6 - depression: pathophysiology and clinical management Flashcards
what is depression?
a state of low mood and aversion to activity that can have a -ve effect on a person’s thoughts, behaviour, feelings, world view, and physical well-being
there is an increased risk of depression in what medical conditions?
hypothyroidism, Addison’s disease, MS, influenza, post-stroke, menopause, alcohol/drug abuse
depression is a side effect of what drugs?
corticosteroids, beta blockers, statins, oral contraceptives (particularly progestogens) etc…..
in psychiatry, what 2 ways is the word ‘depression’ normally used in?
- as a SYMPTOM — ie. feeling down, depressed or hopeless
- as shorthand for a sustained period of mental illness which is more correctly called a major depressive episodes (MDE) or a depressive episode
what is major depressive disorder (MDD)?
a mental disorder characterised by recurrent major depressive episodes or a single chronic episode
what is anhedonia?
having little interest or pleasure in doing things
what is psychomotor retardation?
moving or speaking so slowly that other people could have noticed
what is psychomotor agitation?
being so figety or restless that you have been moving around a lot more than usual
what is the depression test questionnaire?
PHQ-9
how is a major depressive episode diagnosed?
5+ symptoms present during same 2 week period and represent a change from normal
- either anhedonia or depressed mood must be present
- cause significant distress or impairment of functioning
- not part of bipolar disorder
- not due to the direct psychological effects of a substance (alcohol, drug, medication)
- not better accounted for by bereavement
5 or more in green
is the burden of depression 50% higher for females or males?
females
what are the 2 types of monoamines?
catecholamines and indoleamines
name 2 catecholamines
dopamine and noradrenaline
name an indoleamine
serotonin (5-HT)
describe catecholamine structure
catechol moiety + amine side chain
= benzene ring with 2 OH side groups and amine side chain
describe indoleamine structure
- indole moiety + amine side chain
= bicyclic benzene ring fused to form pyrrole ring and amine side chain
what are catecholamines derived from?
tyrosine amino acid
what is serotonin derived from?
tryptophan
both dopamine and 5-HT are synthesised in a 2 stage enzymatic process involving what 2 steps?
- hydroxylation
- decarboxylation
what enzyme is used for the decarboxylation step in both dopamine and 5-HT synthesis?
L-Aromatic amino acid decarboxylase (L-AADC)
describe dopamine synthesis
tyrosine — (tyrosine hydroxylase TH) —> L-DOPA —(L-AADC) —> dopamine
describe noradrenaline and adrenaline synthesis
dopamine —(dopamine B-hydroxylase DBH)—>noradrenaline —(phenylethanolamine N-methyltransferase)—> adrenaline
describe serotonin synthesis
tryptophan —(tryptophan hydroxylase)—> 5-hydroxytryptophan —(L-AADC)—> 5-hydroxytryptamine = serotonin
monoamines function as what?
both neurotransmitters and hormones, depending on where they’re produced
catecholamines act as hormones when produced by what?
adrenal glands (majority of adrenaline made here)
where is 90% of serotonin found?
in enterochromaffin cells in the GI tract — regulate intestinal movements
describe the noradrenaline system
- active transport of tyrosine across BBB
- converted into NA in neuronal cell bodies in pons, particularly locus ceruleus
- NA packaged into vesicles in cell body and transported along axon to terminals for release
NA system extends extensively to entire brain and upper spinal cord
what is tyrosine
a non-essential large neutral amino acids derived from phenylalanine and the diet
where is locus ceruleus?
in dorsal pons
cell bodies of noradrenergic neurons form nuclei where?
only in pons
what is tryptophan?
- a dietary, essential, large neutral amino acid (LNAA)
- absorbed from GI tract into bloodstream
describe the 5-HT system
- active transport of tryptophan across BBB
- converted into 5-HT in neuronal cell bodies in chain of brainstem nuclei (raphe nuclei), particularly the dorsal and medial raphe
- 5-HT packed into vesicles and transported along axon to terminals for release
5-HT system extends extensively to entire brain
where is raphe nuclei?
runs entire length of brainstem from medulla to midbrain
signal by 5-HT and NA after being released into synaptic cleft is terminated by what 2 methods?
reuptake and enzymatic degradation
what are the methods of termination for 5-HT and noradrenaline?
serotonin
- SERT = serotonin reuptake transporter
- MAO-A = monoamine oxidase
NA
- NAT = noradrenaline reuptake transporter
- MAO-A
- COMT = catechol-O-methyl transferase
where is the conc of the reuptake enzymes highest and what is the effect of this?
the conc of these reuptake enzymes is higher in the terminal than in the synapse, so that when the neurotransmitters are taken back up into the terminal the majority undergoes enzymatic degradation there too, by MAO-A for serotonin, and by both MAO-A and COMT in the case of noradrenaline
what happens to the small proportion of neurotransmitters that evade enzymatic degradation after reuptake?
recycled directly into vesicles for further release
what does MAO-A (monoamine oxidase) do?
break down 5-HT and NA into metabolites
what are the main metabolites for 5-HT and NA enzymatic degradation?
