The corticosteroid receptor hypothesis of depression.

The possibility that hypersecretion of corticotropin-releasing factor (CRF) contributes to the hyperactivity of the hypothalamo-pituitary-adrenal axis observed in patients with major depression was investigated by measuring the concentration of this peptide in cerebrospinal fluid of normal healthy volunteers and in drug-free patients with DSM-III diagnoses of major depression, schizophrenia, or dementia. When compared to the controls and the other diagnostic groups, the patients with major depression showed significantly increased cerebrospinal fluid concentrations of CRF-like immunoreactivity; in 11 of the 23 depressed patients this immunoreactivity was greater than the highest value in the normal controls. These findings are concordant with the hypothesis that CRF hypersecretion is, at least in part, responsible for the hyperactivity of the hypothalamo-pituitary-adrenal axis characteristic of major depression.

https://science.sciencemag.org/content/sci/226/4680/1342.full.pdf

Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients

http://clm.utexas.edu/mdlab/wp-content/uploads/2011/05/Neuron-2009-David.pdf

Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety/Depression

In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.

Cytokines and major depression.

OBJECTIVE: Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from de...

http://sites.oxy.edu/clint/physio/article/theroleofinsufficientglucocorticoidsignalinginstressrelateddisorders.pdf

When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders

• Pilot studies suggest that changes in response to the dexamethasone suppression test (DST) in melancholic patients receiving antidepressants might represent a laboratory marker of clinical progress. We performed weekly DSTs in 31 hospitalized patients with major depressive disorder, primary and endogenous subtypes, during drug-free and subsequent treatment periods. Most nonsuppressors had progressive normalization of DST responses in conjunction with clinical improvement, DST normalization usually preceded or coincided with good clinical response, and failure to normalize was often associated with poorer clinical outcome. Occasional patients with baseline dexamethasone suppression become nonsuppressive after withdrawal from medication, but the DST has no apparent value as a serial marker in patients with welldocumented normal DST findings. Our results extend the construct validity of the DST as a state-related marker in nonsuppressors and suggest future clinical applications.

Robert Gardner

Papers

Dexamethasone suppression tests in antidepressant treatment of melancholia. The process of normalization and test-retest reproducibility.

Impaired lymphocyte function in depressive illness

Dexamethasone suppression tests in antidepressant treatment of melancholia. The process of normalization and test-retest reproducibility

Interference by carbamazepine with the dexamethasone suppression test.

Speech pause time: A marker of psychomotor retardation among endogenous depressives