Neurobiology of resilience to depression

Depression is the most common mental health problem, affecting as many as 1 in 5 people during their lives. It is a significant economic and social burden as well as causing distress to affected individuals and their families. Although a number of factors are involved in causing depression, we know that experiencing stressful life events triggers many depressive episodes. By contrast, there are individuals who can experience large amounts of life stress without becoming depressed, a trait called resilience. We know very little about the reasons why some people are more resilient than others. This research will use modern techniques to investigate whether there is an identifiable brain basis for resilience. If a distinct profile associated with resilience exists, this has potential implications for developing therapeutic approaches that could help prevent people with major life stress from developing depression.

Resilience in the face of stressful life events is an important concept for understanding and managing depression. Promoting resilience in people at risk of depression has implications for prevention of depressive episodes. This proposal aims to use neuropsychological and neuroimaging techniques to characterise the neurobiological profile associated with resilient individuals. We will capitalise on our existing database of 2004 subjects recruited in the Manchester community with depression history and life stress information recorded. Using this database we will recruit groups of subjects with and without significant life stress and with and without depression. More detailed interviews will allow us to characterize five groups with differing degrees of resilience and vulnerability to life stress. 40 subjects in each group will complete a thorough neuropsychological assessment using tests specifically targeting putative resilience mechanisms identified in research at the University of Cambridge. A subset of 20 subjects from each group will be scanned using functional magnetic resonance imaging (fMRI) with cognitive challenge tasks. These tasks have been chosen to probe both specific cognitive processes and the functioning of specific brain regions (limbic system and medial prefrontal cortex). Finally we will perform a pharmacological challenge in resilient and vulnerable groups, using acute tryptophan depletion to lower brain serotonin. Following this manipulation, subjects will undergo the same neuropsychological and neuroimaging procedures to determine whether resilient responses are modulated by brain serotonin levels. Planned comparisons between the groups will allow us to test hypotheses about the cognitive mechanisms of resilience and determine whether there is a distinct neurobiological profile associated with this trait. This would represent a potential biomarker for pharmacological and psychological interventions in individuals at risk for depression due to significant life stress.