抑郁症自杀行为的神经生物学研究进展

抑郁症比普通人群有更高的自杀率,如何预防抑郁症自杀是临床工作中的一个重要课题。本文就抑郁症自杀发生的危险因素及神经影像、神经内分泌和分子遗传学等方面研究最新进展进行综述,旨在探讨抑郁症自杀行为的神经生物学机制,为抑郁症自杀行为的预防和进一步研究提供思路。     

Cerebrospinal fluid hypocretin-1 (orexin A) levels in mania compared to unipolar depression and healthy controls

Background: Impairment of sleep–wake cycles and circadian rhythm are found in human narcolepsy which is characterized by deficiency of hypocretin (hcrt) or its receptors. A disturbed electroencephalography (EEG) based vigilance regulation is also found in affective disorders such as major depressive disorder (MDD) and mania. For the first time, in the present study hcrt levels were investigated in patients with a manic episode and compared with age-matched patients with MDD and controls. Methods: 15 subjects were enrolled in the study after admission to hospital: 5 manic (mean YMRS 15.6 ± 2.9) and 5 age-matched patients with MDD (mean HDRS 11.6 ± 8.0), and 5 age-matched controls without any neurological or psychiatric disorder. Cerebrospinal fluid (CSF) hcrt levels were measured in all three groups using a fluorescence immunoassay (FIA). Results: Mean hcrt-1 level in manic patients (77.3 ± 20.7 pg/ml) did not differ significantly compared to patients with MDD (75.6 ± 15.7 pg/ml MDD) or controls (74.9 ± 19.3 pg/ml). Hcrt levels and severity of disease did not show a significant association. Conclusion: In the present study, for the first time hcrt-1 levels in manic patients were investigated but did not reveal significant differences neither compared to age-matched patients with MDD nor healthy controls without any psychiatric or neurological disorder.     

Vigilance Performance and Autonomic Function in Narcolepsy: Effects of Central Stimulants

Twenty female narcoleptic patients treated with central stimulants (CS) were studied during vigilance tests and psychophysiological recordings of autonomic functions, after 3 days off CS, and during CS treatment. Results were compared with healthy female subjects. Narcoleptics were lower in Critical Flicker Fusion (CFF), but did not differ in choice reaction time or continuous vernier visual acuity. CS improved CFF in the narcoleptic group. Narcoleptics had lower skin conductance (SC) level, but did not differ from normals in SC spontaneous fluctuations or heart rate. CS did not affect SC level or heart rate in the narcoleptic group, but counteracted the decrease in SC spontaneous fluctuations normally seen over a monotonous experimental session. CS reduced lowfrequency tremor and increased high-frequency tremor in the narcoleptic group. Comparison with anxiety and psychosomatic patients was also performed. The results of the vigilance tests suggested a specific disturbance of time resolution of stimulus input in narcoleptics, not related to lowered arousal, but alleviated by CS. The psychophysiological findings suggested that narcoleptic patients have a lowered habitual arousal as well as a marked tendency to decreases in phasic arousal. Central stimulants appear to improve only the latter.     

The roles of depression and anxiety in the understanding and treatment of Obstructive Sleep Apnea Syndrome

Obstructive Sleep Apnea Syndrome (OSAS) is a debilitating condition stemming from disruption to the respiratory system during sleep. At present, the nature of the relationship between OSAS and mood, specifically depression and anxiety, is still unclear. The purpose of this paper is to shed some light on this relationship. PsycINFO was used to locate relevant papers on this topic. This literature search formed the basis of our investigation. Results showed that the anxiety and depression methodology is weak. It is now clear that there is an urgent need to better understand the roles of anxiety and depression in OSAS. For example, the research literature suggests that depression and anxiety covary with OSAS. However, because of methodological issues, such as difficulties involved in diagnosis and the use of inappropriate instruments, this conclusion remains tenuous. Future directions are discussed.     

