This month's topic:

Neuroendocrine markers in affective disorders

Specialist : José L. Ayuso Gutiérrez, MD, Ph D

Neuroendocrine disturbances are now increasingly considered pathophysiological changes, contributing to a better understanding of the biological basis of mood disorders.

For example, in depression, one of the most characteristic alterations is a disturbed regulation of the hypothalamus-pituitary-adrenal  (HPA) system. Here, dexamethasone—an exogenous steroid providing negative feedback to the pituitary gland to suppress the secretion of ACTH—has been widely used since the first publication of the Dexamethasone Suppression Test (DST) to assess HPA system regulation in patients with depression (1). DST non-suppression was originally associated with the melancholic and psychotic type of depression, and described as a state- dependent marker characteristic of the symptomatic phase of the disorder. However, its sensitivity and specificity are both rather low. Nearly 4-10 % of normal persons are reported to be DST non-suppressors. It seems that non-suppression gradually increases along a continuum: non-melancholic outpatients with major depression (12 % non-suppression) are at one pole, and severe melancholic inpatients with psychotic features are at the other (64 % non-suppression). On the other hand, non-suppression is often seen in non-affective disorders, such as panic disorder, schizophrenia, Alzheimer, borderline personality disorder and anorexia / bulimia. 

 
In depressive patients, a function test that combines pretreatment with dexamethasone and a challenge using corticotropin-releasing hormone (CRH) reveals a pathological increase in adrenocorticotropin and cortisol release. These changes partially persist after successful treatment with remission, and therefore, might be considered trait markers (2). This approach has shown (3) better diagnostic performance than the DST, with a sensitivity of 62 % for major depression in outpatients, and a specificity of 71 %.

In sum, although the use of DST and the combined dexa/CRH test in clinical settings is not common, these tests may have utility in certain situations (e.g., psychotic depression versus schizophrenia, predicting risk of relapse).   
Regarding the growth hormone, dysregulation of the hypothalamic-pituitary-somatotropic (HPS) function has been described in melancholic depressive inpatients with or without psychotic features.

A blunted GH response in the GHRH test was found in 62 % of the depressive sample, versus 31 % of the controls. The psychotic group exhibited stronger decreases in GH responses than the non-psychotic sample, but this difference was not significant (4). Blunted GH response has been also found in most studies with outpatients. However, this blunted response is not unique to depression, since it has also been reported in schizophrenia, GAD, mania, PTSD and normal populations. Therefore, the abnormalities found in GH regulation are of limited use for the clinician.  

Finally, the hypothalamus-pituitary-thyroid (HPT) axis dysfunction has been associated with pathophysiology in major depression. Moreover, thyroid hormones, particularly triiodothyronine (T3), have been in use for several decades as accelerators and augmenters of antidepressant response. The use of thyroid hormones to supplement antidepressants is based on evidence supporting a connection between thyroid function and depression.

In patients suffering from depression, higher than expected rates of subclinical hypothyroidism-associated with increased values of TSH-have been found, and subjects with subclinical hypothyroidism present a high prevalence of depressive disorders (5). Furthermore, primary hypothyroidism can be associated with mood disturbances, mainly depression, and a reduced response to antidepressants. In addition, subclinical hypothyroidism plays a role in the course of mood disorders. All these data suggest the utility of assessing the thyroid hormone profile in treatment-resistant depression and in patients with frequent relapses.

References

1.Carroll BJ, Martin FI, Davies B, Resistance to suppression by dexamethasone of plasma 11-O.H.C.S. levels in severe depressive illness. Br Med J  1968; 3 (5613):285-7.

2.Ising M et al. The Munich vulnerability study on affective disorders:premorbid neuroendocrine profile of affective high-risk probands. J Psychiatr Res 2005;39 (1):21-28.

3.Watson S et al. The dexa/CRH test, it is better than the DST?.Psychoneuroendocrinology  2006; 31 (7): 889-94.

4.Contreras F et al. Hormonal differences between psychotic and non-psychotic depression. J Affect Disord 2007; 100 (1-3): 65-72.

5.Demartini B  et al. Prevalence of depression in patients affected by subclinical hypothyroidism. Panminerva Med. 2010 Dec;52(4):277-82.

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