Pathways linking late-life depression to persistent cognitive impairment and dementia

There is a strong association between late-life depression, cognitive impairment, cerebrovascular disease, and poor cognitive outcomes, including progressive dementia, especially Alzheimer's disease. While neuroimaging evidence suggests that cerebrovascular disease plays a prominent role, it seems that depression alone may also confer substantial risk for developing Alzheimer's disease. The relationships between the prominent cerebrovascular changes, other structural abnormalities, specific forms of cognitive dysfunction, and increased risk for developing Alzheimer's disease among those with late-life depression have been difficult to reconcile. The varied findings suggest that there are likely multiple pathways to poor cognitive outcomes. We present a framework outlining multiple, non-mutually exclusive etiologic links between depression, cognitive impairment, and progressive decline, including dementia. Importantly, the model is both testable and falsifiable. Going forward, using models such as this to inform research should accelerate knowledge acquisition on the depression/dementia relationship that may be useful for dementia prevention, monitoring the impact of depression treatment on clinical status and course of illness.     

Challenges in the diagnosis and treatment of depression in autism spectrum disorders across the lifespan

Diagnosis and treatment of comorbid neuropsychiatric illness is often a secondary focus of treatment in individuals with autism spectrum disorder (ASD), given that substantial impairment may be caused by core symptoms of ASD itself. However, psychiatric comorbidities, including depressive disorders, are common and frequently result in additional functional impairment, treatment costs, and burden on caregivers. Clinicians may struggle to appropriately diagnose depression in ASD due to communication deficits, atypical presentation of depression in ASD, and lack of standardized diagnostic tools. Specific risk and resilience factors for depression in ASD across the lifespan, including level of functioning, age, family history, and coping style, have been suggested, but require further study. Treatment with medications or psychotherapy may be beneficial, though more research is required to establish guidelines for management of symptoms. This review will describe typical presentations of depression in individuals with ASD, review current information on the prevalence, assessment, and treatment of comorbid depression in individuals with ASD, and identify important research gaps.     

Depression and associated physical diseases and symptoms

Depression can occur in association with virtually all the other psychiatric and physical diagnoses. Physical illness increases the risk of developing severe depressive illness. There are two broadly different mechanisms. The most obvious has a psychological or cognitive mechanism. Thus, the illness may provide the life event or chronic difficulty that triggers a depressive episode in a vulnerable individual. Secondly, more specific associations appear to exist between depression and particular physical disorders. These may turn out to be of particular etiological interest. The best examples are probably stroke and cardiovascular disease. Finally, major depression, but especially minor depression, dysthymia, and depressive symptoms merge with other manifestations of human distress with which patients present to their doctors. Such somatic presentations test the conventional distinction between physical and mental disorder and are a perennial source of controversy.     

Cellular consequences of stress and depression

Stress is known to activate distinct neuronal circuits in the brain and induce multiple changes on the cellular level, including alterations in neuronal structures. On the basis of clinical observations that stress often precipitates a depressive disease, chronic psychosocial stress serves as an experimental model to evaluate the cellular and molecular alterations associated with the consequences of major depression. Antidepressants are presently believed to exert their primary biochemical effects by readjusting aberrant intrasynaptic concentrations of neurotransmitters, such as serotonin or noradrenaline, suggesting that imbalances viihin the monoaminergic systems contribute to the disorder (monoaminergic hypothesis of depression). Here, we reviev the results that comprise our understanding of stressful experience on cellular processes, with particular focus on the monoaminergic systems and structural changes within brain target areas of monoaminergic neurons.     

Simulating the anhedonia symptom of depression in animals

One of the two core symptoms of depression is anhedonia, the loss of interest or pleasure in daily activities. Stressful life events are recognized as predisposing factors in the etiology of depression. Rats subjected to a chronic, mild, unpredictable stress regimen exhibit behavioral deficits consistent with a loss of responsiveness to reward, such as decreased sucrose consumption, decreased ability to associate rewards with a distinctive environment, and decreased sensitivity to rewarding electrical brain stimulation. Normal behavior is restored by chronic treatment with antidepressants or electroshocks. Chronically stressed animals also exhibit sleep abnormalities resembling those observed in depressed patients and recognized as biological markers of depression. Thus, stress-induced anhedonia in rats represents an original animal model of some aspects of human depression offering convergent elements of biological, symptomatological, etiological, and therapeutic validity. This simulation of depression may prove useful for better understanding of the pathophysiological mechanisms involved in depressive disorders.     

