Stress and depression

Stress and depression

Stress, BDNF, and brain atrophy in depression

One candidate mechanism that has been proposed as the site of a possible flaw in signal transduction from monoamine receptors in depression is the target gene for brain-derived neurotrophic factor (BDNF) ( , , ). Normally, BDNF sustains the viability of brainFigures 6-36 6-37 6-38 neurons ( ), but under stress, the gene for BDNF may be repressed ( ). StressFigure 6-37 Figure 6-38 can lower 5HT levels and can acutely increase, then chronically deplete, both NE and DA. These monoamine neurotransmitter changes together with deficient amounts of BDNF may lead to atrophy and possible apoptosis of vulnerable neurons in the hippocampus and other brain areas such as prefrontal cortex ( ). An artist’s concept of the hippocampal atrophy that has been reportedFigure 6-37 in association with chronic stress and with both major depression and various anxiety disorders, especially PTSD, is shown in and . Fortunately, some of this neuronal loss mayFigures 6-39A 6-39B be reversible. That is, restoration of monoamine-related signal transduction cascades by antidepressants ( ) can increase BDNF and other trophic factors ( ) andFigure 6-36 Figure 6-37 potentially restore lost synapses. In some brain areas such as the hippocampus, not only can synapses potentially be restored, but it is possible that some lost neurons might even be replaced by neurogenesis.

Neurons from the hippocampal area and amygdala normally suppress the hypothalamic-pituitary-adrenal (HPA) axis ( ), so if stress causes hippocampal andFigure 6-39A amygdala neurons to atrophy, with loss of

Figure 6-36. . TheMonoamine signaling and brain-derived neurotrophic factor (BDNF) release neurotrophic hypothesis of depression states that depression may be caused by reduced synthesis of proteins involved in neurogenesis and synaptic plasticity. BDNF promotes the growth and development of immature neurons, including monoaminergic neurons, enhances the survival and function of adult neurons, and helps maintain synaptic connections. Because BDNF is important for neuronal survival, decreased levels may contribute to cell atrophy. In some cases, low levels of BDNF may even cause cell loss. Monoamines can increase the availability of BDNF by initiating signal transduction cascades that lead to its release. Thus, if

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monoamine levels are low, then BDNF levels may correspondingly be low. CaMK, calcium/calmodulin-dependent protein kinase; CREB, cAMP response element-binding protein; PKA, protein kinase A.

their inhibitory input to the hypothalamus, this could lead to overactivity of the HPA axis (Figure ). In depression, abnormalities of the HPA axis have long been reported, including elevated6-39B

glucocorticoid levels and insensitivity of the HPA axis to feedback inhibition ( ). SomeFigure 6-39B evidence suggests that glucocorticoids at high levels could even be toxic to neurons and contribute to their atrophy under chronic stress ( ). Novel antidepressant treatments are in testingFigure 6-39B that target corticotropin-releasing factor 1 (CRF-1) receptors, vasopressin 1B receptors, and glucocorticoid receptors ( ), in an attempt to halt and even reverse these HPAFigure 6-39B abnormalities in depression and other stress-related psychiatric illnesses.

Stress and the environment: how much stress is too much stress?

In many ways the body is built for the purpose of handling stress, and in fact a certain amount of “stress load” on bones, muscles, and brain is necessary for growth and optimal functioning and can even be associated with developing resilience to future stressors ( ). However, certainFigure 6-40 types of stress such as child abuse can sensitize brain circuits and render them vulnerable rather than resilient to future stressors ( ). For patients with such vulnerable brain circuits whoFigure 6-41 then become exposed to multiple life stressors as adults, the result can be the development of depression ( ). Thus, the same amount of stress that would be handled without developingFigure 6-42 depression in someone who has not experienced child abuse could hypothetically cause depression in someone with a prior history of child abuse. This demonstrates the potential impact of the environment upon brain circuits. Many studies in fact confirm that in women abused as children, depression can be found up to four times more often than in never-abused women. Hypothetically, epigenetic changes caused by environmental stress create relatively permanent molecular alterations in the brain circuits at the time of the child abuse that do not cause depression per se, but make brain circuits vulnerable to breakdown into depression upon exposure to future stressors as an adult.

Stress and vulnerability genes: born fearful?

Modern theories of mood disorders do not propose that any single gene can cause depression or mania, but as discussed for schizophrenia in Chapter 4

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Figure 6-37. . BDNF plays a role inSuppression of brain-derived neurotrophic factor (BDNF) production the proper growth and maintenance of neurons and neuronal connections (right). If the genes for BDNF are turned off (left), the resultant decrease in BDNF could compromise the brain’s ability to create and maintain neurons and their connections. This could lead to loss of synapses or even whole neurons by apoptosis.