丁酸钠对食管永生化上皮细胞增殖、分化和凋亡的作用

目的 研究丁酸钠对永生化食管上皮的增殖、分化和凋亡的作用。方法 用HPV18E6E7诱发的人胚食管上皮永生化细胞株SHEE,培养在50ml培养瓶和24孔培养板,实验组分别加入1mmol/L和5mmol/L丁酸钠,对照组未加药,作用4d。统计细胞克隆数,细胞超微结构用电镜检查;细胞周期和凋亡细胞数用流式细胞仪检查;Ki-67、细胞角蛋白用免疫组织化学SP法检查;激光共聚焦扫描显微镜检查用鬼臼毒素标记的F-肌动蛋白。结果 加入1mmol/L和5mmol/L丁酸钠4d克隆形成率分别为65.5%和25.5%,比对照组73.5%减少。细胞周期检查1mmol/L组S期细胞明显减少（4.6%),多停留在G0/G1期（83.8%)。与对照组比较,1mmol/L组细胞Ki-67表达降低,F-肌动蛋白和角蛋白表达增加,5mmol/L组细胞凋亡明显增多。结论 丁酸钠可以诱导SHEE细胞增殖停滞和细胞凋亡,并有促细胞分化作用。其与用药剂量和时间有关。     

Associations between anxiety, depression and insomnia in peri- and post-menopausal women

Objectives

To determine the correlation between somatic and psychological symptoms and insomnia and the contribution of depression and anxiety to insomnia in a sample of peri- and post-menopausal women in a clinical setting.

Study design

The responses of 237 peri- and post-menopausal women enrolled in the Systematic Health and Nutrition Education Program (SHNEP) at the Menopause Clinic of the Tokyo Medical and Dental University Hospital between November 2007 and December 2010 to the Menopausal Health-Related Quality of Life (MHR-QOL) and Hospital Anxiety and Depression Scale (HADS) questionnaires were subjected to Spearman's rank correlation and logistic regression analyses.

Results

The analysis revealed that (1) insomnia is highly prevalent, (2) the symptoms of difficulty in initiating sleep (DIS) and experiencing non-restorative sleep (NRS) are more strongly correlated with psychological than somatic symptoms, and (3) DIS is strongly associated with anxiety while NRS is strongly associated with depression in the population studied.

Conclusions

Insomnia is highly prevalent among peri- and post-menopausal female patients in a clinical setting and more closely associated with psychological than somatic symptoms. DIS is strongly correlated with anxiety while NRS is strongly correlated with depression.     

The neurobiology of aging and the neurobiology of depression: is there a relationship?

The relationship between the biology of aging and the biology of affective disorders remains obscure, largely for two reasons. First, and most important, is the equivocal nature of the data that indicates that increasing age predisposes an individual to episodes of major depression. Second, is the lack of tools to assess neurotransmitter turnover and availability in humans. Indirect measures such as neuroendocrine function tests, platelet, plasma and CSF studies contain too many confounding factors, to allow for adequate testing of neurochemical hypotheses. Development of novel approaches based on dynamic brain imaging methods may ameliorate these shortcomings.     

Localization of hypocretin-like immunoreactivity in the brain of the diurnal rodent, Arvicanthis niloticus

The neuropeptide hypocretin (HCRT, also called orexin) acts in the brain to increase arousal and inhibit REM sleep. There is also substantial evidence that disruption of the hypocretin system results in narcolepsy. The distribution of HCRT + fibers in nocturnal animals is consistent with its role in arousal; fibers are concentrated in brain areas important in arousal and the inhibition of REM sleep. The distribution of HCRT-like immunoreactive (HCRT +) cells and fibers has been described in nocturnal but not diurnal rodents. We therefore examined the anatomical distribution of HCRT + cells and fibers in the diurnal murid rodent Arvicanthis niloticus (unstriped Nile grass rat). Arvicanthis niloticus were perfused and brain sections were collected through the forebrain and midbrain and processed for HCRT immunocytochemistry. Hypocretin-like immunopositive cell bodies were located in the lateral hypothalamus, dorsomedial hypothalamus, and perifornical area. The densest staining for HCRT + neuronal fibers was seen in the paraventricular thalamic nucleus, the locus coeruleus, and the raphe nuclei. The distribution of HCRT + cells and fibers is consistent with that found in other rodents such as rats and Syrian hamsters. Although the pattern of HCRT-like immunostaining for cells and fibers is similar in nocturnal rodents and diurnal A. niloticus, it will be important to compare the pattern of HCRT release, as well as activity of HCRT cells, between nocturnal and diurnal species.     

