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Case study: David

  • Current symptoms: depressed mood, low energy, social withdrawal, decreased school performance, poor self esteem, hopelessness
  • Stressors: parent divorce age 12, mother departure, stepmother becoming unavailable due to special needs sibling and depression, chronic family stress and lack of support
  • Genetic risk: mother, sister, uncle with depression
  • Onset of symptoms: first episode minor depression at age 12

Basic Brain Units

  • Neurons
    • Body (contains cell nucleus/instructions)
    • Axon (long connections to send chemical/electrical signals to other neurons)
    • Dendrites (receive the signals)
  • Glial cells - Support and Maintenance of the Neurons

The neuron (diagram)

Gray Matter

  • Neuron bodies
  • Dendrites
    • Short extensions that receive information from other neurons
  • Synapses
    • Gaps over which neurons communicate by passing chemical messages back and forth

White matter

  • Speeds Up Neurons 100x
  • Newborns: few myelinated axons
    • Different regions at different ages

Neurotransmitters

  • Amino acid neurotransmitters: glutamate, gamma-aminobutyric acid (GABA)
  • Monoamines:
    • Serotonin
    • Dopamine
    • Noradrenaline
  • Peptides: corticotrophin releasing factor (CRF)
  • Cytokines

Monoamine synthesis (diagram)

Monoamine theory of depression

  • Observed that MAO inhibitors decreased depression; agents depleting monoamines caused depression: led to first theory that depression due to insufficient monoamines
  • However:
    • Not all drugs that increased monoamines helped depression (cocaine)
    • Not all patients responded
    • Not explain delayed response

Revised monoamine theory

  • Increased levels of neurotransmitter lead to desensitization of regulatory inhibitory receptors, leading to increased monoamine activity
  • Explains delayed course
  • Different pharmaceutical agents affect NA, 5HT, or DA

Other neurotransmitters

  • Peptides:
    • Corticotropin-releasing factor (CRF)
    • secreted by hypothalamus in response to stress, stimulates pituitary to release ACTH
  • Elevated in depression
  • Glutamate
    • Major excitatory neurotransmitter
    • Reports of being elevated in depression
  • GABA
    • Primary inhibitory neurotransmitter
    • Elevated levels in plasma and CSF in response to stress
    • Expression affected by early life stressors; interacts with 5-HT
    • Abnormal GABA receptor expression in suicide victims
    • Affected by sex steroids which could contribute to sex differences in depression

Cytokines

  • Growing evidence that inflammatory processes associated with depression
  • Cytokines: signaling molecules secreted by immune cells (B and T cells)
  • Interferons (IFN), interleukins (IL), tumor necrosis factors (TNF)
  • Cytokines can bind to neurons and glia and affect function
  • Similarities to effects of stressors, including increased activity of HPA
  • Cause behavioral/mood changes such as anhedonia
  • Abnormal levels associated with depression

Brain changes in depression

  • Decreased volume in limbic structures such as hippocampus, amygdala, medial pre-frontal cortex
  • Decreased activity of prefrontal cortex
  • Abnormal response of limbic structures to stressful stimuli such as angry/fearful faces

What causes depression?

"What"

  • Stressors
    • Activation of hypothalamic-pituitary-adrenal (HPA) axis
    • Stress response adaptive in short term: help organism to cope
    • Chronic stressor may result in allostatic overload and vulnerability to pathology
    • Stressors may result in release of monoamines(DA, NA, 5HT)
    • Chronic or severe stress lead to depletion of monoamines
    • Sensitization of receptors: elevated future responses to mild stressors

“Who”

  • Familial factors
    • Family environment
    • Genetics
  • Interactions between genes and environment

Neuroticism and 5-HT transporter (5-HTT)

  • Serotonin transporter removes serotonin from synaptic cleft
  • Gene encoding transporter (SLC6A4) has short variation with reduced activity resulting in higher concentrations of 5-HT in cleft
  • Short form is associated with neuroticism
  • Non-symptomatic carriers:
    • increased activity of amygdala in response to neutral and threatening stimuli
    • decreased volume of subgenual ACC and amygdala
    • decreased functional connectivity between ACC and amygdala (Kanli and Lesch, Nat Neuroscience 2007)
  • Carriers also more likely to develop depression in response to life stressors


“When”

  • Developmental stages: adolescence

Adolescent brain and stress

  • Prolonged stress response in adolescents compared with adults
  • Some evidence that may result in longer- lasting remodeling and future responses to stressors

Effects of sex steroids on the brain

  • Organizational and activational
  • Both occurring in adolescence


Puberty and depression

  • Emergence of two- fold greater risk for depression in females than males, linked to pubertal stages rather than age
  • Why?

(diagram)


Puberty and neurotransmitters

  • Sex differences in response of HPA axis
  • Ovarian hormones increase response of HPA axis in females
  • Oestrogen and testosterone decrease CRH production and HPA effects in males
  • Lower oestrogen levels in adult females associated with increased risk depression; fluctuations during adolescence may increase risk
  • Increased risk for depression in adolescence:
    • Abnormal development of prefrontal cortex (top- down) and/or limbic regions (bottom-up)?

Developmental trajectory

  • Importance of development in understanding risk and mechanisms for mental health syndromes such as depression
    • Vulnerability
    • The ways in which syndromes may manifest
    • Treatment approaches