Professor Declan McLoughlin

Figure 1 Gross neuropathology of Alzheimer’s disease. Coronal slices through the brains of two 75-year persons, one with a 7- year history of dementia due to Alzheimer’s disease (AD) and the other from a non-demented person (N). In the AD case there is evidence of severe cortical atrophy due to neuronal loss and shrinkage plus associated ventricular dilatation.

Prof McLoughlin took up the new post of Research Professor of Psychiatry on July 1, 2007. Prior to this I was a Senior Lecturer in the MRC Centre for Neurodegeneration Research at the Institute of Psychiatry, King’s College London, where I have been investigating the neuronal signalling function of the Alzheimer’s disease amyloid precursor protein (APP) and was among the first to identify the FE65 and X11 adaptor proteins as APPbinding partners (2, 5; Fig 2). To study their functions in vivo, we have made X11 transgenic mice and have demonstrated that the X11s regulate APP processing and reduce cerebral Ab production and deposition.

Figure 2 The APP/X11/FE65 protein network. Members of the X11 and FE65 families of adaptor proteins interact with the APP intracellular domain (AICD) via their PTB (phosphotyrosine binding) domains. Through other interaction domains (e.g. WW and PDZ domains), these adaptor proteins also bind with a wide range of other proteins and provide “scaffolding” for the formation of multi-protein complexes.

Figure 3 Randomised controlled trial of ECT and rTMS for severe depression. Severely depressed patients were randomly allocated to a standard course of ECT or to three weeks of daily rTMS sessions. The graph shows predicted mean Hamilton Depression Rating Scale (HDRS) scores per treatment arm (ECT, n=22; rTMS, n=24) and posttreatment time points, adjusted to sample average baseline values, with 95% confidence intervals. The higher the HDRS score is, the more depressed the patient. HDRS scores at the end of the allocated treatment course were significantly lower in the ECT group than in the rTMS group (p=0.002) and the remission rate was significantly higher in the ECT group (59%) compared to the rTMS group (17%). At the six month follow-up there was no difference between the two groups. These data demonstrate that ECT is superior to rTMS for the acute treatment of severe depression.

On the clinical side, I have also been leading randomised controlled trials of therapeutic neuromodulation techniques (e.g. transcranial magnetic stimulation, electroconvulsive therapy) for neuropsychiatric disorders such as depression and schizophrenia (1, 3, 4; Fig 3). In St Patrick’s Hospital and TCD, we are about to start a 5-year research programme called the EFFECT-Dep Study (enhancing the effectiveness of electroconvulsive therapy in severe depression and understanding its molecular mechanism of action). This programme is supported by a HRB Translational Research Award and its purpose is to improve ECT practice and use it to interrogate the molecular neurobiology of depression. We will carry out a definitive randomised controlled trial comparing bilateral and high-dose unilateral ECT, recruiting 140 patients with severe depression. We will also use an animal model of ECT treatment to characterise changes in global protein expression (i.e. the proteome) in both brain and blood plasma and also carry out similar studies using plasma from depressed patients recruited into the clinical trial. The results of these studies will improve clinical ECT and also help us understand better the molecular mechanism of action of ECT, as well as antidepressant drugs, and lead to identification of candidate peripheral biomarkers for depression, treatment response and depression relapse.

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