Cytokines as mediators of depression: what can we learn from animal studies?

It has recently been postulated that cytokines may cause depressive illness in man. This hypothesis is based on the following observations: 1. Treatment of patients with cytokines can produce symptoms of depression; 2. Activation of the immune system is observed in many depressed patients; 3. Depression occurs more frequently in those with medical disorders associated with immune dysfunction; 4. Activation of the immune system, and administration of endotoxin (LPS) or interleukin-1 (IL-1) to animals induces sickness behavior, which resembles depression, and chronic treatment with antidepressants has been shown to inhibit sickness behavior induced by LPS; 5. Several cytokines can activate the hypothalamo-pituitary-adrenocortical axis (HPAA), which is commonly activated in depressed patients; 6. Some cytokines activates cerebral noradrenergic systems, also commonly observed in depressed patients; 7. Some cytokines activate brain serotonergic systems, which have been implicated in major depressive illness and its treatment. The evidence for each of these tenets is reviewed and evaluated along with the effects of cytokines in classical animal tests of depression. Although certain sickness behaviors resemble the symptoms of depression, they are not identical and each has distinct features. Thus the value of sickness behavior as an animal model of major depressive disorder is limited, so that care should be taken in extrapolating results from the model to the human disorder. Nevertheless, the model may provide insight into the etiology and the mechanisms underlying some symptoms of major depressive disorder. It is concluded that immune activation and cytokines may be involved in depressive symptoms in some patients. However, cytokines do not appear to be essential mediators of depressive illness.     

Delirium phenomenology: what can we learn from the symptoms of delirium?

OBJECTIVES: This review focuses on phenomenological studies of delirium, including subsyndromal and prodromal concepts, and their relevance to other elements of clinical profile. METHODS: A Medline search using the keywords delirium, phenomenology, and symptoms for new data articles published in English between 1998 and 2008 was utilized. The search was supplemented by additional material not identified by Medline but known to the authors. RESULTS: Understanding of prodromal and subsyndromal concepts is still in its infancy. The characteristic profile can differentiate delirium from other neuropsychiatric disorders. Clinical (motoric) subtyping holds potential but more consistent methods are needed. Studies are almost entirely cross-sectional in design and generally lack comprehensive symptom assessment. Multiple assessment tools are available but are oriented towards hyperactive features and few have demonstrated ability to distinguish delirium from dementia. There is insufficient evidence linking specific phenomenology with etiology, pathophysiology, management, course, and outcome. CONCLUSIONS: Despite the major advancements of the past decade in many aspects of delirium research, further phenomenological work is crucial to targeting studies of causation, pathophysiology, treatment, and prognosis. We identified eight key areas for future studies.     

Tolerability of antiepileptic drugs: can we determine differences?

Patient tolerability of adverse effects is integral to successful treatment. Although standard antiepileptic drugs (AEDs) are well tolerated by many patients, the promise of newer AEDs has been the potential for diminished burden of problems with similar seizure control. This report reviews the prevalence of systemic and neurological adverse effects reported in clinical trials of AED monotherapy. A central finding in this report was the unidirectional higher prevalence of selected adverse effects from standard compared with newer AEDs. A system of questioning every patient at every visit to elicit information may be helpful when balancing benefit-to-risk ratio of individualized therapy during everyday practice.     

Maintenance treatment of insomnia: what can we learn from the depression literature?

Insomnia and depression are common problems with profound public health consequences. When left untreated, both conditions have high rates of persistence and recurrence. Maintenance treatment for depression is fairly well established, but there is no evidence-based consensus regarding the safety and efficacy of maintenance therapy for insomnia. Consequently, long-term treatment of insomnia is driven primarily by the individual choices of patients and their clinicians. This article compares and contrasts the current state of research in the maintenance therapy of depression and insomnia and highlights gaps in the insomnia literature.     

Intravenous heparin for acute stroke: what can we learn from the megatrials?

Recently published large clinical trials of heparin and aspirin in acute stroke-the International Stroke Trial, Chinese Acute Stroke Trial, and Trial of ORG 10172 in Acute Stroke Treatment--fail to show a net benefit from heparin. None of these trials used i.v., dose-adjusted, unfractionated heparin as generally employed in the United States. However, the control groups in these trials provide data on acute stroke recurrence in large numbers of patients, and these stroke recurrence rates can be used to establish an upper limit for the potential efficacy of antithrombotic therapy. The rates of recurrent ischemic stroke in the control groups of these trials were low, ranging from 0.6 to 2.2% per week. The low rates of recurrent stroke observed in these groups, coupled with the morbidity and mortality associated with i.v. heparin in this patient population, argue against routine use of i.v. heparin in the acute stroke period.     

Animal models of the ketogenic diet: what have we learned, what can we learn?

Despite its clinical use as a therapy for refractory epilepsy for more than 75 years, the ketogenic diet (KD) remains a therapy in search of an explanation. The mechanism of action of the KD is unclear and the optimal indications for its clinical use are incompletely defined. Animal models could help to elucidate these questions. Surprisingly, there have been very few animal studies of the KD, and those that have been performed are difficult to compare because of wide discrepancies in experimental methods. Earlier models concentrated on the effect of the KD on acute seizure threshold in normal (i.e. nonepileptic) animals. Recent studies are beginning to examine the longer term effects of the KD and its role in epileptogenesis. Some features of clinical experience have been replicated in animal models, including the role of ketosis, elevation of seizure threshold by both classic ketogenic and medium chain triglyceride diets, better effectiveness at younger ages, and rapid reversal of the seizure protective effect when the diet is discontinued. These parallels raise hope that pertinent clinical questions can be addressed in the more controlled setting of the research laboratory. As in the clinical arena, there has been a recent resurgence of interest in pursuing basic questions related to the ketogenic diet, using techniques of modern neuroscience. Experimental approaches such as brain slice neurophysiology, genetic models, dissection of metabolic pathways, and neurohistological techniques hold much promise in the effort to understand this intriguing alternative to standard anticonvulsants.     

