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Cyclic adenosine 3',5'- monophosphate (cAMP) pathways

cAMP response element-binding protein (CREB) is a transcription factor for cyclic adenosine 3',5'- monophosphate (cAMP).

The activation of CREB and cAMP leads to regulation of hippocampul genes especially the brain-derived neurotrophic factor (BDNF) gene. 

 

 

Evidence for this hypothesis

  • It has been found that long term administration  of antidepressants  inluding SNRIs leads to the upregulation  of cAMP synthesis, and CREB  in rats.  

 

  • CREB can be activated by other intracellular  receptors and pathways e.g calcium depenedant protein kinases and the mitogen-activated protein (MAP)  kinase pathway. 

 

  • Phosphodiesterase inhibitors (which breaks down cAMP) have shown antidepressant properties in clinical trials 

 

Cytokines 

 

Studies suggest that depression has been associated with the role of immunological activation, in particular the  hypersecretion of cytokines in the induction and continuation of depression. 

It is thought that it is this hypersecretion by which stress may induce depression. 

 

TCAs, RIMAs, SSRIs  and SNRIs have a negative immunoregulatory effect, counteracting the increased production of proinflammatory cytokines. 

 

  • Cytokines are actively taken up into the CNS which initiates the immune response responsible for depression.

  • Cytokines activate astrocytes and microglial cells. 

  • These will produce more cytokines in response via a feedback mechanism. 

  • Dopamanergic,  serotonergic and noradrenergic is strongly influenced by cytokines. Therefore a possible future treatment may involve the alteration of cytokine concentrations.

 

Phospholipid metabolism hypothesis

In depressive patients there are decreased levels of omega-3 fatty acids and excessive levels of omega-6 fatty acid (arachadonic acid) 

 

 

Evidence  supporting this hypothesis:

Omega-3 (acosapentanoic acid) administration alleviates depressive symptoms   . The causes of such abnormalities may be due to  impairment  of phospholipase enzyme A2 (PA2) and coenzyme A-independent transcyclase (CoAIT). Therefore inhibitors of these two enzymes could be novel drug targets in depression 

Other hypotheses 

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