5-HT —> 5-HIAA = 5-hydrpoxyindole acetic acid
NA —> VMA (vanillyandelic acid) + MHPG
NA that survives reuptake of enzymatic degradation is free to do what?
act at a range of noradrenergic receptors
what noradrenergic receptor is most relevant to depression?
a2 receptor — NA stimulation at this receptor results in the inhibition of transmitter release
what kind of receptors are the 5-HT receptors?
all are G protein coupled receptors apart from the 5-HT3 receptor which is a ligand-gated ion channel
what is the action of serotonin at the 5-HT receptors?
the action of serotonin at all of them is to stimulate neuronal firing, except for the 5-HT1 AND 5-HT5 receptors — these are negatively coupled to the 2nd messenger system so that agonism of these receptors by serotonin causes inhibition of neuronal firing
describe 5-HT and NA interactions at a1 receptors
an important function of the noradrenaline system is to interact with and regulate the serotonin system
- serotonin neuron has a NA a1 stimulatory receptor on it (a heteroceptor)
- NA is released and diffuses across synapse to bind to the a1 heteroceptor on the 5-HT neuron and acts to stimulate the firing of the serotonin neurone so that more serotonin is released from the terminal
the noradrenaline system stimulates the serotonin system via ________
alpha 1 adrenergic heteroceptors
describe NA and 5-HT interactions via alpha 2 noradrenergic receptors
= inhibitory receptors
- a2 autoreceptors on NA neuron — some of NA released stimulates these autoreceptos and inhibits the cell firing
- a2 adrenergic heteroceptor on serotonin adjacent neuron
- NA acts on these to reduce firing of serotonin neuron and the associated serotonin release
what is VMAT?
= vesicular monoamine transporter (VMAT)
- transports free cytoplasmic NA, 5-HT and DA in the presynaptic nerve terminal into storage vesicles for subsequent release
what drug irreversibly blocks VMAT?
reserpine (antihypertensive and antipsychotic agent)
- caused a high rate of depression
- cytoplasmic monoamines broken down by MAO and COMT, leading to long-lasting depletion
- takes days-weeks to replenish new VMAT
what is rapid tryptophan depletion?
a research techniques to transiently, selectively and safely lower CNS 5-HT
MAO-A vs MAO-B inhibitors
MAO-A inhibitors — antidepressants
MAO-B inhibitors — parkinson’s disease - increase dopamine
why must patients on MAOIs stick to a very low tyramine diet?
- they can’t break down monoamines when on an MAOI
- high levels could cause a hypertensive crisis which can be dangerous and even lead to a stroke
name some MAOIs
- irreversible = phenelzine, tranylcypromine
- reversible = moclobomide
what is MAO responsible for?
the breakdown of 5-Ht and (along with COMT) NA
what are imipramine, desipramine, amitriptyline, clomipramine?
- tricyclic antidepressants
- block SERT and NAT = increased synaptic 5-HT and NA
name some SSRIs
- fluoxetine
- paroxetine
- fluvoxamine
- sertraline
- citalopram
- escitalopram
what kind of drugs are venlafaxine and duloxetine?
SNRIs
what types of drugs blocks SERT, NET?
- tricyclic and SNRI ADs block SERT and NET
- SSRIs block only the SERT
why do SSRIs have fewer side effects and are safer in overdose than tricyclics?
lack the unwanted binding at a range of receptors that the tricyclics generally have
through blocking SERT, SSRI antidepressants result in what?
a sustained increase in extracellular 5-HT in a range of brain regions
(similar effect on NA from dual-action antidepressants eg SNRIs, tricyclics)
describe the newer antidepressant mirtazapine
- principally an adrenergic a2 receptor antagonist
- noradrenergic a2 receptor antagonism blocks the -ve feedback which reduces NA release
- the effect is more NA release
- noradrenergic a2R antagonism also blocks the -ve feedback tending to reduce 5-HT release
- not effect of this is increase in 5-HT release
what is the kindling hypothesis of MDD?
kindling = process which occurs by a lowering of the threshold for the impact of stressful life events, or an increase in spontaneous dysregulation
depressive episodes become more easily triggered over time
what are predictors of recurrenct MDD?