Towards achieving remission in the treatment of depression

The burden of depressive illness constitutes a major public health issue. Despite real progress and better tolerance of new antidepressant medications, a significant number of depressed patients still suffer from rather severe residual depressive symptoms.This relative lack of efficacy clearly interferes with their psychosocial functioning and their quality of life. In addition, it is now well-recognized that the failure to reach full clinical remission after antidepressant treatment involves a high risk of relapse or recurrence in patients suffering from major depression. This paper reviews the concept of remission across different definitions, and the potential risk factors associated with the failure to reach clinical remission. The identification of specific residual symptoms in nonremitted patients is also of great importance, in order to assess the predictive value of those symptoms in relation to relapse and recurrence. Some methodological issues are also discussed, as well as various therapeutic strategies aimed at relieving residual depressive symptoms. Clinical remission remains a qold standard and a primary objective of modem antidepressant therapy.     

Challenges in the diagnosis and treatment of pediatric bipolar depression

There has been great public and academic interest in the diagnosis and treatment of bipolar disorders (BD) in children and adolescents over the past decade, originally in the US, but now extending internationally. Much of the interest in pediatric BD has focused on the unique manifestation of mania in younger populations. Depression is often overlooked, both as a topic, and as a clinical reality, in these children. While it is becoming clear that adults with BD spend the majority of their symptomatic time in depressive rather than manic episodes, less is known about the pediatric experience of bipolar depression. However, children and adolescents with BD clearly do experience significant depressive symptoms as well as depressive episodes, and therefore early recognition and treatment is necessary. This review addresses what is known about the prevalence, presentation, and treatment of depressive symptoms and episodes in youth with BD, and includes a discussion about the recognition and treatment of bipolar depressive episodes that occur before the first manic episode.     

Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications

The majority of individuals with depression experience sleep disturbances. Depression is also over-represented among populations with a variety of sleep disorders. Although sleep disturbances are typical features of depression, such symptoms sometimes appear prior to an episode of depression. The bidirectional associations between sleep disturbance (especially insomnia) and depression increase the difficulty of differentiating cause-and-effect relationships between them. Longitudinal studies have consistently identified insomnia as a risk factor for the development of a new-onset or recurrent depression, and this association has been identified in young, middle-aged, and older adults. Studies have also observed that the combination of insomnia and depression influences the trajectory of depression, increasing episode severity and duration as well as relapse rates. Fortunately, recent studies have demonstrated that both pharmacological and nonpharmacological interventions for insomnia may favorably reduce and possibly prevent depression. Together, these findings suggest that sleep-related symptoms that are present before, during, andlor after a depressive episode are potentially modifiable factors that may play an important role in achieving and maintaining depression remission.     

Various forms of depression

The current subtyping of depression is based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR) categorical division of bipolar and depressive disorders. Current evidence, however, supports a dimensional approach to depression, as a continuum/spectrum of overlapping disorders, ranging from bipolar I depression to major depressive disorder. Types of depression which have recently been the focus of most research will be reviewed: bipolar II depression, mixed depression, agitated depression, atypical depression, melancholic depression, recurrent brief depression, minor depressive disorder, seasonal depression, and dysthymic disorder. Most research has focused on bipolar II depression, mixed depression (defined by depression and superimposed manic/hypomanic symptoms), and atypical depression. Mixed depression, by its combination of opposite polarity symptoms, has been found to be common by systematic probing for co-occurring manic/hypomanic symptoms. Mixed depression is a treatment challenge for clinicians, because antidepressants alone (ie, not protected by mood-stabilizing agents) may worsen its manic/hypomanic symptoms, such as irritability and psychomotor agitation, which the Food and Drug Administration (FDA) has listed as possible precursors to suicidality.     

Inflammation in depression: is adiposity a cause?

Mounting evidence indicates that inflammation may play a significant role in the development of depression. Patients with depression exhibit increased inflammatory markers, and administration of cytokines and other inflammatory stimuli can induce depressive symptoms. Mechanisms by which cytokines access the brain and influence neurotransmitter systems relevant to depression have also been described, as have preliminary findings indicating that antagonizing inflammatory pathways may improve depressive symptoms. One primary source of inflammation in depression appears to be adiposity. Adipose tissue is a rich source of inflammatory factors including adipokines, chemokines, and cytokines, and a bidirectional relationship between adiposity and depression has been revealed. Adiposity is associated with the development of depression, and depression is associated with adiposity, reflecting a potentional vicious cycle between these two conditions which appears to center around inflammation. Treatments targeting this vicious cycle may be especially relevant for the treatment and prevention of depression as well as its multiple comorbid disorders such as cardiovascular disease, diabetes, and cancer, all of which have also been associated with both depression and inflammation.     

