Inaugural Lecture of Professor Declan McLoughlin, Research Professor of Psychiatry Outlines New Research in the Treatment of Depression and Alzheimer’s Disease
Posted on: 04 June 2009
“About 1,000 patients are treated annually with electroconvulsive therapy (ECT) in Ireland and about 1 million worldwide. The most common indication is severe treatment-resistant depression. However, use of ECT is limited by stigma and genuine concerns about side-effects, especially upon memory function. There is thus a pressing need to improve ECT to reduce side-effects while maintaining its undoubted effectiveness”, stated Research Professor of Psychiatry, Professor Declan McLoughlin at Trinity College Dublin’s School of Medicine’s Psychiatry Department, and St Patrick’s University Hospital, on the occasion of his recent inaugural lecture. The lecture titled ‘Molecules, Magnetism and Electricity: New Adventures in Hi-Psychiatry’ showcased his research in the treatment of depression and Alzheimer’s disease.
“Alzheimer’s disease, the major cause of dementia, and depression are two of the most common mental health disorders. 40,000 people in Ireland have dementia and this will double over coming decades due to the increasing elderly population. By 2020 major depression will be the world’s second most debilitating illness. In Ireland 300,000 people each year suffer from depression with 10,000 hospitalisations. Recurring episodes are associated with increasing risk of chronicity, psychosocial impairment, and suicide. The cost of depression has been estimated at 1% of total European economy. Understanding the molecular pathology underlying these disorders is essential to developing rational treatments”.
“Introduced over 70 years ago, ECT remains the most powerful treatment available for severe depression. Many advances have been made in ECT practice and understanding its mechanism of action. To develop the treatment further, we have started a randomised trial comparing two different forms of ECT (i.e. standard bilateral ECT versus high-dose unilateral ECT) with a one year follow-up. We are particularly interested in the effects of ECT on retrospective memory function, i.e. the ability to recall previously established memories, e.g. what I did last Christmas, etc. To tease out the effects of depression itself, as well as passage of time, we are also studying retrospective memory function in depressed patients not receiving ECT and matched controls over a one year period. Together, these studies will help us refine ECT practice and minimise side-effects”.
“There is no obvious brain pathology to provide a focus for understanding the molecular neurobiology of depression. However, functional brain imaging and neuropsychology studies have revealed abnormalities in neuronal circuitry within the brain in depression. One therapeutic approach, therefore, is to target implicated brain circuitry to restore normal function. Transcranial magnetic stimulation (TMS) is a non-invasive technique that allows focal stimulation of the brain. We have completed randomised trials of TMS for severe depression in which we compared real versus sham TMS and also real TMS versus electroconvulsive therapy. While the results with TMS were disappointing, the trials confirmed the remarkable effectiveness of ECT for treating severe depression”.
“Basic scientific research has provided crucial insights into the molecular mechanism of action of effective antidepressant treatments. More so than drugs, ECT is a profound inducer of growth factors in the brain and also new nerve cell formation in the hippocampus, a region of the brain important for mood regulation and memory formation and which has been found to be shrunken in depression. Thus, understanding the molecular mechanism of action of ECT is providing an entry into the molecular neurobiology of depression. To investigate this further we are performing detailed “proteomic” studies to characterise the effects of ECT on total protein expression within the brain. In parallel, we are also using this proteomic approach to study blood samples from patients with depression. Our expectation is that these basic studies will translate into clinical biomarkers, e.g. a simple blood test, to aid diagnosis and treatment of depression”.
“Unlike depression, Alzheimer’s disease has well-defined microscopic brain pathologies, such as amyloid plaques, that provide a focus for investigation. Amyloid plaques are comprised of a small protein fragment called -amyloid peptide (A) that is derived from the amyloid precursor protein (APP). Rare mutations in the gene for APP are inheritable causes of Alzheimer’s disease. It is generally believed that abnormalities in processing of APP and production of A are central molecular events in Alzheimer’s disease”.
“To help us further understand Alzheimer’s disease, we identified several novel proteins that interact with APP. One of these is called X11 Using animal models we overexpressed X11and used these to investigate its effect upon APP processing in an Alzheimer mouse model. We found that X11 significantly reduces A and amyloid plaques in the brains of Alzheimer mice. Recently, and most importantly, we have demonstrated that these biochemical changes are associated with major improvements in both nerve cell function and memory loss, a key symptom of dementia. Thus the X11 proteins may be useful therapeutic targets for Alzheimer’s disease and current work is addressing this issue. “
Extracts from a public lecture by Professor Declan McLoughlin on the occasion of his inaugural lecture as Research Professor of Psychiatry . Professor McLoughlin was promoted to the Professorship in 2007. Professor McLoughlin’s research work is supported by grants from Health Research Board, Alzheimer’s Society, Alzheimer’s Research Trust, and Wellcome Trust.