Differential regional N-acetylaspartate deficits in postmortem brain in schizophrenia, bipolar disorder and major depressive disorder

There is substantial evidence for the involvement of the hippocampus and subcortical regions in the neuropathology of schizophrenia. Deficits of N-acetylaspartate (NAA) have been found in schizophrenia and bipolar disorder which may reflect neuronal loss and/or dysfunction. N-acetylaspartylglutamate (NAAG) is the most abundant peptide transmitter in the mammalian nervous system. It is an agonist at presynaptic metabotropic glutamate receptors mGluR3, inhibiting glutamate release. NAA and NAAG and were measured in hippocampal, striatal, amygdala and cingulate gyrus regions of human postmortem tissue from controls and subjects with schizophrenia, bipolar disorder and major depressive disorder. There are significant deficits in hippocampal NAA concentrations in all patient groups. In the amygdala there are significant NAA deficits in schizophrenia and depression and significant deficits of NAAG in the amygdala in the depression group. The deficits in NAA reported in this study confirm the importance of hippocampal and other subcortical structures in the neuropathology of the major psychiatric disorders.     

抑郁症患者外显性与内隐性情绪处理的脑功能磁共振研究

目的以健康者为对照,利用脑功能磁共振研究抑郁症患者的外显性和内隐性情绪处理过程。方法2006年12月-2007年12月,收集临床诊断抑郁症患者14例（DSM-Ⅳ标准）。14例健康志愿者作为对照。采用传统的组块设计,采集患者在高兴与悲伤2组脸像刺激下,判断表情的外显性情绪处理和判断性别的内隐性情绪处理过程的脑功能磁共振图像,利用SPM2统计软件计算出个体及组内在不同表情刺激和不同任务操作下激活的脑功能区。结果①抑郁症患者判断表情时,悲伤脸像的主要激活区位于顶叶、海马旁回、基底节、梭状回、丘脑、岛叶、前扣带回及胼胝体下回;高兴脸像激活区仅有前扣带回;②抑郁症患者判断性别任务时,悲伤脸像激活区分布在额中回、顶下小叶、前扣带回、颞中回;高兴脸像未见明显脑功能激活区。结论①抑郁症患者外显性与内隐性情绪刺激的脑内加工过程不同,悲伤脸像脑功能区激活均强于高兴脸像;②与健康人群相比,不同情绪处理过程中,抑郁症患者的高兴脸像激活区较弱,而悲伤脸像的激活明显增强。提示抑郁症患者情绪处理的神经系统存在异常,对正性情绪的神经反应减弱,而对负性情绪的神经反应增强。     

Low glial numbers in the amygdala in major depressive disorder.

BACKGROUND: Functional imaging studies implicate the prefrontal cortex and amygdala in major depressive disorder and bipolar disorder, and glial decreases have been reported in the prefrontal cortex. Here, glia and neurons were counted in the amygdala and entorhinal cortex in major depressive disorder, bipolar disorder, and control cases. METHODS: Tissue blocks from major depressive disorder (7), bipolar disorder (10), and control (12) cases, equally divided between right and left, were cut into 50 microm sections and stained with the Nissl method. One major depressive disorder and all but two bipolar disorder cases had been treated with lithium or valproate. Neurons and glia were counted using stereological methods. RESULTS: Glial density and the glia/neuron ratio were substantially reduced in the amygdala in major depressive disorder cases. The reduction was mainly accounted for by counts in the left hemisphere. No change was found in neurons. Average glia measures were not reduced in bipolar disorder cases; however, bipolar disorder cases not treated with lithium or valproate had significant glial reduction. Similar but smaller changes were found in the entorhinal cortex. CONCLUSIONS: Glia are reduced in the amygdala in major depressive disorder, especially on the left side. The results suggest that lithium and valproate may moderate the glial reduction.     

部分多模态MRI在重度抑郁症中的研究进展

重度抑郁症是最常见的高致残性的精神疾病之一,其发病机制尚不清楚。MRI技术作为非侵入性的神经影像技术,可揭示重度抑郁症患者大脑功能状态。与健康对照者相比,重度抑郁症患者额叶、颞叶、海马、扣带回、基底节、小脑等脑区功能改变,可能提示重度抑郁症的病理生理异常。现就多模态MRI,包括弥散张量成像(DTI)、弥散峰度成像(DKI)、磁共振波谱成像(MRS)、功能MRI(fMRI)、神经突方向分散度和密度成像(NODDI)在重度抑郁症中的最新研究成果进行综述,以期对其神经生物学机制有更充分的理解。     

CTLA-4 confers a risk of recurrent schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population

