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Semester 3 > Case 6 - Depression Mini Learning Session > Flashcards

Case 6 - Depression Mini Learning Session Flashcards

1
Q

what is major depressive episode diagnosed using

A

DSM-5

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2
Q

what is a depressive episode diagnosed using

A

ICD-10

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3
Q

what is a major depressive episode

A

5 or more of the symptoms present during same 2 week period and represent a change from normal
- either anhedonia or depressed mood must be present
- cause either significant distress or impairment of functioning
- not part of bipolar disorder
- not due to the direct physiological effects of a substance
- not better accounted for by bereavement
- prominent negative cognitions
- when severe can involve psychosis, loss of colour vision, catatonic retardation and suicide

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4
Q

what are monoamines divided into

A

catecholamines - dopamine and noradrenaline
indoleamines - serotonin

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5
Q

what do monoamines function as

A

both hormones and neurotransmitters

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6
Q

catecholamine features

A

when produced by the adrenal gland, they function as circulating hormones and the great majority of adrenaline is synthesised there
- 90% of the serotonin in the body is found in the enteric chromaffin cells In the GI tract and regulates spinal movement
- however, when in the CNS, they act as neurotransmitter and there are significant quantities of dopamine and noradrenaline and serotonin synthesised as neurotransmitters in the. rain

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7
Q

what is the noradrenaline system

A
  • tyrosine is a non-essential large amino acid (LNAA) derived from phenylalanine and the diet
  • active transport across the BBB
  • converted into NA in neuronal cell bodies in the pons particularly locus cerulean
  • NA packaged into vesicles and transported along axon to terminals for release
  • NA system extends extensively into the entire brain
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8
Q

what is the serotonin system

A
  • tryptophan is a dietary essential, large amino acid (LNAA)
  • active transport across the BBB
  • converted into 5-HT in neuronal cell bodies In the chain of brainstem nuclei, particularly the dorsal an medial Raphe
  • 5-HT packaged into vesicles and transported along axon to terminals for release
  • 5-HT system extends extensively to entire brain
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9
Q

what is the release, re uptake and degradation of these systems

A
  • 5-HT and NA released into synaptic Cleft
  • act at a range of pre and post synaptic receptors
  • signal is terminated by 2 methods, re uptake and enxmatic degradation
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10
Q

serotonin re uptake and degradation molecules

A
  • 5-HT re uptake transporter (5HTT, SERT)
  • monoamine oxide (MAO-A)
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11
Q

noradrenaline transporter and degradation molecules

A
  • Noradrenaline re uptake transporter (NET, NAT)
  • MAO-A
  • catechol-0-methyl transferase (COMT)
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12
Q

how are molecules of serotonin transported

A

have been transported in vehicles from the cell bodies and are now at the terminal, where the vesicles fuse with the terminal membrane and the serotonin is released into the synaptic cleft. in the cleft it acts as a neurotransmitter by acting at a range of pre and post synaptic receptors. the process is identical for noradrenaline

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13
Q

how is the serotonin signal terminate

A

re uptake which is the main method
enzymatic degradation

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14
Q

what happens in serotonin reuptake

A

serotonin molecules are taken back up into the terminal via the serotonin re uptake transporter.

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15
Q

what happens in serotonin degradation

A

serotonin molecules which evade reuptake are broken down by the enzyme MAO-A to metabolites

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16
Q

what is the pattern for noradrenaline

A

it either undergoes re uptake via the noradrenaline re uptake transporter or NAT or it under goes enzymatic degradation. but in the case of noradrenaline there are two main enzymes: MAO-A and COMT

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17
Q

where are concentrations of these enzymes the highest

A

in the terminal than in the synapse, so that when the neurotransmitters are taken back into the terminal, the majority undergoes enzymatic degradation there too, by MAO-A in the case of serotonin and both MAO-A and COMT in the case of noradrenaline.

