=2.05,P=0.043],有无环性人格或明显外向者HCL-32评分分别为[(8.4±5.7)分vs(5.3±4.4)分,t=2.58,P=0.011],有无旺盛性人格素质者HCL-32评分分别为[(9.0±6.7)分vs(5.0±3.9)分,t=3.90,P=0.000],有无边缘性人格者HCL-32评分分别为[(8.6±4.3)分vs(5.4±4.7)分,t=2.22,P=0.028],是否呈发作性病程者HCL-32评分分别为[(8.9±5.7)分vs(5.2±4.3)分,t=3.19,P=0.002];(3)男女患者HCL-32评分分别为[(4.3±3.7)分vs(6.6±5.1)分,t=2.87,P=0.005];(4)有抑郁症家族史者、有自杀家族史者、发病年龄≤25岁者、有非典型抑郁者、有精神运动抑制者、有精神病性抑郁者、有生物节律明显者HCL-32评分与对应组的差异无统计学意义;(5)HCL-32＞7分37例(28.9%),＞10分17例(13.3%),＞14分7例(5.5%),其中＞10分者所占比例与软双相所占比例接近.结论 HCL-32＞10分可能有助于在抑郁症患者中筛选诊断双相障碍.     

不同临床相双相障碍患者甲状腺功能的回顾性研究

目的探究双相障碍患者甲状腺功能的临床相和性别差异,以期为双相障碍的诊断和治疗提供参考。方法采用回顾性研究方法,收集河南省精神病医院2015年9月-2018年1月的住院患者甲状腺功能生化指标,包括促甲状腺素(TSH)、三碘甲状腺原氨酸(T_3)、甲状腺素(T_4)、游离三碘甲状腺原氨酸(FT_3)和游离甲状腺素(FT_4),筛选符合《国际疾病分类(第10版)》(ICD-10)诊断标准的双相障碍躁狂发作(双相躁狂)和双相障碍抑郁发作(双相抑郁)患者2 207例,同期选择415例体检人员作为正常对照组,比较不同临床相和不同性别的双相障碍患者甲状腺功能的差异。结果①双相躁狂患者的T_3、FT_3水平高于双相抑郁患者,TSH、T_4水平低于正常对照组;双相抑郁患者的TSH、T_3、T_4、FT_3水平均低于正常对照组(P0. 05或0. 01);②在双相躁狂患者中,男性T_3、FT_3和FT_4水平高于女性,而TSH、T_4水平低于女性,在双相抑郁患者中,男性T_3、FT_3和FT_4水平高于女性,而TSH水平低于女性(P0. 05或0. 01);③在男性患者中,双相躁狂患者的T_3和FT_3水平均高于双相抑郁患者,双相抑郁患者的T_3水平低于正常对照组(P0. 05或0. 01);在女性患者中,双相躁狂患者的T_3和FT_3水平高于双相抑郁患者,双相抑郁患者的T_3、T_4、FT_3水平均低于正常对照组(P0. 05或0. 01)。结论双相障碍患者的甲状腺功能可能存在临床相和性别的差异。     

双相情感性精神障碍患者迟发性运动障碍初探

调查３３例双相情感性精神障碍患者迟发性运动障碍（ＴＤ）有关的因素，并评估其认知功能。用迟发性运动障碍量表（Ｓｉｍｐｓｏｎ量表）、认知功能问卷调查，并收集临床资料。结果发现，有ＴＤ的比无ＴＤ的患者住院总次数多，因躁狂发作住院的次数多，抗精神病药治疗时间长，平均日剂量高，合并抗胆碱能药时间长。表明长期、高剂量抗精神病药治疗可能是双相情感性精神障碍病人ＴＤ产生的高危因素，且长期并用抗胆碱能药增加ＴＤ产生的危险。有无ＴＤ的病人认知功能并无差异。     