Previous studies have reported that the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, which is related to immunological function such as T-cell regulation, is associated with psychiatric disorders. In this study, we studied the relationship between CTLA-4 and three major psychiatric disorders, schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population. We recruited 1140 schizophrenia patients, 1140 major depressive disorder patients, 1140 bipolar disorder patients, and 1140 normal controls to examine the risk conferred by 6 tag SNPs (rs231777, rs231775, rs231779, rs3087243, rs5742909, rs16840252) in the CTLA-4 gene. We found that rs231779 conferred a risk for schizophrenia (P_allele = 0.0003, P_genotype = 0.0016), major depressive disorder (P_allele = 0.0006, P_genotype = 0.0026) and bipolar disorder (P_allele = 0.0004, P_genotype = 0.0018). In addition, rs231777 and rs16840252 had a significant association with schizophrenia (rs231777: P_allele = 0.0201, rs16840252: P_allele = 0.0081, P_genotype = 0.0117), and rs231777 had significant association with bipolar disorder (rs231777: P_allele = 0.0199). However, after 10,000 permutations, only rs231779 remained significant (schizophrenia: P_allele = 0.0010, P_genotype = 0.0145, major depressive disorder: P_allele = 0.0010, P_genotype = 0.0201, bipolar disorder: P_allele = 0.0008, P_genotype = 0.0125). Our results suggest that shared common risk factors for schizophrenia, major depressive disorder and bipolar disorder exist in the CTLA-4 gene in the Chinese Han population.     

Cortisol levels are positively correlated with hippocampal N-acetylaspartate.

BACKGROUND: This study examined the relationship of hypothalamic-pituitary-adrenal measures and hippocampal N-acetylaspartate (NAA) in posttraumatic stress disorder (PTSD) patients and control subjects. METHODS: Eleven patients with combat-related PTSD and 11 control subjects were evaluated with magnetic resonance spectroscopy as well as by morning salivary cortisol samples before and after administration of low-dose dexamethasone (.5 mg). RESULTS: Left hippocampal NAA was strongly associated with both pre-dexamethasone cortisol levels (n = 22, r =.53, p =.013) and post-dexamethasone cortisol levels (n = 22, r =.63, p =.002). After accounting for clinical symptom severity and hippocampal volume, cortisol levels accounted for 21.9% of the variance (F = 5.6, p =.004) in left hippocampal NAA and 12.6% of the variance (F = 3.2, p =.035) in right hippocampal NAA. CONCLUSIONS: This study shows a positive relationship between cortisol levels and hippocampal NAA in subjects without hypercortisolemia. Within the range of values seen in our subjects, cortisol may have a trophic effect on the hippocampus.     

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex is a relatively non-invasive technique with putative therapeutic effects in major depression. However, the exact neurophysiological basis of these effects needs further clarification. Therefore, we studied the impact of ten daily sessions of left, dorsolateral prefrontal rTMS on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 30 patients. As compared to the non-responders, responders (33%) showed changes in parameters pointing towards a reduced cortical excitability. These results suggest that repetitive transcranial magnetic stimulation of the dorsolateral, prefrontal cortex may have inhibitory effects on motor cortical neuronal excitability in patients with major depressive disorder. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of antidepressant stimulation techniques like rTMS.     

艾司西酞普兰治疗后抑郁症患者功能磁共振影像学改变的研究进展

本文目的是探讨抑郁症患者接受艾司西酞普兰治疗前后大脑功能磁共振激活改变.功能磁共振研究显示,治疗前,抑郁症患者前额叶、扣带回和纹状体等脑区的活动存在异常,前扣带回、背外侧前额叶、丘脑异常激活可预测艾司西酞普兰的疗效.经艾司西酞普兰治疗后,患者部分脑区恢复正常,且脑区激活的改变与症状的改善具有相关性.本文对抑郁症患者治疗...     

重性抑郁障碍的临床特征及其性别差异

目的了解重性抑郁障碍的临床特征及其性别差异。方法采用多阶段分层整群抽样方法随机抽取18周岁及以上的人群10073名,以改编后的一般健康问卷12项（GHQ-12）为筛选工具,以美国精神障碍诊断与统计手册第四版（DSM-IV）轴I障碍定式临床检查患者版（SCID-I/P）为调查的诊断工具。结果重性抑郁障碍的抑郁心境、失眠、疲倦或精力缺乏、兴趣或愉快感缺乏、思考力降低、体重减轻或食欲下降、无价值感、自己死亡的想法、精神运动性激越的出现频率较高;在抑郁发作类型、季节特征、既往发作缓解程度、目前类型、症状严重程度、首次发作年龄及反复发作间歇期的性别比较均无统计学差异。结论重性抑郁障碍各种临床症状的出现频率不同,性别对重性抑郁障碍临床特征的影响有待进一步研究。     

