Case 6 - Depression Mini Learning Session Flashcards
what is major depressive episode diagnosed using
DSM-5
what is a depressive episode diagnosed using
ICD-10
what is a major depressive episode
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
what are monoamines divided into
catecholamines - dopamine and noradrenaline
indoleamines - serotonin
what do monoamines function as
both hormones and neurotransmitters
catecholamine features
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
what is the noradrenaline system
- 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
what is the serotonin system
- 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
what is the release, re uptake and degradation of these systems
- 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
serotonin re uptake and degradation molecules
- 5-HT re uptake transporter (5HTT, SERT)
- monoamine oxide (MAO-A)
noradrenaline transporter and degradation molecules
- Noradrenaline re uptake transporter (NET, NAT)
- MAO-A
- catechol-0-methyl transferase (COMT)
how are molecules of serotonin transported
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
how is the serotonin signal terminate
re uptake which is the main method
enzymatic degradation
what happens in serotonin reuptake
serotonin molecules are taken back up into the terminal via the serotonin re uptake transporter.
what happens in serotonin degradation
serotonin molecules which evade reuptake are broken down by the enzyme MAO-A to metabolites
what is the pattern for noradrenaline
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
where are concentrations of these enzymes the highest
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.
5-HT and NA enzymatic degradation diagram
what happens to noradrenaline that survives re uptake or enzymatic degradation
it is free to act at a range of receptors
what is the noradrenaline receptor most relevant to depression
the alpha 2 receptor
one. of the results is the inhibition of transmitters release and is significant for depression medication
what are all of the serotonin receptors except the 5-HT3 receptor
are all G coupled receptors except the 5-HT3 receptor is a fast cation channel - cation gating
what is the action of serotonin at all receptor except for the 5-HT1, 5-HT5
stimulate neuronal firing
the other two are negatively coupled to their secondary receptor to therefore causes inhibition of neural finding
what does NA stimulation at alpha 2 auto and heteroreceptors on NA and 5-HT neurones cause
decrease cell firing
what does NA stimulation at alpha 1 adreno-receptors on 5-HT cell body tends to do what
increase 5-HT cell firing
what is a stimulatory receptor for a serotonin neurone
alpha 1 noradrenergic receptor
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
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
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
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
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
what are MAOI antidepressants
iproniazid found to be an antidepressant but was originally developed for tb
Found to be a monoamine oxidase inhibitor
what are MAO-A inhibitors used as
antidepressants - serotonin and noradrenaline
what are MAO-B inhibitors used for
Parkinson’s disease - increased DA
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
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
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
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
how does mirtazapine
dual acting by blocking a single receptor type
what is mitrazapine
principally an adrenergic alpha 2 receptor anatoginst
what does noradrenergic alpha 2R antagonist do
blocks th negative feedback which is tending to reduce NA release
what is the net effect of mitrazapine
increase in NA release
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
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
what is the ventral neural system important for
identification of the emotional significance of stimuli and the production of affective states
what is the dorsal neural system important for
the integration of emotional inputs ad the performance of executive functions
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
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
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
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
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
what is hippocampal atrophy associated with
chronicity and treatment resistance in other studies
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
where does cortisol come from
the hypothalamus
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
what is amygdala over activity associated with
negative cognitive bias
what does HPA axis dysfunction lead to
low synaptic levels of 5-HT and NA
what does stress and genetic vulnerability elevate
glucocorticoid steroids and alter cellular plasticity via downregulation o f growth factors and glucocorticoid receptor sensitivity
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
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
