Glutamatergic mechanisms in different disease states: overview and therapeutical implications -- an introduction

Summary.  Glutamate is the most widely distributed excitatory transmitter in the central nervous system (CNS). It is acting via large – and still growing – families of receptors: NMDA-, AMPA-, kainate-, and metabotropic receptors. Glutamate has been implicated in a large number of CNS disorders, and it is hoped that novel glutamate receptor ligands offer new therapeutic possibilites in disease states such as chronic pain, stroke, epilepsy, depression, drug addiction and dependence or Parkinson's disease. While an extensive preclinical literature exists showing potential beneficial effects of NMDA-, AMPA-, kainate- and metabotropic receptor ligands, only NMDA receptor antagonists have been characterized clinically to any appreciable degree. In these trials it has been shown that while several compounds are therapeutically active, they also produce serious side effects at therapeutic doses. Current interest largely centers on the development of receptor subtype-selective compounds, namely compounds selective for receptors containing the NR2B subunit. Preclinical findings and the first clinical results are encouraging, and it may be that such subunit-selective compounds may have a sufficiently wide therapeutic window to be safe for human use. Received July 6, 2001 Accepted August 6, 2001 Published online August 9, 2002     

Confidence intervals for the mean of diagnostic test charge data containing zeros

In this paper, we consider the problem of interval estimation for the mean of diagnostic test charges. Diagnostic test charge data may contain zero values, and the nonzero values can often be modeled by a log-normal distribution. Under such a model, we propose three different interval estimation procedures: a percentile-t bootstrap interval based on sufficient statistics and two likelihood-based confidence intervals. For theoretical properties, we show that the two likelihood-based one-sided confidence intervals are only first-order accurate and that the bootstrap-based one-sided confidence interval is second-order accurate. For two-sided confidence intervals, all three proposed methods are second-order accurate. A simulation study in finite-sample sizes suggests all three proposed intervals outperform a widely used minimum variance unbiased estimator (MVUE)-based interval except for the case of one-sided lower end-point intervals when the skewness is very small. Among the proposed one-sided intervals, the bootstrap interval has the best coverage accuracy. For the two-sided intervals, when the sample size is small, the bootstrap method still yields the best coverage accuracy unless the skewness is very small, in which case the bias-corrected ML method has the best accuracy. When the sample size is large, all three proposed intervals have similar coverage accuracy. Finally, we analyze with the proposed methods one real example assessing diagnostic test charges among older adults with depression.     

Latent class model diagnosis

In many areas of medical research, such as psychiatry and gerontology, latent class variables are used to classify individuals into disease categories, often with the intention of hierarchical modeling. Problems arise when it is not clear how many disease classes are appropriate, creating a need for model selection and diagnostic techniques. Previous work has shown that the Pearson chi 2 statistic and the log-likelihood ratio G2 statistic are not valid test statistics for evaluating latent class models. Other methods, such as information criteria, provide decision rules without providing explicit information about where discrepancies occur between a model and the data. Identifiability issues further complicate these problems. This paper develops procedures for assessing Markov chain Monte Carlo convergence and model diagnosis and for selecting the number of categories for the latent variable based on evidence in the data using Markov chain Monte Carlo techniques. Simulations and a psychiatric example are presented to demonstrate the effective use of these methods.     

Selective Increase of α2A-Adrenoceptor Agonist Binding Sites in Brains of Depressed Suicide Victims

Abstract: The α_2A- and α_2C-adrenoceptor subtypes were evaluated in postmortem brains from suicides with depression (n = 22), suicides with other diagnoses (n = 12), and controls (n = 26). Membrane assays with the antagonist [³H]RX821002 (2-[³H]methoxyidazoxan) suggested the presence of α_2A-adrenoceptors in the frontal cortex and both α_2C-adrenoceptors and α_2A-adrenoceptors in the caudate. The proportions in caudate were similar in controls (α_2A, 86%; α_2C, 14%), depressed suicides (α_2A, 91%; α_2C, 9%), and suicides with other diagnoses (α_2A, 88%; α_2C, 12%). Autoradiography of [³H]RX821002 binding under α_2B/C-adrenoceptor-masking conditions confirmed the similar densities of α_2A-adrenoceptors in the cortex, hippocampus, and striatum from controls and suicides. In the frontal cortex of depressed suicides, competition of [³H]RX821002 binding by (?)-adrenaline revealed a greater proportion (61 ± 9%) of α_2A-adrenoceptors in the high-affinity conformation for agonists than in controls (39 ± 5%). Simultaneous analysis with the agonists [³H]clonidine and [³H]UK14304 and the antagonist [³H]RX821002 in the same depressed suicides confirmed the enhanced α_2A-adrenoceptor density when evaluated by agonist, but not by antagonist, radioligands. The results indicate that depression is associated with a selective increase in the high-affinity conformation of the brain α_2A-adrenoceptors.     

Endogenous opiates: 1997

This paper is the twentieth installment of our annual review of research concerning the opiate system. It summarizes papers published during 1997 that studied the behavioral effects of the opiate peptides and antagonists, excluding the purely analgesic effects, although stress-induced analgesia is included. The specific topics covered this year include stress; tolerance and dependence; eating and drinking; alcohol; gastrointestinal, renal, and hepatic function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurologic disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunologic responses; and other behaviors.     

