Lecture 10

• Symptoms of depression


  • Mood disorders
  • Unipolar — depressive episodes only
  • Bipolar disorder — depressive + manic or hypomanic episodes
  • Depressive episode symptoms: Depressed mood, Fatigue, Anhedonia
  • Manic episode: Elevated, expansive or irritable mood, Inflated self esteem, Reduced need for sleep
• Aetiology of depression


  • Genetic predisposition
  • Current stress or adversity: Life events, Daily stress, Marital satisfaction, Physical illness
  • Physical illness
  • Early life adversity
• Genetic predisposition


  Both uni + bipolar depression, Highest in bipolar (62-100% in monozygotic twins), Unipolar low risk (31-42% in monozygotic twins, 19% dizygotic), GWAS: Regions of interest include — 4p16, 12q23-24, 16p13, 21q22 and X24-26 (all for bipolar) 3p25-26 (unipolar), Implicate serotonin transporter promoter (17q11.1-q12) — short allele more susceptible to depression, PTSD + suicide, Multiple genes with small effect + environment
• Current stress or adversity


  Life events, Daily stress — higher incidence in carers/partners of dementia patients, Marital satisfaction — -ve relationship, Physical illness — CVD, diabetes + cancers
• Physical illness


  High degree of comorbidity with depression
• Early life adversity


  Childhood adversity has long lasting effects which impart vulnerability to mood disorders
• Biological mechanisms involved


  HPA function, Monoamine neurotransmission
• HPA axis


  Describe the HPA dysfunction observed in mood disorders (circadian rhythm, DST & Dex/CRH)
• Physiology


  Regulation of cortisol = circadian + stress, Cortisol + depression: Hypercortisolaemia — -ve feedback
• Dexamethasone suppression test (DST)


  Dexamethasone — GR agonist, Activates feedback → suppresses cortisol release, Suppression is attenuated in depressed patients compared to controls, Depressed patients have GR-mediated feedback, Dex non-suppression: GR receptors desensitised/dysfunctional → elevated cortisol
• Dex/CRH test


  Dex/CRH exaggerated in depressed patients, Compromised GR mediated -ve feedback
• Cortisol impact on mood

  Childhood adversity: Long term changes in HPA axis, Increased cortisone, What cortisol does in the brain: GR/MR — nuclear receptors, Homo/heterodimers → bind CORT, translocate to nucleus, Bind to HREs of DNA, Stabilise (+ve regulation) or interfere (-ve regulation) w/ binding of transcription factors, Glucocorticoid receptors (GRs): Low affinity, high capacity, Endogenous agonists: corticosterone + cortisol, Mineralocorticoid receptors: High affinity, low capacity, Endogenous agonists: aldosterone + corticosterone/cortisol, MR is protected from CORT by 11-β-hydroxysteroid dehydrogenase in periphery, MR is receptor for CORT in brain, GRs in the brain: GR + MR present in hippocampus, GR present in PFC, Cortisol + 5-HT neurotransmission: GR + MR present in 5-HT neurones — positioned to affect proteins intrinsic to 5-HT neurones (5-HT1A autoreceptor), GR + MR present in forebrain neurones — positioned to affect postsynaptic 5-HT receptors, Chronic high CORT causes: reduced TPH2 mRNA & TPH2 activity, reduced somatodendritic 5-HT1A function, reduced postsynaptic 5-HT1A receptor number, Net decrease in 5-HT1A receptor-mediated neurotransmission, CORT effect on dendrites + spines: Reduces dendritic complexity + no. of spines, Caused by pruning, CORT effect on grey matter: Reduced grey matter
• Comorbidity with depression

  Causal factors of mood disorders

  A) Physical illness

  B) Cortisol

  C) Physical

  D) Psychological

  E) Inflammation

  F) Metabolic

  G) Perfusion

  H) Nutrition

  I) Reduced activity

  J) Reduced social life

  K) Mood disorder

  
• HPA axis - mood disorders

  Cortisol release

  A) Hypothalamus

  B) CRH + AVP

  C) anterior pituitary

  D) ACTH

  E) adrenals

  F) cortisol

  
• Cortisol release feedback

  Release -> inhibition

  A) CRH + AVP

  B) ACTH

  C) cortisol

  D) GR

  E) -ve feedback

  F) GR