Evidence-Based Reviews

Dissecting melancholia with evidence-based biomarker tools

Current Psychiatry. 2014 February;13(2):41-48, 57

References

1. Eley TC, Sugden K, Corsico A, et al. Gene-environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry. 2004;9(10):908-915.

2. Haber SN, Rauch SL. Neurocircuitry: a window into the networks underlying neuropsychiatric disease. Neuropsychopharmacology. 2010;35(1):1-3.

3. Frodl T, Bokde AL, Scheuerecker J, et al. Functional connectivity bias of the orbitofrontal cortex in drug-free patients with major depression. Biol Psychiatry. 2010; 67(2):161-167.

4. Woolley CS, Gould E, McEwen BS. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 1990;531(1-2): 225-231.

5. Heim C, Nemeroff CB. The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders. Biol Psychiatry. 1999;46(11):1509-1522.

6. Isgor C, Kabbaj M, Akil H, et al. Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus. 2004;14(5):636-648.

7. De Kloet ER, Vreugdenhil E, Oitzl MS, et al. Brain corticosteroid receptor balance in health and disease. Endocr Rev. 1998;19(3):269-301.

8. Philip AM, Kim SD, Vijayan MM. Cortisol modulates the expression of cytokines and suppressors of cytokine signaling (SOCS) in rainbow trout hepatocytes. Dev Comp Immunol. 2012;38(2):360-367.

9. Coplan JD, Lydiard RB. Brain circuits in panic disorder. Biol Psychiatry. 1998;44(12):1264-1276.

10. Anisman H, Merali Z. Cytokines, stress and depressive illness: brain-immune interactions. Ann Med. 2003;35(1):2-11.

11. Crowley JJ, Lucki I. Opportunities to discover genes regulating depression and antidepressant response from rodent behavioral genetics. Curr Pharm Des. 2005;11(2):157-169.

12. Covington HE 3rd, Vialou V, Nestler EJ. From synapse to nucleus: novel targets for treating depression. Neuropharmacology. 2010;58(4-5):683-693.

13. Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004;161(11):1957-1966.

14. Sandi C. Stress, cognitive impairment and cell adhesion molecules. Nat Rev Neurosci. 2004;5(12):917-930.

15. Hartley CA, Phelps EA. Changing fear: the neurocircuitry of emotion regulation. Neuropsychopharmacology. 2010;35(1): 136-146.

16. Kim DK, Lim SW, Lee S, et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport. 2000;11(1):215-219.

17. Ueyama E, Ukai S, Ogawa A, et al, Chronic repetitive transcranial magnetic stimulation increases hippocampal neurogenesis in rats. Psychiatry Clin Neurosci. 2011; 65(1):77-81.

18. Irwin W, Anderle MJ, Abercrombie HC, et al. Amygdalar interhemispheric functional connectivity differs between the non-depressed and depressed human brain. Neuroimage. 2004;21(2):674-686.

19. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007; 87(3):873-904.

20. Gusnard DA, Raichle ME, Raichle ME. Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci. 2001;2(10):685-694.

21. Hulsebosch CE, Hains BC, Crown ED, et al. Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res Rev. 2009;60(1):202-213.

22. Gottfried JA, Dolan RJ. Human orbitofrontal cortex mediates extinction learning while accessing conditioned representations of value. Nat Neurosci. 2004;7(10):1144-1152.

23 Arnone D, McKie S, Elliott R, et al. State-dependent changes in hippocampal grey matter in depression. Mol Psychiatry. 2012;1(8):1359-4184.

24. Brunoni AR, Lopes M, Fregni F. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol. 2008;11(8):1169-1180.

25. Maeng S, Zarate CA Jr. The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep. 2007;9(6):467-474.

26. Vaidya VA, Fernandes K, Jha S. Regulation of adult hippocampal neurogenesis: relevance to depression. Expert Rev Neurother. 2007;7(7):853-864.

27. Lisiecka DM, Carballedo A, Fagan AJ, et al. Altered inhibition of negative emotions in subjects at family risk of major depressive disorder. J Psychiatr Res. 2012;46(2):181-188.

28. Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651-660.

29. Levkovitz Y, Harel EV, Roth Y, et al. Deep transcranial magnetic stimulation over the prefrontal cortex: evaluation of antidepressant and cognitive effects in depressive patients. Brain Stimul. 2009;2(4):188-200.

30. Schlaepfer TE, Lieb K. Deep brain stimulation for treatment of refractory depression. Lancet. 2005;366(9495):1420-1422.