Association of insomnia with mania in Lebanese patients with bipolar disorder

ObjectiveTo assess: (1) the association between insomnia experienced at admission, sociodemographic and other patients’ characteristics and mania; and (2) the variation of insomnia and mania before and after treatment in bipolar patients with manic episodes (type I).MethodsSixty-two patients were interviewed shortly after their admission to the hospital (after 3 to 5 days). The current symptoms experienced by the patients were assessed upon admission and again at discharge from the hospital.ResultsA poorer quality of sleep (higher PSQI scores) (Beta = 0.590) was significantly associated with higher mania, whereas the intake of SSRIs (Beta = ?5.952) and TCAs (Beta = ?8.181) was significantly associated with lower mania. Furthermore, highly significant reductions were reported in the PSQI scores (4.96 vs. 2.75, P < 0.001), ISI scores (8.30 vs. 3.45, P < 0.001) and YMRS scores (8.60 vs. 3.06, P < 0.001) between admission to and discharge from the hospital.ConclusionInsomnia in patients with bipolar disorder type I is associated with mania, with a significant reduction of sleep problems seen during a period of approximately 20 days of hospitalization. Further longitudinal studies are needed to confirm the validity of our results and identify the causes. In the meantime, this research recommends a strategy to improve sleeplessness experienced during inter-episode phases may be helpful in preventing manic episodes in BD.     

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。     

Cortical gray matter deficit in patients with bipolar disorder

Background: cortical gray matter volume deficit and ventricular enlargement are well documented in schizophrenia, but their presence in bipolar disorder is less well established.

Methods: global cortical gray matter, white matter and sulcal CSF, as well as lateral and third ventricular volume measures, were derived from axial MRI brain images obtained on age-matched bipolar (n=9), schizophrenic (n=9), and control (n=16) subjects. All subjects were free of history of alcohol or other substance dependence.

Results: relative to controls, bipolar patients had widespread volume deficits of cortical gray matter but not of cortical white matter. Schizophrenic patients had an even more severe cortical gray matter deficit and greater sulcal and lateral ventricular enlargement than the bipolar patients.

Conclusions: this group of patients with bipolar disorder had a widespread deficit of cortical gray matter similar to, but less pronounced than, that observed in patients with schizophrenia.     

A relative resistance of T cells to dexamethasone in bipolar disorder

OBJECTIVE: A relative resistance of immune cells to steroids has been established in patients with major depression (MD). In this study, we investigated the in vitro responsiveness of T cells to dexamethasone (DEX) of patients with bipolar disorder (BD). METHODS: T cells of outpatients with DSM-IV BD (n = 54) and of healthy control subjects (HC; n = 29) were isolated, cultured and stimulated with phytohemagglutinin (PHA) for 72 h. The suppressive effect of graded concentrations of DEX (5 x 10(-9)-10(-5) M) on PHA-induced CD25 (IL-2R) expression was measured by fluorescence-activated cell sorting (FACS) analysis. Data were correlated to the T-cell activation status in the peripheral blood of the same patients and to their diagnosis, current mood state, ultradian cycling pattern and current use of medication, including lithium. RESULTS: T cells of patients with BD were less sensitive to DEX-induced suppressive effects as compared with T cells of HC. These data were particularly evident at 10(-7) M DEX (mean % suppression +/- SEM BD: 18.9% +/- 3.5 versus HC: 35.8% +/- 4.7, p = 0.001). We found no correlations of this relative in vitro DEX resistance of T cells neither with the previously mentioned clinical characteristics nor with the actual activation status of the T cells in the BD patients. CONCLUSION: A relative T-cell resistance to steroids, as has been observed in MD previously, may be a trait phenomenon of BD, independent of mood state.     

Gender-specific lipid profiles in patients with bipolar disorder

Objective

High rates of dyslipidemia and insulin resistance (IR) are reported in patients with bipolar disorder (BD). We assessed gender effects upon rates of dyslipidemia/IR in outpatients with BD.

Methods

Data from 491 outpatients (ages 18-88) seen in the Stanford Bipolar Disorders clinic between 2000 and 2007 were evaluated. Patients were followed longitudinally and received naturalistic treatment. BD patients (n = 234; 61% female; 42% Type I, 47% Type II, 11% NOS) with a mean age of 40.3 ± 14.0 years, mean BMI 26.8 ± 6.4, and 81% Caucasian, who had one of four lipid measures (total cholesterol, LDL, HDL, TG) at clinicians’ discretion, a psychiatry clinic visit within 2 months of laboratory, and were not medicated for dyslipidemia were included. IR was imputed from TG/HDL ratio.

