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Adult neurogenesis and depression: an introduction.
The following essay provides a summary of a seminar given on the sixth of November, 2010 at the combined annual congress, held at Brussels of the Centro Studi Psichatrici Vrije Universiteit Brussel, Université Catholique de Louvain & the Bedfordshire Centre for Mental Health Research. The talk aimed to present a brief taster, assuming no prior knowledge, of adult neurogenesis, the formation of new nerve cells, in relation to the aetiology and treatment of depression. The talk begins with an introduction to the principles of adult neurogenesis: from initial investigations by Ramon y Cajal in the 19th century, resulting in a "static brain hypothesis", to their subsequent challenge almost one hundred years later. The potential functional implications emerging, especially in relation to depression, are explored. The fascinating effects of corticosteroids and antidepressants are used as examples to explore the possible roles of neurogenesis that have led some to propose a neurogenic theory of depression. Arguments against this theory are then presented. Finally, a consideration of future opinion: could neurogenesis be less important in the aetiology of depression, but involved in its treatment - a property of antidepressant action rather than a central final aetiological pathway. In this young branch of neuroscience controversy abounds: our understanding of the process itself, its relations and most importantly its implications are all in their infancy. This has allowed for some of the most interesting debate of recent years as to the neurological basis and treatment of affective disorders.
Using non-steroidal anti-inflammatory drugs in the treatment of depression.
BACKGROUND: clinicians have long noticed a correlation between physiological markers of inflammation and depression. The best-known example is the activation of the hypothalamus-pituitary-adrenal axis and cortisol secretion; however more recent studies have demonstrated increased salivary prostaglandins and plasma acute phase proteins in depressed patients. To date four randomised controlled trials have used celecoxib or rofecoxib as adjuncts to serotonin selective reuptake inhibitors in the treatment of depression. These suggested a statistically significant decrease in depressive symptoms in the patients taking NSAIDs and SSRIs, compared to patients taking SSRIs alone. Interpretation of these results is limited by the small sample size and short duration of these preliminary studies. The research only considers depressed patients receiving treatment in secondary care; no study has examined the effectiveness of NSAIDs as an adjunct in primary care, even though most cases of depression in the UK are managed in the community by general practitioners. PROPOSAL: we propose a multi-centre double-blinded randomised controlled trial with two objectives: to determine whether citalopram plus celecoxib dual therapy achieves a greater reduction in depressive symptoms (quantified using the Hamilton Depression Rating Scale (HDRS)) within four weeks, compared to citalopram monotherapy; and to determine whether citalopram plus celecoxib dual therapy is more likely to achieve remission (HDRS score ?7) of moderate to severe depression within six months, compared with citalopram monotherapy. The endpoints will be the reduction in HDRS score after 4 weeks of treatment, and the HDRS score after 26 weeks of treatment. The study will enrol 452 participants from general practices who have a moderate or severe, current or recurrent major depressive episode when medication with an SSRI is considered. The study population will be stratified according to age, sex, HDRS score, age of onset of first episode, number of previous depressive episodes and duration of current episode. The population will then be randomised into two groups. Subjects will be interviewed to determine HDRS score, measure blood pressure, count pills and discuss side-effects. This will occur weekly for the first four weeks, and every four weeks thereafter.
What do large scale studies of medication in schizophrenia add to our management strategies?
INTRODUCTION: A number of large naturalistic trials have reported in recent years comparing second generation antipsychotic drugs with their predecessors. The conclusions they draw have rightly sparked much debate, but are these studies truly comparable? If not, which of them are most methodologically robust and are these the studies most suitable as a foundation for clinical care guidelines with a strong evidence base. We aimed to conduct a review of the current literature to establish the appropriateness of several recent major clinical studies being used as the basis for clinical guidelines. METHOD: A literature search using the PUBMED database was carried out. Five major studies comparing antipsychotic efficacy were selected as possible candidates and subjected to further analysis. The studies were: * CUTLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia study); * CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness study); * SOHO (Schizophrenia outpatients Health Outcomes study); * CAFE (Comparison of Atypicals in First Episode study); * EUFEST (European First Episode Schizophrenia Trial). DISCUSSION: The trials: * CAFE - the trial, although well randomised and blinded, uses discontinuation as a primary endpoint - this is hard to draw conclusions from: patients may discontinue due to side effects, due to lack of efficacy or with against medical advice for a multitude of reasons. As a secondary endpoint, the study does make use of a PANSS scoring system to measure efficacy, adding some weight to the conclusion that olanzapine, quetiaine and risperidone in early psychosis patients have equivalent efficacies. * CATIE - This trial was a comparative study, and so lacked a control arm and used discontinuation of medication an inverse measure of efficacy - an easily quantifiable event, but making for difficult interpretation. However most criticism has been directed at the unusually low (quitiapine, ziprasidone) and high (olanzapine and perphenazine) doses of drug used, which were reflected in their differing rates of efficacy. * CUtLASS This trial allows for less generalisation of its findings to the general population as it makes use a specific sub-population (those switching from one medication to another after a period of treatment). Also some patients were prescribed oral medications and some depot injections - making comparisons difficult due to possible differences in compliance. * EUFEST This trial makes use of discontinuation as an endpoint with the weaknesses we have described. Treatment of first episodes of psychosis is shown to be feasible, but it could not suggest if haloperidol or second generation drugs may be more efficacious. * SOHO - This trial hindered by the observational design of the study and small numbers reaching the primary end point (4%) caution should be exercised in the conclusion that olanzapine is superior to risperidone, quetiapine or typical antipsychotics. CONCLUSION: There is much information useful for clinical practice to be gathered from the results of these major studies, however, interpretation is hampered by both variations and weakness in study design. On balance it does appear that different antipsychotics possess differing efficacy, but also of relevance to the development of sound clinical guidelines is their differing side effects profile.