Diagnosis and management of Alzheimer's disease

The diagnosis of Alzheimer's disease (AD) is a 2-stage process, in stage 1, the dementia syndrome, comprising neuropsychologic and neuropsychiatrie components together with deficits in activities of daily living, is differentiated on clinical grounds from a number of other conditions (delirium, concomitant physical illness, drug treatment normal memory loss, etc), in stage 2, the cause is determined, AD being the most common, followed by vascular dementia, Lewy-body dementia, frontal lobe dementia, and a host of so-called secondary causes. Although a mixed Alzheimer/vascular picture is common, gradual onset of multiple cognitive deficits is typical of AD, while abrupt onset, a fluctuating course, hypertension, and focal neurologic signs suggest vascular dementia, in Lewy-body dementia, memory loss may not be an early feature, and fluctuation can be marked by distressing psychotic symptoms and behavioral disturbance, investigations should be minimally invasive and relatively cheap, confined to routine blood tests, chest x-ray and/or electrocardiogram if clinically indicated, cardiologie or neurologic referral in the presence of cerebrovascular signs, and computed tomography if an intracranial lesion is suspected. Accurate diagnosis enables the clinician to outline the disease course to the family and inform them of genetic implications. Numerous instruments for assessing cognitive function, global status, psychiatric well-being, and activities of daily living are briefly reviewed.     

Effects of different antidepressant treatments on the core of depression

Core symptoms of depression are a combination of psychological and somatic symptoms, often combined with psychomotor and cognitive disturbances. Diagnostic classification of depression including the concepts of melancholic, endogenous, or severe depression describe severely depressed patients suffering from most of the core symptoms, together with clinical characteristics of a cyclic unipolar or bipolar course, lower placebo response rates, higher response rates to electroconvulsive therapy, to antidepressant treatments with dually or mixed modes of action, or to lithium augmentation. Higher rates of hypothalamic-pituitary-adrenal axis hyperactivity and specific electroencephalographic patterns have also been shown in this patient group. Summarizing the symptomatology of depression in these patients, a broad overlap between the abovementioned subgroups can be suggested. Because the positive diagnosis of those core symptoms of depression may include clinical consequences, it would be of use to integrate all the mentioned concepts in the upcoming new versions of the diagnostic systems DSM-V and ICD-11.     

Impact of cognitive impairment on the phenomenology of geriatric depression.

OBJECTIVE: Dementia and depressive syndromes demonstrate substantial symptom overlap. As a result, it is challenging to differentiate depression symptoms from nonspecific symptoms of an underlying dementia syndrome. The author addressed the impact of cognitive impairment on the phenomenology of depression symptoms by determining whether more impaired patients were more likely to endorse certain self-report depressive symptoms independent of their underlying level of depression severity. METHODS: Author used data from 576 geriatric rehabilitation inpatients for MIMIC model analyses examining the impact of cognitive impairment on both depression severity and endorsement of symptom clusters. Depressive symptoms were measured with the Geriatric Depression Scale, and cognitive impairment was measured with the Mattis Dementia Rating Scale total score. RESULTS: The reliability (internal consistency) of self-reported depressive symptoms did not change as a function of cognitive impairment. More severe cognitive impairment was associated with greater depression severity but was also associated with two depression symptom clusters after controlling for underlying levels of depression severity. Patients who were more impaired endorsed greater social withdrawal and less psychomotor agitation, independent of their underlying depression severity. Level of cognitive impairment alone did not affect the endorsement of depressed mood and positive affect. CONCLUSIONS: Certain symptoms on depression inventories may be endorsed at a greater level by cognitively impaired patients, independent of their level of underlying depression severity. These symptoms may be nonspecific features of the underlying dementia syndrome and may not be specific to depressive episodes, but instead may represent other syndromes, such as apathy.     

Salience of positive and negative affect in the recognition of depression among elderly persons

Generally, depression is thought of in terms of negative affect However, in the following paper, the contribution of positive affect (PA), as well as negative affect (NA), is demonstrated in the recognition of clinically significant depression. Affect and depression data were collected from 554 residents of a large, urban geriatric center. Statistical analyses demonstrated that both PA and NA were correlated with depression and measures of frailty, and that low PA and high NA were risk factors for depression 1 year later. Results suggest that low PA, or anhedonia, may be particularly important in diagnosing depression among older persons who may not readily report depressive symptoms such as sadness.     

