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 thereafte

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

From Transcriptomics to Treatment in Inherited Optic Neuropathies.

Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process-implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies

From Transcriptomics to Treatment in Inherited Optic Neuropathies.

Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process-implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies

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

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

Comparing optogenetic approaches to visual restoration in a model of retinal degeneration

The inherited retinal degenerations (IRDs) are the most common cause of irreversible visual loss in the young - but therapeutic options have traditionally been limited. While genetically heterogeneous, the IRDs are linked by a final common pathway of visual loss secondary to photoreceptor death, with cells of the neural retina surviving relatively intact. The technique of optogenetics (inducing light sensitivity by exogenous expression of light sensitive proteins within cells) is developing as a therapeutic method to stimulate these surviving cells: returning light signals to the degenerate retina and ultimately restoring lost vision. The aim of this thesis was to compare different optogenetic tools and cellular targets for optogenetic visual restoration in a model of inherited retinal degeneration in order to inform future translational work. Three novel mouse models of retinal degeneration, additionally devoid of native melanopsin and incorporating cell specific Cre recombinase expression were devolved and validated to allow cell population specific targeting of genetic constructs both delivered transgenically and by using intravitreal injections of adenoassociated viral vectors (AAVs). These models were used to isolate ON-bipolar cells from dissociated degenerate retina in the first comparison of gene expression profiles in such cells to their wildtype counterparts. This demonstrated a lack of changes likely to preclude these attractive cellular targets for therapeutic optogenetics. Cell targeted delivery of a candidate optogenetic tool (melanopsin) using these models was compared to conventional (non-specific) AAV delivery. This showed restoration of retinal electrophysiological light responses on ex vivo multiple electrode array recordings with kinetics differing between delivery approaches. Targeted delivery of three candidate tools (melanopsin, rhodopsin and ReaChR- channelrhodopsin) were similarly compared with markedly differing response characteristics demonstrated between tools Finally, translatable, compressed ON-bipolar cell specific promotors were used to produce a potentially translatable cell specific AAV delivery system. This was demonstrated to successfully deliver functional optogenetic tools to a degenerate retina in vivo. Together, these data indicate that the described mouse lines form a useful model system with which to compare optogenetic vision restoration approaches. In addition, while no one optogenetic tool or target was demonstrated to be overall superior to another, the diversity of responses seen could in themselves represent a great opportunity to improve the quality of responses restored by this technique as it moves towards clinical translation for the treatment of inherited retinal degenerations