At any given moment about 10-20% of the population of the USA is depressed. Most of the depressed people suffer from "Major Depression" while some suffer from Bipolar Disorder or "Manic-Depression," and some suffer from Dysthymia. It is estimated that the cost of depression to the U.S. economy is more than $40 billion a year with 55 percent accounting for missed work and lowered productivity (1)

The diagnosis of depression is done on the basis of symptoms. The search for possible biochemical markers of depression is a major focus in research strategies in biological psychiatry.

Biogenic amine - beta adrenergic receptor - cAMP - PKA cascade and Serotonin / Norepinephrine(NE) / Glucocorticoid links play significant roles in the manifestation and therapy of major depression (2-6). A cross-talk between noradrenergic and serotonergic receptor cascades may have significant effect at the level of mechanisms involved in the desensitization of the beta adrenoceptor-coupled adenylate cyclase system (7). Schwaninger et al. (8) have shown that during membrane depolarization antidepressants reduce the in vitro phosphorylation of CREB and inhibit CRE-directed gene transcription. Recently the antidepressant desmethylimipramine (DMI) has been shown to translocate the glucocorticoid receptor (GR) from cytoplasm to the nucleus in mouse fibroblaststs and enhance dexamethasone-induced GR mediated gene transcription. In our laboratory DMI has been found to induce GRII gene expression independent of the influence of NE in rat hippocampus (9,10). These and other studies suggest that DMI influences gene expression by an agonist receptor-cascade independent regulation of genes.

Thus it is observed that several factors like biogenic amines, beta adrenergic and other receptors, different kinases, phosphatases, glucocorticoids etc. working both inside and outside of different cascades may be involved in the mechanism of major depression. It is also observed that different therapeutic agents may tend to rectify the disorder in different ways. However a complete scenario is yet to be evolved.

1. Lock J, Walsh M (1999) Development and implementation of depression care along the health care continuum. J Nurs Care Qual 13(3):13-22.

2. Vetulani J, Sulser F(1975) Action of various antidepressant treatment reduces reactivity of noradrenergic cyclic AMP generating system in limbic forebrain. Nature 257:495-496.

3. Banerjee SP, Kung, LS, Riggi SJ, Chanda SK (1977) Development of betaadrenergic receptor subsensitivity by antidepressants. Nature 268:455-456.

4. Eiring A, Manier DH, Bieck PR, Howells RD, Sulser F (1992) The "Serotonin/Norepinephrine Link" beyond the beta adrenoreceptors. Brain Res Mol Brain Res. 1992 Dec;16(3-4):211-4.

5. Shelton RC, Manier DH, Sulser F (1996) Cyclic AMP dependent protein kinase activity in major depression. Am J Psychiatry 153:1037-1042.

6. Manier DH, Eiring A, Shelton RC, Sulser F (1996) Beta adrenoreceptor-linked protein kinase A (PKA) activity in human fibroblasts from normal subjects and from patients with major depression. Neuropsychophermacology 15:555-561.

7. Nalepa I, Manier DH, Gillespie DD, Rossby SP, Schmidt DE, Sulser F. (1998) Lack of beta adrenoreceptor desensitization in brain following the dual noradrenaline and serotonin reuptake inhibitor venlaflexine. Eur Neuropsychophermacology 8:227-232.

8. Schwaninger M, Schöfl C, Blume R, Rossig L, Knepel W (1995) Inhibition by antidepressant drugs of cyclic AMP response element-directed gene trancription. Molec Pharmacol 147:1112-1118.

9. Rossby SP, Nalepa I, Huang M, Burt A, Perrin C, Schmidt DE, Sulser F (1995) Norepinephrine-independent regulation of GRII mRNA levels in vivo by a tricyclic antidepressant. Brain Res 687:79-82.

10. Eiring A, Sulser F (1998) An increased synaptic availability of norepinephrine is not essential for antidepressant induced increases in hippocampal GR mRNA. J Neural Transmission 104:1255-1258.

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