Teléfonos móviles de tercera generación: voz y datos digitales

Stressful life events can precipitate major depression and influence its onset and course (Kessler, 1997; Kendler et al. 1999; Pine et al. 2002). However, the majority of people do not become depressed after a stressful experience. Exposure to extremely stressful events, such as combat, can result in post-traumatic stress disorder (PTSD), a disorder distinct from depression (Nestler et al. 2002). The response to stress shares many features with depression due to their action on similar brain circuits (Gold and Chrousos, 1999). Therefore, while the development of depression can be related to exposure to stressors in susceptible individuals (Caspi et al. 2003), stress exposure alone is not sufficient to cause depression (Nestler et al. 2002).

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1.5.2.1 The HPA axis

The brain reacts to acute and chronic stress by activation of the HPA axis (Figure 1-3). Hypothalamic paraventricular nuclei neurons secrete corticotrophin-releasing hormone (CRH) stimulating the synthesis and release of adrenocorticotrophin (ACTH) from the anterior pituitary. ACTH in turn stimulates the adrenal cortex and the release of glucocorticoids (Nestler et al. 2002). Glucocorticoids profoundly affect behaviour by interacting directly with different brain regions, including the HPA axis. They are responsible for feedback inhibition on CRH in the hypothalamus and ACTH in the pituitary (Pariante and Lightman, 2008). The HPA axis is controlled by the hippocampus and amygdala, which have inhibitory and excitatory influences respectively.

1.5.2.2 HPA axis dysfunction in depression

HPA axis dysfunction is a biological feature in many depressed patients (Gold and Chrousos, 2002). Hyperactivity of the HPA axis is commonly detected in depressed patients. As the HPA axis is activated in response to stress, a major precipitating factor to depression, the mechanisms underlying HPA axis abnormality are of interest. HPA axis dysfunction is no longer considered to be just an epiphenomenon of this disorder (Pariante, 2003). A greater understanding of this stress response system and its central role in depression may be essential to understand the neurobiology of depression.

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Figure 1-3 The HPA axis

Glucocorticoid release from the adrenal glands forms a negative feedback loop which may be disregulated in depression. The HPA Axis is also regulated by the hippocampus and amygdala.

HPA, hypothalamic pituitary adrenal axis; CRH, corticotrophin releasing hormone; ACTH, adrenocorticotropin.

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Impaired glucocorticoid negative feedback may be related to hyperactivity of the HPA axis. Cortisol, an endogenous glucocorticoid, is present in significantly higher levels in plasma of depressed patients compared to controls (Rubin et al. 1996). Waking salivary cortisol levels are also higher in depression (Bhagwagar et al. 2005). CRH levels in CSF

are higher in depressed patients (Nemeroff et al. 1984). In dexamethasone/corticotrophin-

releasing hormone (DEX/CRH) tests (a sensitive challenge test of HPA axis function), patients with depression release significantly more ACTH and cortisol compared to matched controls, suggesting an alteration in glucocorticoid feedback regulation (Heuser et al. 1994). The hypersecretion of cortisol can be resistant to feedback suppression by dexamethasone, a potent synthetic corticosteroid which depresses ACTH secretion (Kandel et al. 2000).

1.5.2.3 Changes in volume of HPA axis glands

There is also some evidence that pituitary and adrenal gland volume is increased in depressed patients (Kessing et al. 2011). The increase seen in pituitary volume may provide evidence of impairment in the HPA axis; inefficient negative glucocorticoid feedback on the pituitary cells that produce ACTH leads to an increase in the number of those cells (Pariante et al. 2005). In healthy control subjects, adrenal volume correlates positively with dexamethasone suppressed salivary cortisol and total salivary cortisol (Golden et al. 2007) suggesting that increased adrenal gland volume may indicate subclinical hypercortisolism (Kessing et al. 2011). While studies have shown an increase in adrenal gland volume associated with depressed patients compared to controls (Nemeroff et al. 1992; Rubin et al. 1996), it has also been argued that there is no real relationship between adrenal gland size and measures of the HPA axis function in depression; factors other than ACTH may play a role in increasing adrenal gland size but not increasing corticoid production (Rubin et al. 1996).

1.5.2.4 Antidepressants normalise HPA axis dysfunction

Antidepressant treatment is associated with resolving the impaired negative feedback on the HPA axis by glucocorticoids (Heuser et al. 1996; Pariante, 2006).

Glucocorticoid action is mediated by the glucocorticoid receptor (GR). GR levels were reduced in the brains of depressed patients’ post-mortem (Webster and Carlstedt- Duke, 2002). GR function is also impaired in depression (Pariante, 2004). Antidepressant treatment normalises this effect. For example, citalopram, an SSRI, has been shown to increase HPA axis negative feedback by glucocorticoids (Pariante et al. 2004).

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1.5.2.4.1 Effect of ECT on the HPA axis in depression

The changes in the HPA axis in depression were normalised by ECT treatment (Yuuki et al. 2005). Treatment with ECT decreased the pituitary-adrenocortical response of depressed patients, which were increased compared to controls, in the DEX/CRH test (Kunugi et al. 2006). Higher value results in the DEX/CRH test in depressed patients could be used to detect patients at greater risk of relapse than patients who had better-improved cortisol response (Aubry et al. 2007). A meta-analysis study determined the mean effect of antidepressant treatment on pre- and post- treatment cortisol levels in patients was not significantly different between ECT and pharmacotherapy (McKay, 2010). In animals, ECS treatment increased neuronal activation and endothelial cell proliferation in the paraventricular, supraoptic and ventromedial nuclei of the hypothalamus. An angiogenic response to ECT may counteract hypothalamic dysfunction in depression (Jansson et al. 2006).

1.5.2.5 Summary

The HPA axis is dysregulated in a proportion of depressed people (Mello et al. 2007). However, antidepressant treatment appears to normalise HPA axis dysfunction. Changes in the volume of structures of the HPA axis have been investigated in imaging studies to further determine their potential role in depression. The role of volume changes in the HPA axis is not yet well understood. While HPA axis dysfunction may contribute to depression in some patients its overall contribution to the aetiology of depression is yet to be fully elucidated.