Suicide risk and choice of antidepressant.
INTRODUCTION: There is presently concern that patients treated for depression with venlafaxine have a higher suicide rate than those treated with other antidepressants, based on results from observational studies. The aim of this study was to determine whether higher suicide risk, defined as previous suicide attempt or suicidal ideation, influenced the choice of antidepressant prescribed in an outpatient mental health unit, the Bedford East Community Mental Health Team. SUBJECTS AND METHOD: A database held by a the Community Mental Health Team was used to identify patients with Depression who have been treated with Venlafaxine, Citalopram, and patients diagnosed with bipolar II affective disorder. The data was analysed in terms of presence of suicide risk, gender, and whether bipolar II patients on venlafaxine were treated with mood stabilisers. RESULTS: The results showed that a risk of suicide did not prevent the prescription of venlafaxine, that less venlafaxine was prescribed to male patients than females, and that bipolar II patients were indeed treated with mood stabilisers. DISCUSSION: It appears that in this Community Mental Health Team, the possibility of suicide risk with venlafaxine therapy is considered and appropriately managed. CONCLUSION: Early diagnosis and appropriate treatment of bipolar disorder is likely to be the most effective step that we can take to reduce the risk of suicide in patients with bipolar disorder .Appropriate care regarding the judicious use of Venlafaxine as a first line treatment in Unipolar Depression is secondary to this.
Early warning score adjusted for age to predict the composite outcome of mortality, cardiac arrest or unplanned intensive care unit admission using observational vital-sign data: a multicentre development and validation
<jats:sec><jats:title>Objectives</jats:title><jats:p>Early warning scores (EWS) alerting for in-hospital deterioration are commonly developed using routinely collected vital-sign data from the whole in-hospital population. As these in-hospital populations are dominated by those over the age of 45 years, resultant scores may perform less well in younger age groups. We developed and validated an age-specific early warning score (ASEWS) derived from statistical distributions of vital signs.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Observational cohort study.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>Oxford University Hospitals (OUH) July 2013 to March 2018 and Portsmouth Hospitals (PH) NHS Trust January 2010 to March 2017 within the Hospital Alerting Via Electronic Noticeboard database.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Hospitalised patients with electronically documented vital-sign observations</jats:p></jats:sec><jats:sec><jats:title>Outcome</jats:title><jats:p>Composite outcome of unplanned intensive care unit admission, mortality and cardiac arrest.</jats:p></jats:sec><jats:sec><jats:title>Methods and results</jats:title><jats:p>Statistical distributions of vital signs were used to develop an ASEWS to predict the composite outcome within 24 hours. The OUH development set consisted of 2 538 099 vital-sign observation sets from 142 806 admissions (mean age (SD): 59.8 (20.3)). We compared the performance of ASEWS to the National Early Warning Score (NEWS) and our previous EWS (MCEWS) on an OUH validation set consisting of 581 571 observation sets from 25 407 emergency admissions (mean age (SD): 63.0 (21.4)) and a PH validation set consisting of 5 865 997 observation sets from 233 632 emergency admissions (mean age (SD): 64.3 (21.1)). ASEWS performed better in the 16–45 years age group in the OUH validation set (AUROC 0.820 (95% CI 0.815 to 0.824)) and PH validation set (AUROC 0.840 (95% CI 0.839 to 0.841)) than NEWS (AUROC 0.763 (95% CI 0.758 to 0.768) and AUROC 0.836 (95% CI 0.835 to 0.838) respectively) and MCEWS (AUROC 0.808 (95% CI 0.803 to 0.812) and AUROC 0.833 (95% CI 0.831 to 0.834) respectively). Differences in performance were not consistent in the elder age group.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Accounting for age-related vital sign changes can more accurately detect deterioration in younger patients.</jats:p></jats:sec>