Predictors of depressive symptoms at hospital discharge in patients with major depressive disorder

Abstract

Objective. Often patients with major depressive disorder (MDD) leave the hospital with continued significant symptomatology. This study sought to evaluate demographic, clinical, and psychosocial predictors of the presence of clinically significant depressive symptoms, defined as a Modified Hamilton Rating Scale for Depression score of ≥ 14, immediately following hospitalization for MDD. Methods. The study enrolled 135 patients with MDD as part of a larger clinical trial investigating the efficacy of post-hospitalization pharmacologic and psychosocial treatments for depressed inpatients. Structured clinical interview and self-report data were available from 126 patients at hospital admission and discharge. Results. Despite the significant decreases in depressive symptoms over the course of hospitalization, 91 (72%) displayed clinically significant depressive symptoms at discharge. Multivariate logistic regression analysis revealed that female sex, earlier age of onset, and poorer social adjustment were unique predictors of symptom outcome. Conclusions. Results suggest that a large proportion of patients leave the hospital with continued significant symptomatology, and the presence of such symptoms following hospitalization for MDD is likely to be explained by a combination of factors.     

Longitudinal MRI study of cortical thickness, perfusion, and metabolite levels in major depressive disorder

Järnum H, Eskildsen SF, Steffensen EG, Lundbye‐Christensen S, Simonsen CW, Thomsen IS, Fründ E‐T, Théberge J, Larsson E‐M. Longitudinal MRI study of cortical thickness, perfusion, and metabolite levels in major depressive disorder. Objective: To determine whether patients with major depressive disorder (MDD) display morphologic, functional, and metabolic brain abnormalities in limbic‐cortical regions at a baseline magnetic resonance (MR) scan and whether these changes are normalized in MDD patients in remission at a follow‐up scan. Method: A longitudinal 3.0‐Tesla (T) magnetic resonance imaging (MRI) study was carried out with cortical thickness measurements with a surface‐based approach, perfusion measurements with three‐dimensional (3D) pseudo‐continuous arterial spin labeling (pCASL), and spectroscopy (1H‐MRS) measurements in the anterior cingulate cortex (ACC) with water as an internal reference adjusted for cerebrospinal fluid content. We examined 23 MDD patients and 26 healthy controls. MDD patients underwent a baseline MRI at inclusion and were invited to a follow‐up scan when they were in remission or after a 6‐month follow‐up period. Results: Major findings were a significantly thinner posterior cingulate cortex in non‐remitters than in remitters, a significant decrease in perfusion in the frontal lobes and the ACC in non‐remitters compared with healthy controls at baseline and significantly reduced N‐acetylaspartate, myo‐inositol, and glutamate levels in MDD patients compared with healthy controls at baseline. Conclusion: Using novel MRI techniques, we have found abnormalities in cerebral regions related to cortical‐limbic pathways in MDD patients.     

Evidence for GABAergic inhibitory deficits in major depressive disorder

Converging evidence suggests that deficits in gamma-aminobutyric acid (GABA) functioning are implicated in the pathophysiology of major depressive disorder (MDD). This is highlighted by research investigating cortical inhibition (CI), a process whereby GABAergic interneurons selectively attenuate pyramidal neurons. Transcranial magnetic stimulation (TMS) paradigms evaluate this marker of neuronal inhibitory activity in the cortex. This review will examine the neuroanatomic and neurophysiological evidence from neuroimaging, molecular, treatment, and TMS studies linking dysfunctional GABAergic neurotransmission to MDD.     

Circadian genes in major depressive disorder

Abstract

Background: Sleep disturbances are a common symptom of major depressive disorder (MDD). Sleep is highly regulated by circadian rhythms, controlled by circadian genes, that act through a series of feedback loops to regulate the sleep-wake cycle.

Objectives: To the best of our knowledge, a systematic review regarding the core circadian genes and their role in MDD has not been published recently. Also, a review of these genes and their role in sleep disturbances in depressed individuals appears to have never been done. We decided to integrate both concepts into one comprehensive review.

Method: The review was done using the appropriate search terms in the following search engines: OVID Medline, Embase, PsycINFO and Pubmed.

Results: Based on the data reviewed, none of the circadian genes appear to be associated with MDD, but some are more promising than others. These genes are: CRY1, CRY2, PER2 and NPAS2. When investigating the role of circadian genes in sleep disturbances among individuals with MDD, the most promising candidate gene is TIMELESS. Although the results in this area are limited.