丁酸钠对人乳头状瘤病毒诱导的永生化食管上皮细胞恶性转化的促进作用

目的 在人乳头状瘤病毒（HPV）18E6E7基因诱导人胚食管上皮细胞永生化的基础上,观察高、低剂量丁酸钠在细胞恶性转化过程中的促癌作用。方法 永生化食管上皮细胞SHEE先用高剂量于酸钠（80mmol/L),后用低剂量丁酸钠（5mmol/L)各处理8周,再经无丁酸钠条件继续培养14周。用相差显微镜、免疫组织化学SABC法和流式细胞仪检查细胞形态、增殖和调亡状况;用Hoechst33342和碘化丙啶检查活细胞和死细胞;细胞软琼脂集落形成及移植裸小鼠和严重联合免疫缺陷小鼠检查成瘤性。结果 当细胞暴露在80mmol/L丁酸钠,细胞死亡,只剩少量活细胞。在含5mmol/L丁酸钠培养基中细胞出现第一增殖期;撤去丁酸钠,细胞进入危象期,细胞倍增时间延长,如老化细胞。度过危象期,细胞进入第二增殖期,细胞继续增生和异型增生。在第二增殖期末细胞出现恶变,软琼脂培养有大集落形成,移植裸小鼠和SCID小鼠成瘤。结论 SHEE永生化上皮由丁酸钠诱导的恶性变通过了两个阶段的死亡威胁：高浓度丁酸钠引起细胞死亡,缺乏丁酸钠引起细胞危象。高剂量丁酸钠引起永生化细胞死亡,低剂量引起细胞增殖,说明丁酸钠对体外培养细胞有促恶变作用。     

Excitation and depression of cortical neurones during spreading depression

Summary Variations in the excitability of individual cortical neurones during the invasion of spreading depression (SD) have been monitored by observing the alterations of spontaneous and L-glutamate-induced firing. Invasion of many neurones during SD is marked by a brief burst of firing which occurs concurrently with the onset of the negative slow extracellular potential. Other neurones do not fire, although the microelectrode records a negative slow wave. Depression of glutamate-induced and spontaneous firing follows and may last for several minutes. The initial loss of excitability of those neurones that discharge during SD invasion may be due to excessive depolarization. This phase is rapidly succeeded by a period of depressed excitability, during which the neurones can be invaded by an antidromic spike or excited by increased amounts of L-glutamate. These findings indicate that SD propagation initially involves the release of an excitant substance, possibly glutamic acid. The continuing effects of SD are due to the reduction in cell excitability. As many neurones are depressed without undergoing an initial excitation, it appears that a depressant substance is also involved. This may be gamma-aminobutyric acid.     

A longitudinal study of depression, pain, and stress as predictors of sleep disturbance among women with metastatic breast cancer

