Stress and Depression


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1 : Stress and Depression Mario Gil November 10, 2005
2 : Depression Defining feature is loss of pleasure (anhedonia) Sapolsky: “genetic/neurochemical disorder requiring a strong environmental trigger whose characteristic manifestation is an inability to appreciate sunsets.”
3 : Depression Delusional/distorted thinking Depressives see the world in a negative way (glass always half empty) Psychomotor retardation (person moves & speaks slowly) Problems with hippocampal-dependent memory (explicit memory) Different types of depression: unipolar, bipolar (manic), seasonal affective disorder
4 : Neurochemistry and Depression Depression involves abnormal levels of norepinephrine, serotonin, & dopamine Drugs (antidepressants) that lessen depression increase amount of signaling by these neurotransmitters Tricyclics? block reuptake of monoamines (nonspecific)
5 : Neurochemistry and Depression Monoamine oxidase inhibitors? block degradation of monoamines in the synapse (nonspecific) SSRIs? inhibits reuptake of serotonin (specific) Theory 1: too much neurotrasmitter Theory 2: too little neurotransmitter
6 : Neurotransmitter dysfunction Serotonin? incessant ideation in depression Norepinephrine? psychomotor retardation Dopamine? dysfunctional pleasure pathways Substance P?
7 : Neuroanatomy and Depression Anterior cingulate cortex? resting level of activity higher in depressives Amygdala? hyperactive in depressives Left PFC (positive mood)? decreased activity Right PFC (neg. mood)? increased activity Hippocampus? smaller than average in many depressives HPA axis? overactive in some depressives
8 : Genetics and Depression Depression has a genetic component Siblings share 50% of their genes, and if one has history of depression? 25% chance that the other will also have depression Identical twin share 100% of their genes, and if one has history of depression? 50% chance that the other will also have depression Sapolsky: “The more genes in common, the more likelihood of sharing this disease”
9 : Other factors Interactions between immune function and mood? Psychosocial factors Sex differences: higher incidence of unipolar depression in females Women may be more at risk for depression at certain reproductive points (estrogen & progesterone)
10 : How does stress interact with depression?
11 : Stress & Depression Chronic exposure to stressful life events has been associated with development of depression Major depressives often have elevated levels of glucocorticoids (GCs)
12 : Stress Response HPA system receives and integrates various inputs indicative of stress, converging in the Paraventricular nucleus (PVN) of the hypothalamus CRH ? ACTH ? glucocorticoid release Glucocorticoid receptors (GRs) Mineralocorticoid receptors (MRs)
13 : Glucocorticoids (GCs) Adrenal steroids secreted during stress Mobilize energy Increase cardiovascular tone Suppress growth, tissue repair, etc. Important for survival
14 : Glucocorticoids (GCs) Excessive GCs ? deleterious effects Hypertension Insulin-resistant diabetes mellitus Impotency Immune suppression Effects on the central nervous system
15 : Hippocampal formation Region of the limbic cortex (temporal lobes) Includes subicular complex, hippocampus, & dentate gyrus Dentate gyrus: outer molecular layer, middle granular layer, & deep polymorphic layer Hippocampus: molecular layer, pyramidal cell layer, & polymorphic layer
16 :
17 : Hippocampal formation Neurons in the entorhinal cortex relay incoming information to gentate gyrus (and hippocampus) Neurons in the gentate gyrus send axons to field CA3 of the hippocampus CA3 pyramidal cells send axons to field CA1 neurons and other sites CA1 pyramidal cells provide primary output of the hippocampus
18 :
19 : Hippocampal formation Hippocampus sends projections (via the fornix) to hypothalamus Hippocampus ? paraventricular nucleus of hypothalamus (CRH containing cells) Hippocampus plays a role in the regulation of GC release from adrenal glands
20 : HPA system and hippocampus Increased levels of GCs? down-regulation of hippocampal GRs? alterations of negative feed-back mechanism HPA system is overactive? excessive GC release
