Stress and Depression

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Stress and Depression

• Mario Gil
• November 10, 2005

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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.

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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

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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)

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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

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Neurotransmitter dysfunction

• Serotonin? incessant ideation in depression
• Norepinephrine? psychomotor retardation
• Dopamine? dysfunctional pleasure pathways
• Substance P?

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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

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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

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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)

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How does stress interact with depression?
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Stress Depression

• Chronic exposure to stressful life events has
  been associated with development of depression
• Major depressives often have elevated levels of
  glucocorticoids (GCs)

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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)

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Glucocorticoids (GCs)

• Adrenal steroids secreted during stress
• Mobilize energy
• Increase cardiovascular tone
• Suppress growth, tissue repair, etc.
• Important for survival

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Glucocorticoids (GCs)

• Excessive GCs ? deleterious effects
• Hypertension
• Insulin-resistant diabetes mellitus
• Impotency
• Immune suppression
• Effects on the central nervous system

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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

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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

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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

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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

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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)

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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

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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

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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

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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

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Hippocampal neurogenesis

• Aged rats? remove elevated GC levels? facilitates
  neurogenesis
• NMDA receptor activation inhibits dentate
  neurogensis
• Antidepressants, ECT, physical activity
  stimulate neurogenesis

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How does disturbed adult neurogenesis contribute
to development of depression?
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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

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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)

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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?

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How does an excess of GCs increase the risk of
depression?
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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

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Whats 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

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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

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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

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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.