major depressive disorder

Question 1

What is MDD?

Answer 1

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

Question 2

What is needed for a diagnosis of MDD?

Answer 2

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)

Question 3

What is kindling hypothesis?

Answer 3

depressive episodes become early triggered over time

Question 4

name some catecholamine?

Answer 4

dopamine

noradrenaline

Question 5

name some indoleamines

Answer 5

serotonin

Question 6

explain the process of going from tyrosine to adrenaline

What is the rate determining step? what clinical relevance?

Answer 6

(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

Question 7

explain the process of doing from tryptophan to serotonin

Answer 7

tryptophan - (tryptophan hydroxylase)–> 5-Hydroxytryptophan- (L-AADC) –> 5-Hydroxytryptamine (serotonin)

Question 8

What is tyrosine?
How is it transported not the brain?
-where is it converted?

Answer 8

• 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)

Question 9

What is tryptophan?
How does it get into the brain?
where is it converted

Answer 9

-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

Question 10

How is the reuptake and degradation of serotonin?

Answer 10

• 5-HT reuptake transporter (5HTT, SERT)

- monoamine oxidase Aldehyde dehydrogenase (MOA-A) (turns 5-HT into 5-HIAA)

Question 11

How is the reuptake and degradation of noradrenaline?

Answer 11

• noradrenaline reuptake transporter (NET, NAT)
• MAO-A
• COMPT (catechol-O-methyl transferase°

Question 12

What type of receptors are serotonin receptors?

Answer 12

• 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)

Question 13

How many serotonin receptors?

Answer 13

5-HT1-7

Question 14

How do NA and 5-HT interact?

Answer 14

• 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

Question 15

What is the monoamine hypothesis of depression?

Answer 15

depletion of serotonin, dopamine or noradrenaline in the CNS is the underlying pathophysiology of depression

Question 16

What does reserpine do?

Answer 16

irreversibly block vesicular monoamine transporter (VMAT) depleting monoamine and causing depression

Question 17

What do SSRIs block?

Answer 17

5-HT re-uptake transporter (SERT)

Question 18

What do tricyclic antidepressants block?

Answer 18

both NA and 5-HT re-uptake transporters (SERT and NET)

Question 19

What does iproniazid do?

Answer 19

monoamine oxidase inhibitor

Question 20

What is the mechanism of action of mirtazapine?

Answer 20

• 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

Question 21

What is in the ventral neural system?

Answer 21

• ventral anterior cingulate
• lateral orbitofrontal cortex
• ventral striatum
• amygdala
• medial thalamus

Question 22

What is the ventral neural system important for?

Answer 22

important for identification of emotional significance of stimuli and production of affected states

Question 23

What comprises of the dorsal neural system?

Answer 23

• dorso lateral prefrontal cortex
• dorsal anterior cingulate
• hippocampus

Question 24

What is the dorsal neural important for?

Answer 24

integration of emotional inputs and the performance of executive functions

Question 25

What are the functional abnormalities in MDD in regards to ventral and dorsal neural systems?

Answer 25

- -> 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

Question 26

Which are the three areas the are dysfunctional in MDD?

Answer 26

- amygdala - hippocampus - stress hormones

Question 27

What is the role of the amygdala and how is it dysfunction in MDD?

Answer 27

-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)

Question 28

What is the role of the hippocampus and how is it dysfunction in MDD?

Answer 28

- memory consolidation - MDD: reduction of hippocampal volume: can be associated with dementia type symptoms but antidepressants can reverse this

Question 29

How are the stress hormones dysfunctional in MDD?

Answer 29

- 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

Question 30

Where is the only place neurones can be produced in adult life and what is the functional consequence of MDD in regards to this?

Answer 30

-hippocampus: if you suppress it, hippocampal volume will decrease because no neurones will be produced

Question 31

What is the action of SSRIs in the first two weeks of taking them? (acute reaction)

Answer 31

block SERT: 5-HT activate somatodendritic (in raphia nuclei) 5-HT1A auto receptors: inhibits firing --> decrease terminal release

Question 32

What is the chronic reaction to SSRIs?

Answer 32

autoreceptors desensitised, firing restored, terminal release restored, reuptake remains blocked, forebrain 5-HT rises