OBJECTIVE: Sleep disturbances are common among women with breast cancer and can have serious consequences. The present study examined depression, pain, life stress, and participation in group therapy in relation to sleep disturbances in a sample of women with metastatic breast cancer. METHODS: Ninety-three women with metastatic breast cancer participated in a large intervention trial examining the effect of the group therapy on their symptoms. They completed measures of depression, pain, life stress, and sleep disturbance at baseline, 4, 8 and 12 months. RESULTS: The results showed that higher initial levels of depression at baseline predicted problems associated with getting up in the morning, waking up during the night, and daytime sleepiness. Increases in depression over the course of 12 months were associated with fewer hours of sleep, more problems with waking up during the night and more daytime sleepiness. Higher levels of pain at baseline predicted more problems getting to sleep. Increases in pain predicted more difficulty getting to sleep and more problems waking up during the night. Greater life stress at baseline predicted more problems getting to sleep and more daytime sleepiness. CONCLUSIONS: Depression, pain, and life stress scores were each associated with different types of negative change in self-reported sleep disturbances. Depression, especially worsening depression, was associated with the greatest number of types of negative change. The relationships found between sleep disturbance and depression, pain, and life stress suggest specific ways to address the problem of sleep disturbance for women with metastatic breast cancer and show how different types of disturbed sleep may be clinical markers for depression, pain, or life stress in this population.     

Resolving the relationship between ApolipoproteinE and depression

Several studies have reported an association between the ApolipoproteinE-?4 (APOE4) allele and depression among elders. However others have failed to find an association. Since APOE4 is a well recognized risk factor for Alzheimer dementia, cognitive status may represent an important confounder between APOE4 and depression. In this investigation, we examined the relationship between the ApolipoproteinE-?4 allele and depression among elders accounting for cognitive status. Using a case-control design (n = 1052), we investigated the association between ApolipoproteinE-?4 and depression in Alzheimer disease patients (n = 528) and in cognitively intact controls (n = 524). We demonstrated an apparent association between the APOE4 allele and depression in the combined dataset (p = 0.001) when not controlling for cognitive status. However, once stratified by the presence of Alzheimer disease, there was no association in either the Alzheimer group (p = 0.290) or the cognitively intact controls (p = 0.494). In this dataset there is no association between the ApolipoproteinE-?4 allele and depression among those with Alzheimer disease or among cognitively intact elders. However there is a significant association between female gender and depression in the cognitively intact (p = 0.003) but not among those with Alzheimer disease. Additionally, individuals with Alzheimer disease and depression had a significantly younger age of onset for their Alzheimer disease than those without depression (p = 0.017).     

The role of fast and slow EEG activity during sleep in males and females with major depressive disorder

Sleep difficulties are highly prevalent in depression, and appear to be a contributing factor in the development and maintenance of symptoms. However, despite the generally acknowledged relationship between sleep and depression, the neurophysiological substrates underlying this relationship still remain unclear. Two main hypotheses were tested in this study. The first hypothesis states that sleep in depression is characterized by inadequate generation of restorative sleep, as indexed by reduced amounts of slow‐wave activity. Conversely, the second hypothesis states that poor sleep in depression is due to intrusions of fast‐frequency activity that may be reflective of a hyperaroused central nervous system. This study aimed to test both hypotheses in a large sample of individuals with clinically validated depression, as well as to examine sex as a moderator. Results suggest that depression is better characterized by an overall decrease in slow‐wave activity, which is related to elevated anxious and depressed mood the following morning. Results also suggest that females may be more likely to experience fast frequency activity related to depression symptom severity.     

Plasma nortriptyline and clinical response in depression

Plasma levels of nortriptyline below 50 ng/ml or above 150 ng/ml have been reported to yield results inferior to intermediate levels. In the present study, patients with uncomplicated primary, nonbipolar depression were randomly assigned to 12 weeks of treatment with NT alone or with cognitive therapy. Nine of 35 patients had mean NT plasma levels less than 50 ng/ml. Five of them improved clinically to the criterion level of less than or equal to 7 on the Hamilton Rating Scale for Depression. This improvement rate was not at all different from that of patients with mean plasma levels within the presumed therapeutic window. The upper limit of 150 ng/ml was not tested. This study is presented in the hope of reviving the apparently dormant search for optimal therapeutic plasma levels of antidepressants.     