Results

Women, compared with men, had significantly lower mean triglycerides (105.58 ± 64.12 vs. 137.99 ± 105.14, p = 0.009), higher mean HDL cholesterol (60.17 ± 17.56 vs. 46.07 ± 11.91 mg/dl, p < 0.001), lower mean LDL cholesterol (109.84 ± 33.47 vs. 123.79 ± 35.96 mg/dl, p = 0.004), and lower TG/HDL ratio (1.98 ± 1.73 vs. 3.59 ± 3.14 p < 0.001). Compared to men, women had a significantly lower prevalence of abnormal total cholesterol, LDL, TG, HDL, and TG/HDL ratio. No significant differences were found between men and women with regard to age, BMI, ethnicity, educational attainment, smoking habits, bipolar illness type, illness severity or duration, or weight-liable medication exposure.

Discussion

In outpatients with BD, women had more favorable lipid profiles than men despite similar demographic variables. This sample of primarily Caucasian and educated patients, receiving vigilant clinical monitoring, may represent a relatively healthy psychiatric population demonstrating gender differences similar to those in the general population.     

Monocyte-derived dendritic cells in bipolar disorder.

BACKGROUND: Dendritic cells (DC) are key regulators of the immune system, which is compromised in patients with bipolar disorder. We sought to study monocyte-derived DC in bipolar disorder. METHODS: Monocytes purified from blood collected from DSM-IV bipolar disorder outpatients (n = 53, 12 without lithium treatment) and healthy individuals (n = 34) were differentiated into DC via standard granulocyte-macrophpage colony-stimulating factor/interleukin-4 culture (with/without 1, 5, and 10 mmol/L lithium chloride). The DC were analyzed for DC-specific and functional markers and for T-cell stimulatory potency. RESULTS: Monocytes of bipolar patients showed a mild hampering in their differentiation into fully active DC, showing a weak residual expression of the monocyte marker CD14 and a relatively low potency to stimulate autologous T cells. Lithium treatment abolished this mild defect, and monocyte-derived DC of treated bipolar patients showed signs of activation (i.e., an up-regulated potency to stimulate autologous T cells and a higher expression of the DC-specific marker CD1a). This activated phenotype contrasted with the suppressed phenotype of monocyte-derived DC exposed to lithium in vitro (10 mmol/L) during culture. CONCLUSIONS: Dendritic cells show mild aberrancies in bipolar disorder that are fully restored to even activation after in vivo lithium treatment.     

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.     

The effects of DISC1 risk variants on brain activation in controls, patients with bipolar disorder and patients with schizophrenia

Three risk variants (rs1538979, rs821577, and rs821633) in the Disrupted-in-Schizophrenia-1 (DISC1) gene have previously been associated with both schizophrenia and bipolar disorder in a recent collaborative analysis of European cohorts. In this study we examined the effects of these risk variants on brain activation during functional magnetic resonance imaging (fMRI) of the Hayling Sentence Completion Task (HSCT) in healthy volunteers (n = 33), patients with schizophrenia (n = 20) and patients with bipolar disorder (n = 36). In the healthy controls the risk associated allele carriers of SNPs rs1538979 and rs821633 demonstrated decreased activation of the cuneus. Moreover, there was an effect of SNP rs1538979 in the pre/postcentral gyrus with decreased activation in healthy controls and increased activation in patients with schizophrenia. In the bipolar group there was decreased activation in the risk carriers of SNP rs821633 in the inferior parietal lobule and left cingulate cortex. Clusters in the precentral gyrus, left middle temporal gyrus and left cerebellum were found to be significant on examining the group × genotype interactions. These findings may provide a better understanding of the neural effects of DISC1 variants and on the pathophysiology of schizophrenia and bipolar disorder.