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18
Q

5-HT and NA enzymatic degradation diagram

A
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19
Q

what happens to noradrenaline that survives re uptake or enzymatic degradation

A

it is free to act at a range of receptors

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20
Q

what is the noradrenaline receptor most relevant to depression

A

the alpha 2 receptor

one. of the results is the inhibition of transmitters release and is significant for depression medication

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21
Q

what are all of the serotonin receptors except the 5-HT3 receptor

A

are all G coupled receptors except the 5-HT3 receptor is a fast cation channel - cation gating

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22
Q

what is the action of serotonin at all receptor except for the 5-HT1, 5-HT5

A

stimulate neuronal firing

the other two are negatively coupled to their secondary receptor to therefore causes inhibition of neural finding

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23
Q

what does NA stimulation at alpha 2 auto and heteroreceptors on NA and 5-HT neurones cause

A

decrease cell firing

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24
Q

what does NA stimulation at alpha 1 adreno-receptors on 5-HT cell body tends to do what

A

increase 5-HT cell firing

25
what is a stimulatory receptor for a serotonin neurone
alpha 1 noradrenergic receptor
26
why is the alpha 1 noradrenergic receptor a heroceptor
as it is a receptor of one type sitting on and regulating the firing of a neurone of another type. so when noradrenaline is released from the noradrenergic terminal at the top, it diffuses across the synapse, binds to the serotonin neurone so that more 5-HT is released from the terminal at the bottom right. so the noradrenaline system stimulates the serotonin system via alpha 1 adrenergic heteroeptors
27
features of the alpha 2 noradrenergic receptors
they are inhibitory receptors. when the neurone is stimulated to release noradrenaline into the synapse, some of the noradrenaline stimulates these alpha 2 auto receptors and this causes inhibition of the cell firing. however, there are also alpha 2 adrenergic heteroxeptors on the terminal of the adjacent serotonin neurone, and the action of noradrenaline there is to reduce the firing of the serotonin neurone and the associated serotonin release. so you can see that the tone of the serotonin system is the result of finely balance stimulation and inhibition of the serotonin system by the noradrenaline system acting as an acceleration and a brake via the alpha 1 and 2 heteroceptors respectively
28
what drug causes depression
reserpine caused high rate of depression. it depletes monoamine neurotransmitters in neurones through its action as a vesicular monoamine transporter VMAT blocker transient reduction of brain 5-HT causes a recurrence of depression in vulnerable subjects
29
what is reserpine
a VMAT blocker vesicular monoamine transporter transports free cytoplasmic NA, 5-HT and DA in the presynaptic nerve terminal into storage vesicles for subsequent release - in vesicle membranes reserpine irreversibly blocks VMAT cytoplasmic monoamines broke down by MAO and COMT leading to long lasting depletion takes days to weeks to replenish new VMAT
30
what is rapid tryptophan depletion
is a research technique to transiently, selectively and safely lower CNS 5-HT achieved by drinking mixture of LNAAs devoid of tryptophan reduction in CNS serotonin is associated with a. rapid return of depressive symptoms in MDD patients, in the early stages of remission on ADs and other vulnerable subjects
31
what are MAOI antidepressants
iproniazid found to be an antidepressant but was originally developed for tb Found to be a monoamine oxidase inhibitor
32
what are MAO-A inhibitors used as
antidepressants - serotonin and noradrenaline
33
what are MAO-B inhibitors used for
Parkinson's disease - increased DA
34
what are the MAO-A inhibitors
MAO-A inhibitors: Irreversible: phenelzine, tranylcypromine Reversible: moclobomide NB: can’t metabolise either monoamines e.g red wine and cheese
35
monoamine oxidase activity in MDE
comparison of monoamine oxidase A specific distribution volumes between depressed and healthy stay participants is done using the C-Harmine PET. On average, MAO-A DVs was elevated by 34% in depressed individuals High MAO-A activity will lead to chronically low synaptic 5-HT and NA
36
tricyclic, SNRI, SSRI antidepressants
imipramine developed as antipsychotic but ineffective Effective antidepressant Found to reversibly block SERT and NAT - increased synaptic 5-HT and NA Many tricyclic ADs developed (desipramine, amitriptyline, clomiprmaine etc) Selective serotonin re uptake inhibitors ADs developed Serotonin and noradrenaline re uptake inhibitors e.g venlafaxine and duloxetine
37
how do antidepressants increase 5-HT
SSRI antidepressant result in sustained increase in extracellular 5-HT in a range of brain regions similar effect on NA from dual action antidepressant
38
how does mirtazapine
dual acting by blocking a single receptor type
39
what is mitrazapine
principally an adrenergic alpha 2 receptor anatoginst
40
what does noradrenergic alpha 2R antagonist do