Circadian distribution of motor activity and immobility in narcolepsy: Assessment with continuous motor activity monitoring

The circadian distribution of motor activity and immobility of 14 unmedicated narcoleptics and matched controls was evaluated by monitoring continuous wrist motor activity 5 successive days and nights at home. Sleep was also assessed by sleep logs. The amplitude of the circadian rhythm of motor activity and immobility was significantly lower in narcoleptics than in controls. The variables that best distinguish narcoleptics from controls were the diurnal and nocturnal mean duration of uninterrupted immobility, which can be explained by excessive daytime sleepiness and frequent nocturnal awakenings, respectively. Thus, measures of diurnal and nocturnal motor activity and immobility appear useful for the objective assessment of some of the sleep-wakefulness manifestations of narcolepsy.     

曲唑酮对治疗脑卒中后抑郁患者睡眠障碍的临床观察

目的探讨曲唑酮治疗脑卒中后抑郁患者睡眠障碍的疗效。方法将脑卒中后抑郁并出现睡眠障碍的患者60例随机分为曲唑酮治疗组和对照组各30名,治疗前,治疗后4、6周分别给予匹兹堡睡眠指数量表(PSQI)及汉密尔顿抑郁量表(HAMD)评分。结果治疗前两组两个量表得分差异无统计学意义,治疗后4周及治疗后6周得分差异均有统计学意义。治疗4周(PSQI:t=5.577,P0.01;HAMD:t=4.917,P0.01),治疗6周后(PSQI:t=7.007,P0.01;HAMD:t=7.888,P0.01),治疗组睡眠质量明显改善,且明显高于对照组(P0.01),曲唑酮治疗组抑郁状态改善明显优于对照组(P0.01)。结论曲唑酮可有效改善脑卒中后抑郁患者睡眠障碍。     

Narcolepsy, 2009 A(H1N1) pandemic influenza,and pandemic influenza vaccinations: What is known and unknown about the neurological disorder,the role for autoimmunity,and vaccine adjuvants

The vaccine safety surveillance system effectively detected a very rare adverse event, narcolepsy, in subjects receiving AS03-adjuvanted A(H1N1) pandemic vaccine made using the European inactivation/purification protocol. The reports of increased cases of narcolepsy in non-vaccinated subjects infected with wild A(H1N1) pandemic influenza virus suggest a role for the viral antigen(s) in disease development. However, additional investigations are needed to better understand what factor(s) in wild influenza infection trigger(s) narcolepsy in susceptible hosts. An estimated 31 million doses of European AS03-adjuvanted A(H1N1) pandemic vaccine were used in more than 47 countries. The Canadian AS03-adjuvanted A(H1N1) pandemic vaccine was used with high coverage in Canada where an estimated 12 million doses were administered. As no similar narcolepsy association has been reported to date with the AS03-adjuvanted A(H1N1) pandemic vaccine made using the Canadian inactivation/purification protocol, this suggests that the AS03 adjuvant alone may not be responsible for the narcolepsy association. To date, no narcolepsy association has been reported with the MF59®-adjuvanted A(H1N1) pandemic vaccine. This review article provides a brief background on narcolepsy, outlines the different types of vaccine preparations including the ones for influenza, reviews the accumulated evidence for the safety of adjuvants, and explores the association between autoimmune diseases and natural infections. It concludes by assimilating the historical observations and recent clinical studies to formulate a feasible hypothesis on why vaccine-associated narcolepsy may not be solely linked to the AS03 adjuvant but more likely be linked to how the specific influenza antigen component of the European AS03-adjuvanted pandemic vaccine was prepared. Careful and long-term epidemiological studies of subjects who developed narcolepsy in association with AS03-adjuvanted A(H1N1) pandemic vaccine prepared with the European inactivation/purification protocol are needed.     

Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children

Study Objective:

To report on symptoms and therapies used in childhood narcolepsy-cataplexy.

Design, Patients, and Setting:

Retrospective series of 51 children who completed the Stanford Sleep Inventory. HLA-DQB1*0602 typing (all tested, and 100% positive), polysomnography or Multiple Sleep Latency Test (76%), and cerebrospinal fluid hypocretin-1 measurements (26%, all with low levels) were also conducted. Prospective data on medication response was collected in 78% using a specially designed questionnaire.

