Neurobiology of depression – examining resilience to stress

Stress is part of living. Stress shows us to be sophisticated. Our adaptive responses in cognitive and emotional behaviour in the face of stress, are what distinguish humans from animals. Yet some stressors can prove overwhelming, driving stress-induced depression.

Speaking during an APA symposium, Professor Gustavo Tafet of the Maimondes University Department of Psychiatry and Neurobiology in Buenos Aires, Argentina, described the efforts psychiatrists are making to understand why some people are more resilient than others to stress. By characterizing the neurobiological and psychosocial basis of stress-resilience, clues might be found to help in the management of depression.

Adapt and cope

Professor Tafet reminded delegates that whether stress is bio-ecological or psychosocial, the body has two main means of coping: through adaptive responses mediated by neuronal networks, and through neuroendocrine responses mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis.

Helplessness a gateway to depression

He said that resilience is the ability to continually adapt successfully to stress and to cope with adversity. Without such resilience, too much chronic stress can lead to “learned helplessness” – which he said can be a gateway to depression. In learned helplessness, cognitive resources are decreased, while in resilience, cognitive resources are employed to cope, recover and learn from stress.

In our make-up

Professor Tafet said that early life adversity may play a part in eroding resilience, by generating what he described as a ‘kind of trauma’ in the long-term memory that makes a person more prone or vulnerable to depression in later life. Beliefs and self-knowledge also shape our resilience or susceptibility to stress and more unavoidably – our genes play a part too.

Many polymorphisms have been identified that are linked with increased vulnerability or greater resilience to depression. For example, Professor Tafet said that genetic polymorphisms in the serotonin transporter gene (5HTT) are associated with increased activation of the HPA axis and increases in cortisol - so increasing stress, and he said that polymorphisms in BDNF have been shown to affect neurogenesis and plasticity in ways that affect cognitive processing and the ability to cope with stress. People with both of these polymorphisms are at increased risk for depression especially if exposed to life stresses.

Professor Tafet said that polymorphisms of the chaperone protein to glucocorticoid receptors render cortisol less effective, leading to a deficient negative feedback on HPA axis activity, and so increasing stress and predisposing towards MDD.

Endogenous sources of resilience

Certain physiological substances may be important for resilience to stress. Professor Tafet said that the naturally occurring glucocorticoid DHEA blocks the effects of cortisol, and neuropeptide Y is another endogenous substance which has been shown to have anxiolytic properties.

Stress and psychosis in depression

Speaking during the same APA symposium, Professor Alan Schatzberg of the Department of Psychiatry at Stanford University Medical School, provided additional insights on the role played by cortisol in stress, and reminded delegates that in the past, attempts had been made to manage certain forms of depression by using cortisol-blocking agents.

Professor Schatzberg said that in patients with depression – increased levels of glucocorticoids – hypercortisolism – may play a role in the development of psychosis, possibly mediated by cortisol induced changes to the regulation of dopaminergic function. He said that although the reported number of MDD patients with depression plus psychosis is quite low, epidemiological studies suggest that as many as 1 in 5 MDD patients have psychotic features.

Once again, genes appear to play a part. Professor Schatzberg said that certain variants for the glucocorticoid receptor contribute to risk for depression and to a degree of psychosis.

Mental flexibility and attitude is everything

Both Professor Tafet and Professor Schatzberg, also described the psychosocial factors and characteristics that are thought to engender stress resilience – features such as optimism, humour, cognitive flexibility, abilty to perceive stressful events in less threatening ways and a mixture of altruism and what Professor Tafet described as healthy egotism.

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