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The Role of Neurobiologic Processes in Symptoms of Depression

Michael E. Thase, MD

Departments of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia Veterans Affairs Medical Center, and the University of Pittsburgh Medical Center, Philadelphia and Pittsburgh

Gene-Environment Interactions in Depression

Depression is a neurobiologically complex disorder with no single identifiable cause. Like other complex disorders, such as cardiovascular disease, cancer, and type 2 diabetes, depression is produced by multiple gene alterations and their interactions with various environmental factors that provide risk (like stress) or confer protection (such as social support).1,2

Evidence of gene-environment interaction was provided by Caspi et al3 in a study examining why some people develop depression after stressful life events while others do not. In this prospective longitudinal study, a sample of healthy individuals was divided into 3 groups according to polymorphisms in the promoter region of the serotonin transporter gene. Individuals may carry 2 copies of the long allele of this gene (which is fully functional for serotonergic neurotransmission), 2 copies of the short allele (which is less functional), or have 1 of each. Stressful life events experienced between the ages of 21 and 26 years were shown to be predictors of a diagnosis of major depression, increased depressive symptoms, and suicidality for individuals carrying 1 or 2 copies of the short allele but not for those who carried 2 copies of the long allele (P=.056). The risk for developing depression increased for those carrying the short allele as the number of stressful life events increased; however, no relationship was found between genetic risk and lifetime rate of depression for those individuals carrying the short allele in the absence of stressful life events. These findings suggest that a person’s genetic makeup moderates his or her response to environmental insults.

 

Although environmental stressors can influence the initial development of depression in susceptible individuals, once the pattern of vulnerability is established, new episodes may emerge over time after progressively less provocation, and, eventually, episodes may appear spontaneously. This concept is similar to the neurologic model of seizure progression in epilepsy known as kindling.4 In relation to depression, kindling means that episodes of depression early in life are often associated with adversity, but, as the number of lifetime depressive episodes increases, the association between stressful life events and the onset of a depressive episode becomes progressively weaker. In a large study of female twins (N=2,395), Kendler and colleagues5 demonstrated that, after 4 episodes of depression, the number of previous depressive episodes became a greater predictor of subsequent episodes than the occurrence of recent stressful life events (AV 1AV 1).

Pathophysiology of Depression

 

Five key areas of the brain associated with the neurobiology of depression are the prefrontal cortex, which includes the orbital, dorsolateral, and anterior cingulate cortices, and the amygdala and hippocampus, which are part of the limbic system (AV 2AV 2).6 The prefrontal cortex is involved in executive functions such as problem-solving, abstraction, planning, and judgment.7 The orbitofrontal cortex may regulate impulses, compulsions, and drives8 and is relevant to attachment and social interaction.9 The anterior cingulate cortex is a critical area for the appreciation or anticipation of reward and for the regulation of certain emotions.7 The amygdala is a key relay point for processing both positive and negative affective arousal, whereas the hippocampus is important for the retrieval and storage of new memories, is the site of neurogenesis in the brain, and provides feedback inhibition to the HPA axis, which is involved in stress response.7

Using PET scans, these regions of the brain have been identified in depressed individuals as showing either increased or decreased cerebral blood flow and glucose metabolism relative to controls.10 The amygdala and the medial orbital cortex most consistently show increased activity among depressed subjects, while the dorsolateral prefrontal cortex most often shows decreased activity.11,12 Neuroimaging studies10,13 of the brains of individuals with depression have also identified structural changes or volume losses within an interconnected neurologic circuit composed of the deeper limbic structures (such as the amygdala and the hippocampus) and regions of the frontal cortex, suggesting that depression is associated with disruptions within multiple linked regions of the brain rather than within a particular structure. These neurologic circuits are partially innervated by neurotransmission from noradrenergic and serotonergic bundles that originate in nuclei in the brain; decreased noradrenergic and serotonergic neurotransmission are associated with depression. Noradrenergic and serotonergic pathways are frequently co-localized and, for many functions, have somewhat opposing functional relationships, ie, if noradrenergic activation is alerting in a particular region, serotonergic activation in that region is inhibitory. While these monoamine neurotransmitters contribute to depression in complex ways, their exact role is not known at this time.

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Effect of Gene-Environment Interactions on Brain Regions Implicated in Depression

Genetic vulnerability might lead to changes in the brain from repeated exposure to environmental factors. For example, carrying the short allele of the promoter region of the serotonin transporter gene leads to hyperactivity of the amygdala in response to environmental stress, although this genetic polymorphism alone is not enough to predict a mood disorder.14 However, as discussed above, individuals carrying 1 or 2 copies of the short allele are more likely to receive a diagnosis of depression than carriers of the long allele when exposed to repeated stressful life events.3 Thus, these individuals show an inherited vulnerability to emotional reactivity in an area of the brain that has been implicated in depression. Additionally, structural MRI scans have shown a relationship between the short allele genotype and a reduction in gray matter volume of the amygdala and the anterior cingulate, suggesting that not only does having this genetic vulnerability convey greater amygdala reactivity to environmental stressors, but also that greater reactivity of the amygdala may, over time, result in structural changes in the brain.15