Neuropsychiatric manifestations in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-artery disease of mid-adulthood caused by mutations of the NOTCH3 gene. The disease is responsible for widespread white-matter lesions associated with lacunar infarctions in various subcortical areas. The disease is responsible for migraine with aura and ischemic strokes, and is associated with various degrees of cognitive impairment and with mood disturbances. CADASIL is considered as a unique model to investigate what is known as "subcortical ischemic vascular dementia." Recent data suggest that the number of lacunar infarctions and severity of cerebral atrophy are the main magnetic resonance imaging markers associated with cognitive and motor disabilities in this disorder. Mood disturbances are reported in 10% to 20% of patients, most often in association with cognitive alterations. Their exact origin remains unknown; the presence of ischemic lesions within the basal ganglia or the frontal white matter may promote the occurrence of these symptoms. Further studies are needed to better understand the relationships between cerebral lesions and both cognitive and psychiatric symptoms in this small-vessel disease of the brain.     

Treatments in depression

Major depression is believed to be a multifactorial disorder involving predisposing temperament and personality traits, exposure to traumatic and stressful life events, and biological susceptibility. Depression, both unipolar and bipolar, is a "phasic" disease. Stressful life events are known to trigger depressive episodes, while their influence seems to decrease over the course of the illness. This suggests that depression is associated with progressive stress response abnormalities, possibly linked to impairments of structural plasticity and cellular resilience. It therefore appears crucial to adequately treat depression in the early stages of the illness, in order to prevent morphological and functional abnormalities. While evidence suggests that a severely depressed patient needs antidepressant drug therapy and that a non-severely depressed patient may benefit from other approaches (ie, "nonbiological"), little research has been done on the effectiveness of different treatments for depression. The assertion that the clinical efficacy of antidepressants is comparable between the classes and within the classes of those medications may be true from a statistical viewpoint, but is of limited value in practice. The antidepressant drugs may produce differences in therapeutic response and tolerability. Among the possible predictors of outcome in depression treatment, those derived from clinical assessment, neuroendocrine investigations, polysomnographic sleep parameters, genetic variables, and brain imaging techniques have been extensively studied. This article also reviews therapeutic strategies used when initial treatment fails, and describes briefly new concepts in antidepressant therapies such as the regulation of disturbances in circadian rhythms. The treatment of depressive illness does not stop with treatment of acute episodes, and has to be envisaged as a continuous therapeutic intervention, of which we are still not able to determine the optimal duration of treatment and the moment that it should be ceased.     

尼麦角林在脑血管病中的应用

尼麦角林是一种麦角生物碱衍生物，广泛应用于脑血管病患者认知障碍的治疗。多项临 床前研究显示，尼麦角林对于认知障碍的改善可能与以下因素有关：尼麦角林除能够改善脑循环， 促进神经递质释放外，还具有营养神经及抗氧化等作用。目前的研究认为，尼麦角林能够改善患者 卒中后抑郁相关的情绪障碍以及有效改善血管性痴呆，提高患者的日常生活能力。同时，尼麦角林具 有良好的安全性，目前暂无尼麦角林治疗导致纤维化或麦角中毒的研究报道。本文就尼麦角林在神 经系统的作用机制、临床疗效及安全性进行综述，以期为临床应用提供参考。     

Characteristics,correlates, and outcomes of childhood and adolescent depressive disorders

Depressive illness beginning early in life can have serious developmental and functional consequences. Therefore, understanding the disorder during this developmental stage is critical for determining its etiology and course, as well as for deveiopinq effective intervention straieqies. This paper summarizes current knoviedqe reqardinq the etiology, phenomenoiogy, correlates, natural course, and consequences of unipolar depression in children and adolescents. Using adult depression as a framevork, the unique aspects of childhood and adolescence are considered in order to better understand depression within a developmental context. The data suggest that the clinical presentation, correlates, and natural course of depression are remarkably similar across the lifespan. There are, however, important developmental differences. Specifically, the familial and psychological context in which depression develops in youngsters is associated with variability in the frequency and nature of depressive symptoms and comorbid conditions among children and adolescents. Maturational differences have also been identified in the neurobiological correlates of depression. These developmental differences may be associated with the observed variability in clinical response to treatment and longitudinal course. Characterization of the developmental differences will be helpful in developing more specific and effective interventions for youngsters, thereby allowing them to reach their full potential as adults.