Structural and neurocognitive correlates of treatment resistant depression: From acute illness to symptomatic recovery.
2017-02-14T00:24:09Z (GMT) by
Major depressive disorder (MDD) is a widespread chronic, debilitating and difficult to treat psychiatric disorder that is often resistant to treatment with standard approaches. Despite an enormous amount of research effort, much still remains unknown about the underpinnings of persistent treatment non-response. Neuroimaging studies have linked a number of structural brain abnormalities, in particular volume reductions of medial temporal lobe (MTL) structures the hippocampus and amygdala to inferior treatment response. Preclinical evidence, however, has shown hippocampal and amygdalar neurogenesis following successful antidepressant treatment, highlighting the importance of these structures in modulating treatment outcomes. The role of related structures such as the entorhinal cortex and the impact of MTL abnormalities on neurocognitive function has not been systematically investigated. However, improvements in MTL dependent episodic memory deficits have been consistently found upon symptomatic remission. Taken together, these findings suggest that MTL structural abnormalities and episodic memory deficits are potentially reversible with successful response to antidepressant treatment, providing a strong impetus for further investigation. Repetitive transcranial magnetic stimulation (rTMS) is an innovative brain stimulation technique that has proven antidepressant efficacy in treatment resistant MDD (TRD) populations. Whether structural abnormalities and neurocognitive deficits resolve upon antidepressant response to rTMS treatment is yet to be conclusively investigated. Recent evidence, however, suggests that rTMS may hold similar potential as antidepressant pharmacotherapy in promoting neurogenesis in the hippocampus and surrounding structures. Thereby, investigation of structural and functional changes during an acute major depressive episode and following treatment response/non-response may provide critical insights into the neural circuitry of treatment resistance and may aid in the identification of unique markers of differential response outcomes to treatment. The current thesis therefore aimed to further our understanding of the pathophysiology of MDD by investigating the structural and neurocognitive correlates depressive illness in a more homogeneous patient group characterised by severe TRD before and after treatment with rTMS. To that end, a series of studies were undertaken that focussed on MTL structures as well as related deficits in MTL dependent episodic memory processes in order to a) determine the neurobiological correlates of TRD and whether these could be used to predict treatment response and b) prospectively investigate the differential changes in structure and neurocognitive function as a consequence of antidepressant response or non-response. Specifically, the investigations focussed on the pathophysiological correlates of antidepressant response to rTMS, which also allowed exploration of whether rTMS holds similar neuroplastic potential as other antidepressant treatment modalities. The aims of the current thesis were partially achieved. The investigations were able to elucidate a specific pattern of neurocognitive impairment in TRD characterised by deficits in attention, processing speed and aspects of executive function. A relationship between structural pre-treatment MTL volumes and antidepressant response to rTMS treatment was also identified but of insufficient strength to have statistical value as a predictor of favourable treatment outcome. Finally, successful attainment of antidepressant response to rTMS several months post treatment was found to hold neuroprotective potential in preventing further cell loss in MTL volumes. The main findings of this thesis, however, were limited by a small sample size and subsequently inadequate study power. Therefore although preliminary, the findings have contributed towards our understanding of the pathophysiological underpinnings of treatment resistance and indicate that TRD is a disorder within which neuronal plasticity is possible following successful response to antidepressant therapy. It is hoped that these findings will provide the impetus for future research, which may in time lead to more effective and targeted treatments for this devastating mental illness.