The association between structural changes in the brain and stress has been demonstrated in animal models. For example, Czéh and colleagues16 subjected adult male tree shrews to 5 weeks of psychosocial stress and found that stress reduced both the number and somal volume of astroglia in the hippocampus by one-fourth. One possible mediator of this brain-altering effect involves suppression of various neurotrophic factors that are responsible for preserving both brain health and the connectivity between neurons and that may be involved in the differentiation of new neurons in the hippocampus. Animal models have demonstrated that chronic stress or persistent pain can suppress the synthesis of brain-derived neurotrophic factor by at least 50% and sustain those losses over time, providing 1 potential pathway for these changes in particular regions of the brain.17

Sheline and colleagues18 studied hippocampal gray matter volume in humans with depression and found an inverse relationship between the number of lifetime days of untreated depression and hippocampal volume, ie, the longer that patients were untreated, the smaller their hippocampus. As no relationship between hippocampal volume and the number of lifetime days of treated depression was found, the mediating factor in the progressive reduction in hippocampal size could be the stress associated with untreated depression. However, a relationship does not guarantee causality, and longitudinal studies are warranted to determine the causes of the lower hippocampal volume seen in these patients.

 

The loss of volume in frontolimbic brain structures in patients with depression may be the result of a reduction not in neuronal cell number, but in neuronal volume and in glial cell density. The reduction in glial cell density appears to be the most prominent feature of cell pathology in depression,19–22 which is significant because glial cells are involved in several supportive processes for adjacent neurons. Glial cells supply glucose to neurons, protect neurons against the deleterious effects of excitatory amino acids such as glutamate, participate in neurotransmitter modulation, and facilitate neuronal repair and survival by synthesizing and releasing neurotrophic factors.20 The reduction in number and volume of glial cells may, in turn, make individual neurons decrease in size as well as in connectivity. Thus, what began as a stress-sensitive process that was amplified in individuals with certain vulnerabilities begins to manifest as a more autonomous process as the patient gets older and experiences more depressive episodes (AV 3AV 3).20 The progressive changes evident in glial cells and neurons over time point to the need for the early identification of depression and for vigorous psychosocial and pharmacologic treatments for these patients.

For Clinical Use

  • Depression is a neurobiologically complex disorder with no single identifiable cause
  • Environmental stressors can influence the initial development of depression in genetically susceptible individuals
  • Once the pattern of vulnerability to depressive episodes is established, new episodes may emerge after progressively less environmental provocation, and, eventually, episodes may appear spontaneously due to changes in the brain over time

Abbreviations

HPA=hypothalamic-pituitary-adrenal
MRI=magnetic resonance imaging
OR=odds ratio
PET=positron emission tomography

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References

  1. National Human Genome Research Institute. Genetic analysis tools help define nature and nurture in complex disorders. http://www.genome.gov/10000865. Published September 25, 2007. Accessed January 26, 2010.
  2. Kendler KS, Kessler RC, Walters EE, et al. Stressful life events, genetic liability, and onset of an episode of major depression in women. Am J Psychiatry. 1995;152(6):833–842.
  3. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386–389.
  4. Post RM. Do the epilepsies, pain syndromes, and affective disorders share common kindling-like mechanisms? Epilepsy Res. 2002;50(1–2):203–219.
  5. Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the "kindling" hypothesis. Am J Psychiatry. 2000;157(8):1243–1251.
  6. Charney DS, Nestler EJ, eds. Neurobiology of Mental Illness. 2nd ed. New York, NY: Oxford University Press Inc; 2004.
  7. Stahl MS. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York, NY: Cambridge University Press; 2008.
  8. Öngür D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000;10(3):206–219.
  9. Nitschke JB, Nelson EE, Rusch BD, et al. Orbitofrontal cortex tracks positive mood in mothers viewing pictures of their newborn infants. Neuroimage. 2004;21(2):583–592.
  10. Drevets WC. Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med. 1998;49:341–361.
  11. Drevets WC, Videen TO, Price JL, et al. A functional anatomical study of unipolar depression. J Neurosci. 1992;12(9):3628–3641.
  12. Siegle GJ, Thompson W, Carter CS, et al. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry. 2007;61(2):198–209.
  13. Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry. 2003;54(3):338–352.
  14. Hariri AR, Drabant EM, Munoz KE, et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry. 2005;62(2):146–152.
  15. Pezawas L, Meyer-Lindenberg A, Drabant EM, et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci. 2005;8(6):828–834.
  16. Czéh B, Simon M, Schmelting B, et al. Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology. 2006;31(8):1616–1626.
  17. Duric V, McCarson KE. Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience. 2005;133(4):999–1006.
  18. Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160(8):1516–1518.
  19. Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45(9):1085–1098.
  20. Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets. 2007;6(3):219–233.
  21. Si X, Miguel-Hidalgo JJ, O’Dwyer G, et al. Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology. 2004;29(11):2088–2096.
  22. Öngür D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A. 1998;95(22):13290–13295.