Mechanosensitive channels: what can we learn from 'simple' model systems?

Mechanosensitive ion channels, which convert external mechanical forces into electrical and chemical signals in cells, are diverse. Presently, there is no known common sequence 'signature' that identifies mechanosensitivity. Bacterial mechanosensitive channels gated by membrane tension represent convenient models allowing us to combine structural information with the insights gained from biophysical analysis, biochemistry, genetic screens, bacterial physiology and molecular computation. Here, the conformational transition driven by membrane tension in the bacterial channel MscL is discussed. The predicted pathway suggests roles for distinct protein domains, surrounding lipids and water in the gating process. MscL, a simple system, thus helps us obtain a coherent picture of molecular events, and build concepts and strategies that can be applied to more elaborate mechanosensory systems in the near future.     

How can we learn about developmental processes from cross-sectional studies, or can we?

OBJECTIVE: Cross-sectional studies are often used in psychiatric research as a basis of longitudinal inferences about developmental or disease processes. While the limitations of such usage are often acknowledged, these are often understated. The authors describe how such inferences are often, and sometimes seriously, misleading. METHOD: Why and how these inferences mislead are here demonstrated on an intuitive level, by using simulated data inspired by real problems in psychiatric research. RESULTS: Four factors with major roles in the relationship between cross-sectional studies and longitudinal inferences are selection of time scale, type of developmental process studied, reliability of measurement, and clarity of terminology. The authors suggest how to recognize inferential errors when they occur, describe how to protect against such errors in future research, and delineate the circumstances in which only longitudinal studies can answer crucial questions. CONCLUSIONS: The simple conclusion is that one must always use the results of cross-sectional studies to draw inferences about longitudinal processes with trepidation.     

The phenomenology of bipolar disorder: what drives the high rate of medical burden and determines long‐term prognosis?

Bipolar disorder (BD) has been classically described as one of episodic mood disturbances. New evidence suggests that a chronic course and multisystem involvement is the rule, rather than the exception, and that together with disturbances of circadian rhythms, mood instability, cognitive impairment, a high rate of medical burden is often observed. The current diagnostic approach for BD neither describes the multisystem involvement that the recent literature has highlighted nor points toward potential predictors of long- term outcome. In light of the new evidence that the long-term course of BD is associated with a high prevalence of psychiatric comorbidity and an increased mortality from medical disease, we propose a multidimensional approach that includes several symptom domains, namely affective instability, circadian rhythm dysregulation, and cognitive and executive dysfunction, presenting in various combinations that give shape to each individual presentation, and offers potential indicators of overall long-term prognosis.     

An exploration of research into substance misuse and psychiatric disorder in the UK: what can we learn from history?

BACKGROUND AND AIM: This review explores UK-based research developments in substance misuse and mental illness over the last 25 years. The main body of work comprises policy-orientated projects funded by the Department of Health from the late 1990s. Early research tended to focus on alcohol, especially alcoholic hallucinosis: the relationship of the latter with schizophrenia-like illness was examined, with the finding that very few cases did develop into schizophrenia. METHOD AND IMPLICATIONS: Parallels are drawn with the current debate around the link between cannabis and psychosis, urging caution in too rapid an assertion that cannabis is necessarily 'causal'. The clinical and policy implications of the misinterpretation of evidence are discussed. A proposal is put forward that the genesis of psychotic illness in alcohol misuse be revisited using more sophisticated research methodologies. Given the changing landscape of substance use in the UK, particularly the fashion of polysubstance use and the recognition that this is associated with psychotic illness, other drugs that are associated with psychotic illness should be similarly investigated to determine whether there is a common mechanism that might throw light on understanding the relationship between substance use and psychotic illness or schizophrenia.     

The place of race and racism in cultural competence: what can we learn from the English experience about the narratives of evidence and argument?

This paper outlines the history of workforce strategies for providing mental health care to "black and ethnic minorities" in England. Universal mental health policies failed to deliver equity in care, and thus specific policies were launched to address ethnic inequalities in care experiences and outcomes. The emphasis on race equality rather than cultural complexity led to widespread acceptance of the need for change. The policy implementation was delivered in accord with multiple regional and national narratives of how to reduce inequalities. As changes in clinical practice and services were encouraged, resistance emerged in various forms from clinicians and policy leaders. In the absence of commitment and then dispute about forms of evidence, divergent policy and clinical narratives fuelled a shift of attention away from services to silence issues of race equality. The process itself represents a defence against the pain of acknowledging systemic inequities whilst rebutting perceived criticism. We draw on historical, psychoanalytic, and learning theory in order to understand these processes and the multiple narratives that compete for dominance. The place of race, ethnicity, and culture in history and their representation in unconscious and conscious thought are investigated to reveal why cultural competence training is not simply an educational intervention. Tackling inequities requires personal development and the emergence and containment of primitive anxieties, hostilities, and fears. In this paper we describe the experience in England of moving from narratives of cultural sensitivity and cultural competence, to race equality and cultural capability, and ultimately to cultural consultation as a process. Given the need to apprehend narratives in care practice, especially at times of disputed evidence, cultural consultation processes may be an appropriate paradigm to address intersectional inequalities.     

What new can we learn from cardiac sympathetic neuroimaging in synucleinopathies?

Clinical Autonomic Research -