31. Astrup, J. Energy-requiring cell functions in the ischemic brain. Their critical supply and possible inhibition in protective therapy. J Neurosurg. 1982;56(4):482-497.

32. Fletcher JM. Childhood mistreatment and adolescent and young adult depression. Soc Sci Med. 2009;68(5):799-806.

33. Warner-Schmidt JL, Duman R. VEGF as a potential target for therapeutic intervention in depression. Curr Opin Pharmacol. 2008;8(1):14-19.

34. Clark-Raymond A, Halaris A. VEGF and depression: a comprehensive assessment of clinical data. J Psychiatr Res. 2013;47(8):1080-1087.

35. Alonso R, Griebel G, Pavone G, et al. Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression. Mol Psychiatry. 2004;9(3):278-286.

36. Thomas RM, Peterson DA. A neurogenic theory of depression gains momentum. Mol Interv. 2003;3(8):441-444.

37. Jacobs BL. Adult brain neurogenesis and depression. Brain Behav Immun. 2002;16(5):602-609.

a decrease in the production of BDNF

increased susceptibility to neuropsychiatric disorders, including depression, anxiety disorder, and bipolar disorder (Figure 7).³²

People with the MM allele have been found to have a small hippocampal neuronal density and poor hippocampus-dependent memory function in neuroimaging studies.²³ They also displayed diminished ventromedial prefrontal cortex volume and presented with aversive memory extinction deficit (ie, “holding grudges”).

Another neurotrophic factor, vascular endothelial growth factor (VEGF), is a survival factor for endothelial cells and neurons and a modulator of synaptic transmission. Understanding the molecular and cellular specificity of antidepressant-induced VEGF will be critical to determine its potential as a therapeutic target in depression.³³ Delineating the relationship between VEGF and depression has, ultimately, the potential to shed light on the still elusive neural mechanisms that underlie the pathophysiology of depression and the mechanisms by which antidepressants exert their effects.³⁴

Genetic polymorphisms in monoamine receptors (5-HT2A), transporters (SERTPR, 5-HTTLPR, STin2, rs25531, SLC6A4), and regulatory enzymes should not be overlooked.³⁵ There is reproducible evidence that variability in these polymorphisms are associated with variability in:

vulnerability to depression

the response to treatment with existing antidepressant medications.¹

Most studies that look at changes in neuronal circuitry focus on the integrity of synaptic connections between the frontal cortex and limbic system; few of them have closely examined the importance of the anatomic proximity of the 2 regions. It might be that having an amygdala that is relatively closer to the frontal cortex and the hippocampus reduces a person’s risk of depression, and vice versa. This association needs to be investigated further with imaging studies.

Environmental risk factors. The brain is thought to be plastic until age 30.⁵ Plasticity diminishes with age after age 7—except for the hippocampus, which can regenerate throughout life.³⁶Early life experiences play an important role in forming synaptic connections between the frontal cortex and the limbic system, through a process known as fear conditioning.

Children learn early in life which stimuli are to be perceived as threatening or aversive and how to respond to best preserves their safety and internal sense of well-being. Those who grow up in a hostile environment learn to perceive more stimuli as threatening than children who grow up in a nurturing environment.³² It is possible that the amygdala is larger in children who grow up in less-than-ideal circumstances because this region is constantly being recruited—at the expense of the more rational frontal cortex.

Evidence suggests that these conditions reduce hippocampal neurogenesis³⁷:

increasing age

substance abuse (opiates and methamphetamines)

inadequate housing

minimal physical activity

little opportunity for social stimulation

minimal learning experience.

Bottom Line

Depression has been understood as a neurotransmitter deficiency in the brain; treatments were engineered to increase release, or block degradation, of those neurotransmitters. Novel theories—all interconnected—of the neuroanatomical pathophysiology of depression focus more on differences in neuron density in the brain; effects of stress on neurogenesis and neuronal cell apoptosis; alterations in feedback pathways connecting the pre-frontal cortex to the limbic system; and the role of pro-inflammatory mediators evoked during the stress response.

Related Resources

Fuchs E. Neurogenesis in the adult brain: is there an association with mental disorders? Eur Arch Psychiatry Clin Neurosci. 2007;257(5):247-249.

Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004; 161(11):1957-1966.

Disclosure

The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgement

Anita Rao, second-year medical student, Stritch School of Medicine, Loyola University, Chicago, Illinois, assisted in the preparation of this manuscript.