当归抗抑郁作用及配伍应用

旨在探讨当归在抑郁症治疗中发挥的作用。通过分析相关文献,结合当归的临床功效和抑郁症的疾病特点,概括当归抗抑郁作用规律。当归在抑郁症治疗中具有补血以养肝体、活血以通心脉、通便以利肠腑的作用,以其为主药的抗抑郁复方临床应用广泛。当归的抗抑郁作用值得进一步深入研究。     

运动疗法对慢性阻塞性肺疾病患者抑郁状态的效果观察

目的:探讨运动疗法对慢性阻塞性肺疾病(COPD)患者抑郁状态的临床效果。方法:选取52例COPD患者,随机分为试验组和对照组,各26例。对照组给予支气管扩张、健康教育、氧疗,试验组在对照组的基础上实施运动疗法,采用焦虑自评量表(SAS)、抑郁自评量表(SDS)、ADL生活质量量表对两组患者治疗前后进行评估。结果:对照组患者SAS、SDS评分治疗前后无明显变化,试验患者SAS、SDS评分均明显低于治疗前(P0.05),两组治疗后组间比较,差异亦有统计学意义(P0.05);试验组生活质量的改善优于对照组(P0.05)。结论:运动疗法能有效的改善COPD患者焦虑、抑郁负性情绪,提高患者的生存质量。     

东濮凹陷沙河街组(古近纪)植物活动痕迹类型及其环境与层序地层学意义

植物活动痕迹即根迹,是层序地层学中识别低位期沉积的重要标志。东濮凹陷沙河街组(古近纪)根迹发育,形态各异,可分为A、B、C、D、E五种类型,分别被解释为五类次级沉积环境下的产物。其中A型根迹、B型根迹与河口湾沉积环境相关,前者见于河口湾陆方一侧的河口沙坝(bay head bar),后者则出现于海方一侧易受海浪冲蚀的盐碱凹地。已有资料证明,植物活动痕迹,结合动物活动痕迹和古生物学、沉积学研究,可为判别河口湾沉积环境、层序界面提供重要实据,从而在层序地层学研究和储层沉积环境探索中显示重要作用。     

Signs of attenuated depression-like behavior in vasopressin deficient Brattleboro rats

Vasopressin, a peptide hormone functioning also as a neurotransmitter, neuromodulator and regulator of the stress response is considered to be one of the factors related to the development and course of depression. In the present study, we have tested the hypothesis that congenital deficit of vasopressin in Brattleboro rats leads to attenuated depression-like behavior in tests modeling different symptoms of depression. In addition, hypothalamic-pituitary-adrenocortical axis activity was investigated. Vasopressin deficient rats showed signs of attenuated depression-like behavior in forced swimming and sucrose preference tests, while their behavior on elevated plus maze was unchanged. Vasopressin deficiency had no influence on basal levels of ACTH and corticosterone and had only mild impact on hormonal activation in response to forced swimming and plus-maze exposure. However, vasopressin deficient animals showed higher level of dexamethasone induced suppression of corticosterone response to restraint stress and higher basal levels of corticotropin-releasing hormone mRNA in the hypothalamic paraventricular nucleus. In conclusion, present data obtained in vasopressin deficient rats show that vasopressin is involved in the development of depression-like behavior, in particular of the coping style and anhedonia. Moreover, behavioral and endocrine responses were found to be dissociated. We suggest that brain vasopressinergic circuits distinct from those regulating the HPA axis are involved in generating depression-like behavior.     

Preliminary Results of an Open Label Study of Heart Rate Variability Biofeedback for the Treatment of Major Depression

Major depressive disorder (MDD) is a common mood disorder that can result in significant discomfort as well as interpersonal and functional disability. A growing body of research indicates that autonomic function is altered in depression, as evidenced by impaired baroreflex sensitivity, changes in heart rate, and reduced heart rate variability (HRV). Decreased vagal activity and increased sympathetic arousal have been proposed as major contributors to the increased risk of cardiovascular mortality in participants with MDD, and baroreflex gain is decreased. STUDY OBJECTIVES: To assess the feasibility of using HRV biofeedback to treat major depression. DESIGN: This was an open-label study in which all eleven participants received the treatment condition. Participants attended 10 weekly sessions. Questionnaires and physiological data were collected in an orientation (baseline) session and Treatment Sessions 1, 4, 7 and 10. MEASUREMENTS AND RESULTS: Significant improvements were noted in the Hamilton Depression Scale (HAM-D) and the Beck Depression Inventory (BDI-II) by Session 4, with concurrent increases in SDNN, standard deviation of normal cardiac interbeat intervals) an electrocardiographic estimate of overall measure of adaptability. SDNN decreased to baseline levels at the end of treatment and at follow-up, but clinically and statistically significant improvement in depression persisted. Main effects for task and session occurred for low frequency range (LF) and SDNN. Increases in these variables also occurred during breathing at one's resonant frequency, which targets baroreflex function and vagus nerve activity, showing that subjects performed the task correctly. CONCLUSIONS: HRV biofeedback appears to be a useful adjunctive treatment for the treatment of MDD, associated with large acute increases in HRV and some chronic increases, suggesting increased cardiovagal activity. It is possible that regular exercise of homeostatic reflexes helps depression even when changes in baseline HRV are smaller. A randomized controlled trial is warranted.