major depressive disorder Flashcards
What is MDD?
a state of low mood and aversion to activity that can have negative effects on a person’s thoughts, behaviour, feelings, world view and physical well-being
What is needed for a diagnosis of MDD?
Must have been more than 2 weeks and represent change from normal:
-has had minimum of 5 of the symptoms on DSM-IV criteria for half the days
-must have at least anhedonia or depressed moods
-no cut off for suicidal thoughts
-cause significant distress or impairment in functioning
(-no part in bipolar disorder
-not due to physiological effects of substance
-not better accounted for by bereavement)
What is kindling hypothesis?
depressive episodes become early triggered over time
name some catecholamine?
dopamine
noradrenaline
name some indoleamines
serotonin
explain the process of going from tyrosine to adrenaline
What is the rate determining step? what clinical relevance?
(L-) tyrosine - (tyrosinehydroxylase (TH)) –> L-DOPA - L-Aromatic amino acid decarboxylase (L-AADC)) –> dopamine - (Doamine beta hydroxyls (DBH))–> noradrenaline - (phenylethanolamine N-methyltransferase) –> adrenaline
tyrosine hydroxyls is the rate determining step (as it is normally saturated by substrate): can’t give tyrosine in Parkinson’s as a treatment
explain the process of doing from tryptophan to serotonin
tryptophan - (tryptophan hydroxylase)–> 5-Hydroxytryptophan- (L-AADC) –> 5-Hydroxytryptamine (serotonin)
What is tyrosine?
How is it transported not the brain?
-where is it converted?
- dietary, non essential large neutral amino acid (LNAA)
- active transport across BBB
- converted into NA in neuronal feel body in pons (particularly in locus ceruleus which then project widely in rest of brain)
What is tryptophan?
How does it get into the brain?
where is it converted
-dietary, essential large neutral amino acid
-active transport across BBB
-converted into 5-HT in neuronal cell bodies in chain of brainstem (dorsal and medial raphé nuclei)
package into vesicles and transported along axon to terminals for release
5-HT system extends to entire brain
How is the reuptake and degradation of serotonin?
- 5-HT reuptake transporter (5HTT, SERT)
- monoamine oxidase Aldehyde dehydrogenase (MOA-A) (turns 5-HT into 5-HIAA)
How is the reuptake and degradation of noradrenaline?
- noradrenaline reuptake transporter (NET, NAT)
- MAO-A
- COMPT (catechol-O-methyl transferase°
What type of receptors are serotonin receptors?
- G protein coupled except 5-HT3 (which is ligand gated ion channel)
- all stimulatory receptor (except 5-HT1 and 5-HT5 which are inhibitory receptors)
How many serotonin receptors?
5-HT1-7
How do NA and 5-HT interact?
- NA stimulates alpha 2 auto and heteroreceptor on NA and 5-HT receptors: tend to decrease firing
- Na stimulate alpha1 adrenoreceptors on 5-HT cell body tends to increase 5-HT cell firing
–> NA regulates itself and stimulates and inhibits 5-HT
What is the monoamine hypothesis of depression?
depletion of serotonin, dopamine or noradrenaline in the CNS is the underlying pathophysiology of depression
What does reserpine do?
irreversibly block vesicular monoamine transporter (VMAT) depleting monoamine and causing depression
What do SSRIs block?
5-HT re-uptake transporter (SERT)
What do tricyclic antidepressants block?
both NA and 5-HT re-uptake transporters (SERT and NET)
What does iproniazid do?
monoamine oxidase inhibitor
What is the mechanism of action of mirtazapine?
- adrenergic alpha2 autoreceptor antagonist
- blocks neg feedback which would normally tend to reduce NA release
- increase NA release
- also alpha2 heteroreceptor antagonist : blocks neg feedback tending to reduce 5-HT release: increase 5-HT release
What is in the ventral neural system?
- ventral anterior cingulate
- lateral orbitofrontal cortex
- ventral striatum
- amygdala
- medial thalamus
What is the ventral neural system important for?
important for identification of emotional significance of stimuli and production of affected states
What comprises of the dorsal neural system?
- dorso lateral prefrontal cortex
- dorsal anterior cingulate
- hippocampus
What is the dorsal neural important for?
integration of emotional inputs and the performance of executive functions
What are the functional abnormalities in MDD in regards to ventral and dorsal neural systems?
- -> dorsal neural system underachieve:
- DLPFC and dorsal ACC: psychomotor retardation, apathy, and deficits in attention and working memory
- hippocampus: memory consolidation
- -> ventral system overactive
- ventromedial orbitofrontal cortex: enhanced sensitivity to pain, anxiety, depressive rumination and tension
- ventral anterior cingulate: depressed moods
- amygdala: differential processing of positive versus negative stimuli
Which are the three areas the are dysfunctional in MDD?
- amygdala
- hippocampus
- stress hormones
What is the role of the amygdala and how is it dysfunction in MDD?
-important in social cognition: modulates visual and attentional processing, particularly of facial expression
-in depression, amygdala is overactive when shown sad stimuli and under active when shown positive stimuli (–> negative cognitive bias which can be treated with CBT)
+ larger in MDD (could be depression causing it to be larger or the fact that it is larger that causes the depression)
What is the role of the hippocampus and how is it dysfunction in MDD?
- memory consolidation
- MDD: reduction of hippocampal volume: can be associated with dementia type symptoms but antidepressants can reverse this
How are the stress hormones dysfunctional in MDD?
- higher level of cortisol due to dysfunctional in HPA axis:
1. chronic stress: excessive glucocorticoids and corticotrophin releasing hormone (cry) release
2. increase glucocorticoids dysregulates amygdala function
3. increase adrenal activity leads to increase sympathetic tone which leads to release of pro inflammatory cytokines
4. pro inflammatory cytokines and glucocorticoids lead to increase MAO which leads to decrease 5-HT, NA, DA
5. cytokines and glucocorticoids: decrease neurotropic factors (e.g. BDNF)
6. decrease BDNF: decrease neurogenesis and hippocampal volume
7. dysregulated amygdala and hippocampus maintain abnormal glucocorticoids BDNF and cytokines
8. increase pro-inflammatory cytokines: increase physical illness symptoms, increase risk of inflam disorders such as CVS, diabetes etc
Where is the only place neurones can be produced in adult life and what is the functional consequence of MDD in regards to this?
-hippocampus: if you suppress it, hippocampal volume will decrease because no neurones will be produced
What is the action of SSRIs in the first two weeks of taking them? (acute reaction)
block SERT: 5-HT activate somatodendritic (in raphia nuclei) 5-HT1A auto receptors: inhibits firing –> decrease terminal release
What is the chronic reaction to SSRIs?
autoreceptors desensitised, firing restored, terminal release restored, reuptake remains blocked, forebrain 5-HT rises
