Spatial memory processes in bipolar depression :neuropsychological and HPA axis correlates

PhD ThesisBackground/ aims: Bipolar disorder is associated with significant impairment in a broad range of neuropsychological processes in addition to hypothalamic-pituitary-adrenal (HPA) axis dysfunction and hypercortisolaemia. As both animal and human models have highlighted the role of cortisol in the modulation of memory processes, attempting to understand this link is of critical importance. The aims of this thesis are to first profile neuropsychological and HPA axis function in individuals with a diagnosis of bipolar disorder, before examining if these functions can be altered through an intervention with an antiglucocorticoid drug. The subsequent chapters of this thesis will report analyses designed to explore specific aspects of these changes in more detail, principally alterations in spatial memory processes. Method: The thesis reports two broad phases of research. The first is a study of 20 participants diagnosed with bipolar disorder (with depressive symptoms) who first completed a broad neuropsychological assessment and profiling of afternoon cortisol and DHEA levels. These individuals then entered a randomised crossover study to examine the effects of mifepristone (RU-486), a glucocorticoid receptor antagonist, on neuropsychological functions and mood. A second cohort of 53 participants diagnosed with bipolar depression (BD) and 47 healthy controls was recruited to explore aspects of the results in more detail, particularly the fractionation of spatial memory and the integration of neuropsychological processes and their relationship with measures of HPA axis function. Results: 1) BD participants exhibited broad neuropsychological impairment across a range of cognitive domains in addition to hypercortisolaemia. 2) Administration of an antiglucocorticoid drug significantly reduced cortisol levels and improved spatial working memory performance. 3) The underlying neuropsychological component structure of BD and controls differed. 4) BD participants exhibited impairments in fine-grain metric spatial memory which, unlike other spatial processes, could not be explained by other measures. 5) A unique profile of processes underpinning aspects of visuospatial memory was observed in BD, suggesting a form of cognitive ‘scaffolding’. 6) A simple link between neuropsychological processes and peripheral HPA axis measures was not observed. Conclusion: Spatial memory processes in bipolar depression can be altered by direct HPA axis manipulation. A number of interesting avenues for future research have been identified that will further our knowledge of the integration between the biological mechanisms underlying neuropsychological impairment in mood disorders and should develop our understanding of integration between cognitive processes in general.Stanley Medical Research Institute, Medical Research Council: The Mental Health Foundation