blocks th negative feedback which is tending to reduce NA release
41
what is the net effect of mitrazapine
increase in NA release
42
what does noradrenergic alpha 2 R antagonism also do B
Blocks the negative feedback tending to reduce 5-HT release. net effect is increased 5-HT release increased NA release also
43
what is the Kindling hypothesis
depressive episodes become more easily triggered over time: as the number of depressive episodes increase, further episodes are predicted more by the number of prior episodes rather than by life stress Kindling = process which occurs by a lowering of the threshold for the impact of a stressful life event, or an increase in spontaneous dysregulatio
44
what is the ventral neural system important for
identification of the emotional significance of stimuli and the production of affective states
45
what is the dorsal neural system important for
the integration of emotional inputs ad the performance of executive functions
46
what are the functional abnormalities of the ventral neural system in MDE
overactive Ventromedial orbitofrontal cortex enhanced sensitivity to pain, anxiety, depressive ruminations and tension Ventral ACC: depressed mood Amygdala: preferential processing of negative stimuli compared to positive Normalises with treatment
47
what are the functional abnormalities of the dorsal neural system in MDE
underachieve DLPFC and dorsal ACC: psychomotor retardation, apathy, and deficits in attention and working memory Hippocampus: impaired memory consolidation Normalises with treatment
48
What happens in the amygdala in MDD
the amygdala is overactive when people are shown sad stimuli, but is relatively under active when shown positive stimuli like things that they would be rewarded by, or even smiling faces amygdala modulates visual and attentional processing particularly of facial expression enlarged In size bilaterally in patients with a first episode of depression
49
what is the negative balance inMDD
MDD is associated with a negative cognitive bias Patients process visual and other sensory inputs less positively and think about themselves, the world and their future more pessimistically elevated 5-HT reveres this negative bias Elevated 5-HT is the shared outcome of all current antidepressant drug and physical therapies and reversal of negative bias can be detected before mood improvement Reversal of negative cognitive bias is also the aim of CBT, and increased 5-HT facilitates this Combined CBT and antidepressants is better than either alone
50
why is there a reduced hippocampal volume in MDD
longer durations during which dqeoressuve episodes go untreated with anti depressant medication are associated with reduction in hippocampal volume antidepressants may have a neuroprotective effect during depression
51
what is hippocampal atrophy associated with
chronicity and treatment resistance in other studies
52
what is the role of stress hormones in MDD
a consistent finding in pateints with MDD is a high level of the stress hormone cortisol
53
where does cortisol come from
the hypothalamus
54
chronic stress flow chart
CHRONIC STRESS: external and internal Hypothalamus: excessive CRH release Pituitary: excessive ACTH Adrenal cortex: excessive glucocorticoids Increase glucocorticoids dysregulates amygdala function Increased adrenal activity leads to increased sympathetic tone which leads to pro inflammatory cytokines Pro inflammatory cytokines and glucocorticoids lead to increase MAO, lead to decreases 5-HT, NA, DA Cytokines and glucocorticoids also lead to decreased neurotrophic factors e.g BDNF Decreased BDNF leads to decreased neurogenesis and hippocampus volume Dysregulated amygala and hippocampus maintain abnormal glucocorticoids, BDNF, and cytokines Increased pro inflammatory cytokines leads to psychical illness symptoms, increased risk of inflammatory disorders such as cardiovascular disease, diabetes etc Dysregulated amygdala and hippocampus maintain abnormal glucocorticoids, BDNF and cytokines
55
what is amygdala over activity associated with
negative cognitive bias
56
what does HPA axis dysfunction lead to
low synaptic levels of 5-HT and NA
57
what does stress and genetic vulnerability elevate
glucocorticoid steroids and alter cellular plasticity via downregulation o f growth factors and glucocorticoid receptor sensitivity
58
clinical management of mild depression
do not use anti depressants routinely to treat mild depression But consider using them if there is a history of moderate to severe recurrent depression or the depression has persisted for more than 2-3 months offer a low intensity psychosocial intervention: Individual guided self help based on the principles of CBT Computerised CBT A structured group physical activity programme
59
what is the clinical management of severe depression
provide a combination of antidepressant medication and a high intensity psychological intervention such as CBT Antidepressants SSRI e.g sertraline Change to venlafaxine, mirtzapaine, escitalopram or vortioxetine Add an augmenting agent e.g second generation antipsychotic or lithium Change the antidepressant to tricyclic; amitriptyline or clomipramine Change the antidepressant to an MAOI e.g phenelzine

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