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Mechanisms of Depression

Though the exact mechanisms of depression are unknown, evidence suggests that social, psychological, and biological correlates all play a significant role in the mechanism of depression.

The exact mechanisms of depression are unknown. This may be a consequence of our limited understanding of neurobiology of brain functioning. Another factor may be that depression is a heterogeneous disorder that may have a common phenomenology but has variable presentations and different etiologies.1 Evidence suggests that social, psychological, and biological correlates all play a significant role in the mechanism of depression. Genetic factors contribute about 30% to 40% of an individual’s susceptibility to depression.2 The remaining 60% to 70% of susceptibility are environmental factors specific to the individual3, such as adverse events in childhood, recent stressors, or traumatic events, etc.4,5

Neuroplasticity Theory

The neuroplasticity theory, which is gathering increasing evidence, demonstrates that patients with major depressive disorder (MDD) have altered neuronal and structural plasticity.6 Brain-imaging studies demonstrated cortical and limbic atrophy with decreased volume in the prefrontal cortex and hippocampus are related to the duration of illness in patients with depression.7,8  Neuroplasticity may be regulated by neurotropic factors such as brain derived neurotropic factor (BDNF). Brain-derived neurotrophic factor (BDNF) is a neurotrophin that has been linked to the viability of neurons in brain circuits that regulate emotion, memory, learning, sleep and appetite.9 The neurotrophin hypothesis of depression is based on the theory that stress decreases BDNF expression and contributes to neuronal atrophy and lack of neuroplasticity important for brain function.10

HPA Axis Suppression

An average 50% of patients with depression secrete excessive amounts of cortisol.11 Abnormalities with the HPA axis in patients with depression include increased average cortisol levels, diminished suppression of cortisol when given dexamethasone, increased adrenal gland volume, increased waking salivary cortisol, diminished expression of peripheral glucocorticoid receptors, and increased CRF in cerebral spinal fluid.12,13

Neurochemical Changes

Serotonin (5-HT) is the most researched monoamine in the context of depression, possibly due to the use of selective serotonin reuptake inhibitors (SSRIs) to treat depression.11 Patients with depression have decreased endocrine responses to 5-HT, especially through presynaptic 5-HT neurons.12 The role of noradrenaline and dopamine is less understood in depression, but substantial evidence exists that they also play a role in depression. Pharmacological agents that target both of these neurotransmitters have demonstrated antidepressants effects.14

There is growing evidence that glutamate, the most prolific neurotransmitter plays a critical role in regulating a number of important brain functions including mood, emotional regulation, cognition, and neuroplasticity. Abnormal glutamate signaling has been seen in depression and pharmacological agents that modulate glutamate have antidepressant properties. This is a growing area of interest for developing new treatment for depression.15

 The main inhibitory neurotransmitter in the brain is g-aminobutyric acid (GABA).12 Several studies have demonstrated lower levels of GABA, both in the CSF and plasma.12 While data is developing regarding the role of depleted GABA in depression, to date medications that potentiate GABA are not beneficial as antidepressants.12   

References

  1. Goldberg D. The heterogeneity of "major depression". World Psychiatry. 2011;10(3):226-228. doi:10.1002/j.2051-5545.2011.tb00061.x
  2. Sullivan PF, Neal MC, and Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. The American Journal of Psychology. October 2000; 157(10):1552-1562. DOI: 10.1176/appi.ajp.157.10.1552
  3. Hasler, G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World Psychiatry. October 2010; 9(3):155-161. DOI: 10.1002/j.2051.5545.2010.tb00298.x
  4. Kendler KS, Gardner CO, Prescott CA. Toward a comprehensive developmental model for major depression in women. Am J Psychiatry. 2002;159(7):1133-1145. doi:10.1176/appi.ajp.159.7.1133
  5. Kendler KS, Gardner CO, Prescott CA. Toward a comprehensive developmental model for major depression in men. Am J Psychiatry. 2006;163(1):115-124. doi:10.1176/appi.ajp.163.1.115
  6. Uchida S, PhD; Yamagata H, MD, PhD; Seki T, MD; and Watanabe Y, MD, PhD. Epigenetic mechanisms of major depression: targeting neuronal plasticity. Psychiatry and Clinical Neurosciences. 2018; 72 (4):212-227. https://doi.org/10.1111/pcn.12621
  7. MacQueen G, Frodl T. The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Mol Psychiatry. 2011;16(3):252-264. doi:10.1038/mp.2010.80
  8. Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology. 2010;35(1):192-216. doi:10.1038/npp.2009.104
  9. Duman RS, Malberg J, Nakagawa S, D'Sa C. Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000;48(8):732-739. doi:10.1016/s0006-3223(00)00935-5
  10. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59(12):1116-1127. doi:10.1016/j.biopsych.2006.02.013
  11. Nelson JC, Davis JM. DST studies in psychotic depression: a meta-analysis. The American Journal of Psychiatry. 1997;154(11):1497-1503. doi: 10.1176/ajp.154.11.1497
  12. Cowen PJ. Neuroendocrine and neurochemical processes in depression. Psychopathology Review. 2016;3(1):3-15. doi: 10.5127/pr.034513
  13. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends in Neurosciences. 2008;31(9):464-468. doi: 10.1016/j.tins.2008.06.006
  14. Moret C, Briley M. The importance of norepinephrine in depression. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):9-13. doi:10.2147/NDT.S19619
  15. Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62(1):63-77. doi:10.1016/j.neuropharm.2011.07.036