Conclusion: Given the promising leads from this review, future studies should investigate circadian genes in sleep disturbances among the depressed population.     

抑郁症对海马及背外侧前额叶皮质神经元变与1HMRS表现及明尼苏达多项个性测量的相关性

Background and Purpose The present study was undertaken to elucidate neuro-structural and neuro-chemical characteristics of hippocampi and dorsolateral prefrontal cortex in patients with depressive disorder by using 1H-MRS and to study the association between 1H-MRS and Minnesota Mutiphasic Personality Inventory-2 in relation to the severity of the depression.. Methods Magnetic resonance imaging and 1H-MRS were performed on 33 patients with depressive disorder and age-18 and gender-matched healthy controls. Minnesota Mutiphasic Personality Inventory-2 test was performed on all depressive subjects and control subjects. Results Magnetic resonance imaging and 1H-MRS examinations showed widened sulcus and cisterns as well as the absence of abnormal signal in depressive patients. In addition, the N-acetyl aspartate/total creatine ratios in the bilateral hippocampi and dorsolateral prefrontal cortex were significantly lower in depressive patients than in the control subjects (P<0.01). In contrast, the choline-containing compounds/total creatine ratios in dorsolateral prefrontal cortex were remarkably higher in depressive patients than in the control subjects (Left: P<0.01, Right: P<0.01), the ratios of which were also significantly positively correlated with the depression scores of the patients assessed by Minnesota Mutiphasic Personality Inventory-2 scale (Right: r = 0.8787, Left: r = 0.9347). Conclusions 1H-MRS can be used to reveal reduced neuronal viability or function in the hippocampus and dorsolateral prefrontal cortex and altered membrane phospholipid metabolism in the dorsolateral prefrontal cortex in patients with depressive disorder. The 1H-MRS findings partially reflect the severity of the depressive disorder.     

Duloxetine-induced liver injury in patients with major depressive disorder

Duloxetine is a balanced serotonin-norepinephrine reuptake inhibitor. Duloxetine-induced liver injury in patients with preexisting liver disease or chronic alcohol use is known. However, we have found that duloxetine can also induce liver injury in cases without those risk factors. We recommend that clinicians should monitor liver function carefully following duloxetine treatment.     

Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder

Reductions in gray matter volume of the medial prefrontal cortex (mPFC), especially the rostral and subgenual anterior cingulate cortex (rACC, sgACC) are a widely reported finding in major depressive disorder (MDD). Inflammatory mediators, which are elevated in a subgroup of patients with MDD, activate the kynurenine metabolic pathway and increase production of neuroactive metabolites such as kynurenic acid (KynA), 3-hydroxykynurenine (3HK) and quinolinic acid (QA) which influence neuroplasticity. It is not known whether the alterations in brain structure and function observed in major depressive disorders are due to the direct effect of inflammatory mediators or the effects of neurotoxic kynurenine metabolites. Here, using partial posterior predictive distribution mediation analysis, we tested whether the serum concentrations of kynurenine pathway metabolites mediated reductions in cortical thickness in mPFC regions in MDD. Further, we tested whether any association between C-reactive protein (CRP) and cortical thickness would be mediated by kynurenine pathway metabolites. Seventy-three unmedicated subjects who met DSM-IV-TR criteria for MDD and 91 healthy controls (HC) completed MRI scanning using a pulse sequence optimized for tissue contrast resolution. Automated cortical parcellation was performed using the PALS-B12 Brodmann area atlas as implemented in FreeSurfer in order to compare the cortical thickness and cortical area of six PFC regions: Brodmann areas (BA) 9, 10, 11, 24, 25, and 32. Serum concentrations of kynurenine pathway metabolites were determined by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection, while high-sensitivity CRP concentration was measured immunoturbidimetrically. Compared with HCs, the MDD group showed a reduction in cortical thickness of the right BA24 (p < 0.01) and BA32 (p < 0.05) regions and MDD patients with a greater number of depressive episodes displayed thinner cortex in BA32 (p < 0.05). Consistent with our previous findings in an overlapping sample, the KynA/3HK ratio and the log KynA/QA were reduced in the MDD group relative to the HC group (p’s < 0.05) and symptoms of anhedonia were negatively correlated with log KynA/QA in the MDD group (p < 0.05). Both KynA/3HK and log KynA/QA at least partially mediated the relationship between diagnosis and cortical thickness of right BA32 (p’s < 0.05). CRP was inversely associated with BA32 thickness (p < 0.01) and KynA/3HK partially mediated the relationship between CRP and the thickness of right BA32 (p < 0.05). The results raise the possibility that the relative imbalance between KynA and neurotoxic kynurenine metabolites may partially explain the reductions in mPFC thickness observed in MDD, and further that these changes are more strongly linked to the putative effects of neuroactive kynurenine metabolites than those of inflammatory mediators.     