Measurements and Results:

Patients were separated into children with onset of narcolepsy prior to (53%), around (29%), and after (18%) puberty. None of the children had secondary narcolepsy. Clinical features were similar across puberty groups, except for sleep paralysis, which increased in frequency with age. Common features included excessive weight gain (84% ≥ 4 kg within 6 months of onset of narcolepsy) and earlier puberty (when compared with family members), notably in subjects who gained the most weight. Streptococcus-positive throat infections were reported in 20% of cases within 6 months of onset of narcolepsy. Polysomnographic features were similar across groups, but 3 prepubertal children did not meet Multiple Sleep Latency Test diagnostic criteria. Regarding treatment, the most used and continued medications were modafinil (84% continued), sodium oxybate (79%), and venlafaxine (68%). Drugs such as methylphenidate, tricyclic antidepressants, or selective serotonin reuptake inhibitors were often tried but rarely continued. Modafinil was reported to be effective for treating sleepiness, venlafaxine for cataplexy, and sodium oxybate for all symptoms, across all puberty groups. At the conclusion of the study, half of children with prepubertal onset of narcolepsy were treated “off label” with sodium oxybate alone or with the addition of one other compound. In older children, however, most patients needed more than 2 drugs.

Conclusion:

This study reports on the clinical features of childhood narcolepsy and documents the safe use of treatments commonly used in adults in young children.

Citation:

Aran A; Einen M; Lin L; Plazzi G; Nishino S; Mignot E. Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. SLEEP 2010;33(11):1457-1464.     

The dexamethasone suppression test, the Hamilton Depression Rating Scale and the DSM-III depression categories

The Hamilton Depression Rating Scale (HDRS) score and plasma cortisol values were measured in 100 depressed patients at 8 a.m., 4 p.m. and 11 p.m. after oral administration of 1 mg dexamethasone the previous night. The patients were categorized according to DSM-III as suffering from either minor depression (including dysthymic disorder, 300.40; adjustment disorder with depressed mood, 309.00; atypical depression, 296.82) or major depression (without melancholia, 296.X2; with melancholia, 296.X3; with psychotic features, 296.X4). Plasma cortisol levels of 3.5 μ/dl at 8 a.m. were found to be the most sensitive (56.9%) and specific (94.3%) discriminator between minor and major depression. Plasma cortisol levels at 4 p.m. and 11 p.m. or the combination of several cortisol values also differentiated between minor and major depression; however, the results were not so conclusive. According to the rating on the Hamilton Depression Scale the patients with major depression were more severely depressed (P < 0.001) than patients suffering from minor depression. Cortisol values at 8 a.m., 4 p.m., 11 p.m. and the highest levels were significantly (P < 0.001) correlated with the HRDS score. A maximum of 20.2% of the score variance could be explained by the correlation with the highest cortisol value observed. Severity of illness does not exclusively account for the biological differences between minor and major depression.     

Effects of daytime,night and sleep pressure on long-term depression in the hippocampus in vivo

Although long-term depression (LTD) is generally considered as one of the underlying mechanisms of learning and memory, the induction of it in vivo seems difficult. Evidence demonstrates that the total synaptic weight is associated with circadian rhythm, with up-regulation in wakefulness and down-regulation during sleep, suggesting that the induction of LTD may also be affected by it. In this study, we found that in two well-established rat models, low-frequency stimuli (LFS) induced LTD upon daytime anesthesia, but not at night. Upon further study, we found that the induction of LTD could not be blocked at night if we deprived sleep of the rats during the daytime. These results indicate that the induction of LTD is facilitated by daytime or sleep deprivation. Since rats both in the daytime and after sleep deprivation share the same character of high sleep pressure, our results suggest that LTD is actually facilitated by high sleep pressure. Our study also provides a possible explanation why some labs can induce LTD in vivo while others cannot. Sleep pressure should be taken into account as one of the key factors on the induction of LTD in vivo.