(see also ), mood disorders are theoretically caused by a “conspiracy” among manyFigure 4-33 vulnerability genes and many environmental stressors leading to breakdown of information processing in specific brain circuits and thus the various symptoms of a major depressive or manic episode. There is a great overlap between those genes thought to be vulnerability genes for schizophrenia and those thought to be vulnerability genes for bipolar disorder. A comprehensive discussion of genes for bipolar disorder or for major depression is beyond the scope of this book, but one of the vulnerability genes for depression is the gene coding for the serotonin transporter or SERT (i.e., the serotonin reuptake pump), which is the site of action of SSRI and SNRI antidepressants. The type of serotonin transporter (SERT) with which you are born determines in part whether your amygdala is more likely to over-react to fearful faces ( ), whether youFigure 6-43 are more likely to develop depression when exposed to multiple life stressors, and how likely your depression is to respond to an SSRI/SNRI or whether you can even tolerate an SSRI/SNRI (Figure


Specifically, an excessive reaction of the amygdala to fearful faces for carriers of the s variant of the gene for SERT is shown in . Fearful faces can be considered a stressful load on theFigure 6-43 amygdala and its circuitry, and can be visualized using modern neuroimaging techniques. For those with the s genotype of SERT, they are more likely to develop an affective disorder when exposed to multiple life stressors and may have more hippocampal

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Figure 6-38. . One factor that could contribute toStress and brain-derived neurotrophic factor (BDNF) potential brain atrophy is the impact that chronic stress can have on BDNF, which plays a role in the proper growth and maintenance of neurons and neuronal connections. During chronic stress, the genes for BDNF may be turned off, potentially reducing its production.

Figure 6-39

A. . The normal stress response involves activation of theHypothalamic-pituitary-adrenal (HPA) axis hypothalamus and a resultant increase in corticotropin-releasing factor (CRF), which in turn stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary. ACTH causes glucocorticoid release from the adrenal gland, which feeds back to the hypothalamus and inhibits CRF release, terminating the stress response.

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B. . In situations of chronic stress, excessiveHippocampal atrophy and hyperactive HPA axis in depression glucocorticoid release may eventually cause hippocampal atrophy. Because the hippocampus inhibits the HPA axis, atrophy in this region may lead to chronic activation of the HPA axis, which may increase risk of developing a psychiatric illness. Because the HPA axis is central to stress processing, it may be that novel targets for treating stress-induced disorders lie within the axis. Mechanisms being examined include antagonism of glucocorticoid receptors, corticotropin-releasing factor 1 (CRF-1) receptors, and vasopressin 1B receptors.

atrophy, more cognitive symptoms, and less responsiveness or tolerance to SSRI/SNRI treatment. Exposure to multiple life stressors may cause the otherwise silent overactivity and inefficient information processing of affective loads in the amygdala to become an overt major depressive episode ( ), an interaction of their genes with the environment (nature plus nurture). TheFigure 6-43 point is that the specific gene that you have for the serotonin transporter can alter the efficiency of affective information processing by your amygdala and, consequently, your risk for developing major depression if you experience multiple life stressors as an adult ( ). On the other hand, the lFigure 6-43 genotype of SERT is a more resilient genotype, with less amygdala reactivity to fearful faces, less likelihood of breaking down into a major depressive episode when exposed to multiple life stressors, as well as more likelihood of responding to or tolerating SSRIs/SNRIs if you do develop a depressive episode ( ).Figure 6-43

Whether you have the l or the s genotype of SERT accounts for only a small amount of the variance for whether or not you will develop major depression after experiencing multiple life stressors, and thus cannot predict who will get major depression and who will not. However, this example does prove the importance of genes in general and those for serotonin neurons in particular in the regulation of the amygdala and in determining the odds of developing major depression under stress. Thus, perhaps one is not born fearful, but born vulnerable or resilient to

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Figure 6-40. . In a healthy individual, stress can cause a temporaryDevelopment of stress resilience activation of circuits which is resolved when the stressor is removed. As shown here, when the circuit is unprovoked, no symptoms are produced. In the presence of a stressor such as emotional trauma, the circuit is provoked yet able to compensate for the effects of the stressor. By its ability to process the information load from the environment, it can avoid producing symptoms. When the stressor is withdrawn, the circuit returns to baseline functioning. Individuals exposed to this type of short-term stress may even develop resilience to stress, whereby exposure to future stressors provokes the circuit but does not result in symptoms.

developing major depression in response to future adult stressors, especially if they are chronic, multiple, and severe.

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