Pituitary volume in treatment-na?ve pediatric major depressive disorder.

BACKGROUND: Prior pilot investigation identified a larger pituitary gland volume (PGV) in pediatric patients with major depressive disorder (MDD) compared with healthy pediatric control subjects that was most prominent in boys with MDD. In this independent sample, we focus on gender differences in pituitary volume in a larger sample of pediatric patients with MDD. METHODS: Volumetric magnetic resonance imaging studies were conducted in 35 psychotropic drug-na?ve children (15 boys, 20 girls), ages 8-17 years, and 35 case-matched healthy control subjects. RESULTS: The MDD boys had larger PGV (19%) compared with male control subjects. No significant diagnostic group differences in pituitary volume were observed in girls. Healthy boys had significantly smaller PGV (27%) than healthy girls, whereas MDD boys did not differ from girls with MDD. Nonfamilial (without a family history of mood disorder) boys with MDD had significantly larger PGV (35%) than male healthy control subjects and tended to have a larger PGV (27%) than familial (at least one first-degree relative with MDD) boys with MDD. Boys with familial MDD did not differ from control subjects. CONCLUSIONS: These findings provide new evidence of increased pituitary volume in psychotropic-na?ve pediatric patients with MDD that seems to be more prominent in male patients with nonfamilial MDD.     

Adjunctive atomoxetine for residual fatigue in major depressive disorder

OBJECTIVE: To assess the effectiveness and safety of atomoxetine as an adjunctive medication for residual fatigue in a naturalistic treatment setting. METHODS: A retrospective chart review was conducted to identify major depressive disorder (MDD) patients who had experienced significant symptom improvement (either partial response or remission) following treatment with conventional antidepressants but who were continuing to complain of fatigue. Fourteen such patients (42.2+/-13.4 years of age, five women, baseline HDRS 6.2+/-2.4) with a 17-item Hamilton Depression Rating Scale (HDRS17)<11 who received adjunctive atomoxetine for fatigue were included in the report. Antidepressants augmented were the selective serotonin reuptake inhibitors (SSRIs) (n=11; 78.6%), mirtazapine (n=2, 14.3%), and amitriptyline (n=1, 7.1%). RESULTS: Twelve (85.7%) patients (nine remitters, three partial responders) received at least 4 weeks of atomoxetine treatment. The remaining two (partial responders) discontinued atomoxetine within 1-3 days due to increased anxiety. The brief fatigue inventory (BFI) and Clinical Global Impressions Scale (CGI) were administered when atomoxetine was first prescribed, and following 4-10 weeks of treatment (mean of 5.4+/-1.8 weeks). There was a significant decrease in BFI scores (41.9+/-14.9 versus 24.3+/-13.4, p=0.0015), and HDRS-17 scores (6.2+/-2.4 versus 3.5+/-2.8, p=0.0466), but not CGI-S scores (1.3+/-1.4-1.0+/-0.0, p=0.08) following treatment with atomoxetine. 5/12 (41.6%) patients had a 50% or greater decrease in BFI scores. All 12 patients were remitters at follow-up. The mean atomoxetine dose was 42.8+/-10.6 mg. Side effects included insomnia (n=6), increased anxiety (n=3), nausea (n=1) and dry mouth (n=1). CONCLUSIONS: Although preliminary, these results suggest a possible augmentation role for atomoxetine when used in conjunction with conventional antidepressants for residual fatigue in MDD. Prospective as well as controlled studies are necessary to further explore the role of atomoxetine augmentation in MDD.     

抑郁症的睡眠质量及其相关影响因素

目的了解保定市抑郁症睡眠质量特点及其相关影响因素。方法采用多阶段分层整群抽样方法随机抽取≥18周岁的人群，共10073名，用扩展的一般健康问卷（GHQ-12）将调查对象分为高、中、低危险组，以美国精神障碍诊断与统计手册-第四版（DSM—Ⅳ）轴Ⅰ障碍定式临床检查病人版（SCID—L／P）对调查对象进行抑郁症的诊断。以匹兹堡睡眠质量指数（PSQI）评定睡眠质量。结果8773人完成了TPSQI调查，抑郁症现患125例，睡眠障碍（PSQI总分〉7）的发生比率为68．8％；PSQI总分与有无支持群体、社会环境、教育、职业、住房、经济、卫生保健、法律与犯罪等社会心理与环境问题无相关。结论睡眠障碍是抑郁症的常见症状，受社会心理与环境问题的影响较小。