21 : Hippocampal atrophy Prolonged stress decreases number of apical dendritic branch points in hippocampus of rodents and nonhuman primates Glucocorticoid treatment? produces the same effects (correlates w/ impaired explicit memory)
22 : Hippocampal atrophy Reduced hippocampal volumes in people w/depression Occurs in both early-onset and late-onset disorders Hippocampal atrophy associated w/ deficits in visual and verbal memory performance In depressives, atrophy may be irreversible
23 : Hippocampal atrophy GC-induced atrophy may be mediated by excitatory amino acids (EAAs) GC increase EAA concentrations in the hippocampus Blocking NMDA receptors prevents GC-induced atrophy GC? adverse effects on levels (or efficacy) of neurotrophins
24 : Hippocampal atrophy Also occurs in other disorders Cushing Syndrome- tumors in the brain that cause hypercortisolism More severe atrophy associated with more severe hypercortisolism For this disorder, atrophy is reversible Subset of cushingoid patients become depressed Note: Extremely high levels of CG ? neurotoxic effects
25 : Hippocampal neurogenesis Neurogenesis occurs in hippocampal gentate gyrus Neurogenesis can be stimulated by an enriched environment GC or stress inhibit neurogenesis Aged rats? elevated GC levels? decreased neurogenesis
26 : Hippocampal neurogenesis Aged rats? remove elevated GC levels? facilitates neurogenesis NMDA receptor activation inhibits dentate neurogensis Antidepressants, ECT, & physical activity stimulate neurogenesis
27 : How does disturbed adult neurogenesis contribute to development of depression?
28 : Hippocampal neurogenesis Hypothesis: inhibition of neurogenesis may reduce ability of hippocampus to cope w/ novelty and complexity, and there may be a disturbance of other hippocampal-dependent processes However, a role of hippocampal neurogenesis in normal hippocampal function must be established
29 : Hippocampal neurogenesis Serotonin plays a role in neurogenesis SSRIs ? increase neurogenesis in dentate gyrus Lesions of the raphe nuclei decrease neurogenesis in dentate gyrus Serotonin ? 5-HT receptors ? increase cAMP levels ? CREB activation ? Brain Derived Neurotrophic factor (BDNF)
30 : Hippocampal neurogenesis Administration of BDNF into the dentate gyrus exerts antidepressant effects Stress reduces hippocampal BDNF levels in rats; this effect can be reversed by antidepressants & ECT Effects of BDNF on neurogenesis?
31 : How does an excess of GCs increase the risk of depression?
32 : Consequences of elevated GC levels Elevated GC levels ? may alter neurotransmitter synthesis, degradation, receptor function, & gene expression (e.g., 5-HTT) Elevated GC levels ? may be involved in immunosuppression (occurs in some depressives) Elevated GC levels? hippocampal atrophy Elevated GC levels? inhibition of hippocampal neurogenesis
33 : What’s going on? Hypothesis 1: depression is immensely stressful and stimulate GC secretion Hypothesis 2: stress & GC excess may be a cause of depression, rather than merely a consequence
34 : Link between stress & depression Stress is a predisposing factor in human depression Genes that predispose to depression only do so in a stressful environment GCs, major stress hormone, can bring about depression-like states in animals and cause depression in humans
35 : Additional Readings Hickie, I., Naismith, S., Ward, P. B., Turner, K., Scott, E., Mitchell, P., Wilhelm, K., & Parker, G. (2005). Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression. British Journal of Psychiatry, 186, 197-202. Kempermann, G., & Kronenberg, G. (2003). Depressed new neurons?—adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biological Psychiatry, 54, 499-503
36 : Additional Readings Sapolsky, R. M. (2000). Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Archives of General Psychiatry, 57 (10), 925-935. Tafet, G. E., Bernardini, R. (2003). Psychoneuroendocrinological links between chronic stress and depression. Progress in Neuro-Pharmacology & Biological Psychiatry, 27, 893-903.

 

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