The most widely-accepted account of the relationship between stress and depression is the "Stress-Diasthesis" model, which links chronic adverse environmental events with the presence of specific genes to engender elevated responses in bodily systems that are related to survival of the organism under conditions of major threat (eg, the Sympatho-Adrenal-Medullary axis and the Hypothalamic-Pituitary-Adrenal axis). Despite their immediate value to the organism, the continued elevation of the SAM and HPA axes has been shown to contribute to development of many physical diseases and also to anxiety and depression.

In terms of genetic factors, it has been convincingly established for some time that having relatives with depression is a major risk factor for development of that disorder. For example, family studies of depression reliably produce a figure of up to 80% heritability, with some data identifying specific alleles that are responsible for parent-child transmission of a tendency to develop depression under adverse environmental conditions. Environmental factors that elicit exaggerated SAM and HPA axes responses (and lead to depression) in people with specific genetic characteristics have yet to be comprehensibly identified, although there are some links between early childhood deprivation and hyperactivation of genes which control one of the outcomes of the HPA axis (cortisol).

Changes in heart rate and skin conductance are reliable methods of measuring SAM responses to stressors, and cortisol is the recognised biomarker for stress in the HPA axis. Although cortisol can be measured in saliva, blood or urine, a new way of collecting cortisol is via hair, which is relatively non-invasive and may also constitute a record of ongoing stressor reactivity over time (unlike saliva, blood or urine).

(1) Genetic Factors: The Role of Polymorphisms in the serotonin transporter gene:
Most genes have different forms, called 'polymorphisms', which produce slightly different phenotypes and thereby promote phenotypic diversity among a given population. There may be many of these polymorphisms for each particular gene, with only one or two of those polymorphisms causing significantly different outcomes in the organism. The gene SCL6A4 encodes the serotonin transporter protein 5-HTT, which carries serotonin away from the synapse after a nerve has transmitted a signal across that synapse. In humans, SCL6A4 resides on chromosome 17q11.1, but its ability to encode 5-HTT is influenced by the presence of the coding sequence 5-HTTLPR in the upstream transcriptional control region.

The 5-HTTLPR polymorphism of the gene SCL6A4 gene may occur in 'short' (s) or 'long' (l) forms, referring to the number of base pairs (the components of DNA) in each form. The short form has 44 fewer base pairs than the long form. In humans, a person may carry a single short form (s), a single long form (l), a combination of each (sl), or double short (ss) or long (ll) forms. The short (s) form polymorphism of 5-HTTLPR restricts the transcriptional activity of the promoter, producing low functional expression of SCL6A4 and hence lowering 5-HTT and reducing serotonin reuptake; the long (l) form does not have this effect.

(2) Environmental stressors:
By examining the kinds of environmental events and changes that are associated with development of anxiety and depression among different populations, the commonality of those events may be determined. To do this, we have used samples of breast cancer patients, prostate cancer patients, university students, and parents of children with an Autism Spectrum Disorder. Each of these populations has experienced a major but different range of stressors, and our investigations have identified the specific kinds of stressors which are associated with anxiety and depression in these populations. From that data, we can build a model of what constitutes the kind of environmental stressor that is likely to interact with the ss form of the 5-HTTLPR to result in depression.

(3) Subtypes of depression: Although commonly used as a unitary construct, depression can be subdivided into various subtypes such as melancholic depression, cognitive depression, somatic depression, anhedonic depression, atypical depression and subsyndromal depression. These appear to be associated with different stressors, and the links between these different stressors, different types of depression, and the ss form of the 5-HTTLPR polymorphism are being investigated.

(4) Use of hair cortisol as an indicator of immediate and chronic stress: To elaborate on the ways in which hair cortisol responds to short-term and chronic stress, we are currently "mapping" the effects of gender, age, body site, type of stressor (acute vs chronic, brief vs long, physical vs psychological stressors) upon hair cortisol, and the presence of variation in cortisol concentration over diurnal periods. Part of this work with hair cortisol is also focussed upon the confusion as to whether cortisol concentrations in human hair decrease over time to reach a stable low or 'basal' level, or whether they continue to react immediately and frequently to environmental threats of long or short duration. That is, is the hair shaft a dynamic or static environment for cortisol-do concentrations change quickly and transitorily with stressor intensity?