- positive family history of depressive illness
- earlier age of onset of index episode
as the number of depressive episodes increase, future episodes are predicted more by _____ than by _____
predicted more by the number of prior episodes than life stresses
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?
integration of emotional imputs and the performance of executive functions
what is the dorsal neural system like in major depressive episodes? explain
UNDERACTIVE
- dorsao-lateral prefrontal cortex (DLPFC) and dorsal anterior cingulate cortex — psychomotor retardation, apathy, and deficits in attention and working memory
- hippocampus : impaired memory consolidation
NORMALISES WITH TREATMENT
what is the ventral neural system like in major depressive episodes?
OVERACTIVE
- ventromedial oribotfrontal cortex (3) : enhanced sensitivity to pain, anxiety, depressive ruminations and tension
- ventral anterior cingulate cortex (ACC) : depressed mood
- amygdala : preferential processing of -ve stimuli compared to +ve
NORMALISES WITH TREATMENT
what plays a key role in the processing of memory, decision-making and emotional responses?
amygdala
where are the amygdala and hippocampus and what are they a part of?
- situated near each other in medial temporal lobe bilaterally
- part of limbic system
what is the amygdala like in a MDE?
overactive when people are shown sad stimuli, but is relatively under-active when shown positive stimuli
what does the amygdala modulate?
visual and attentional processing, particularly of facial expression
MDD is associated with a negative cognitive bias. explain
patients princess visual and other sensory inputs less positively and think about themselves, the world, and their future more pessimistically
what reverses the negative cognitive bias seen in MDD?
elevated 5-HT
reversal of cognitive bias can be detected before what?
mood improvement
relationship between CBT and antidepressants?
- both aim to reverse the negative cognitive bias
- combined antidepressants and CBT is better than either aline
longer durations during which depressive episodes go untreated with antidepressant medication are associated with reductions in what?
hippocampal volume (opposite to amygdala, which enlarges)
how can antidepressants affect hippocampi atrophy?
may prevent or slow this atrophy — thoguht to be due to the neuroprotctive effects of increased 5-HT and other neuronal growth factors
when is hippocampal atrophy particularly marked?
when depression is chronic and resistant (therefore important to treat depression robustly and appropriately as soon as poss)
cortisol in MDD?
problem of release is normal, however significantly more is released
high levels of cortisol cannot be physiologically suppressed (impaired dexamethasone suppression) indicating what?
dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis
shows the drive is coming from ABOVE the level of the pituitary, the hypothalamus
describe in full the role of stress hormones in MDD
So, moving anticlock-wise round the slide, chronic stress acts at the level of the hypothalamus to cause excessive release of corticotropin-releasing hormone (CRH), which in turn
*
acts at the level of the pituitary to cause excessive release of ACTH, which in turn
*
acts at the level of the adrenal cortex to cause excessive release of glucocorticoid hormones like cortisol, which I showed you in the previous slide.
*
The excessive glucocorticoids cause the dysregulation of the amygdala function I showed you a few slides back, with its processing bias towards sad stimuli.
*
The increased adrenal activity also releases adrenaline, and this increased sympathetic tone causes the release of pro-inflammatory cytokines such as TNF and interleukin 1 and 6 into the blood stream.
*
These proinflammatory cytokines and glucocorticoids act on the monoamine oxidase enzyme to upregulate it, and you will recall that in Section 3 slide 6 I showed you the results of a brain PET study where MAO-A concentration was higher across all brain regions in
4
patients with depression. This is due to the proinflammatory cytokines and increased glucocorticoids I have just referred to. You will also recall that MAO is the enzyme that breaks down monoamines, so this upregulation of MAO causes the levels of serotonin, noradrenaline and dopamine in the brain to fall. As well as neurotransmitters these are nerve growth factors and with lowered levels the structural integrity of the neurons will start to deteriorate.
*
In addition, the raised pro-inflammatory cytokines and glucocorticoids will also cause reductions in other important nerve growth factors such as brain derived neurotrophic factor or BDNF.
*
Reduced trophic factors cause a failure of neurogenesis in the hippocampus and subsequent reduction in hippocampal volume. This is the cause of the hippocampal atrophy in depression I showed you several slides back.
*
The dysregulated amygdala and hippocampus feed back high into the HPA axis to maintain abnormal glucocorticoids, BDNF and cytokines, in a vicious circle.
*
Finally, this pathophysiology has unhealthy effects far beyond the brain. The elevated pro- inflammatory cytokines in untreated depression increase the risk of inflammatory physical conditions, particularly cardiovascular disease, but also others
see diagram for role of stress hormones in MDD
how can smoking affect MAO? what happens if a depressed smoker stops smoking?
- cigarette smoke is a potent upregualtor of MAO
- as a result smokers have lower levels of monoamines than non-smokers whether depressed or not (depressed smokers have lowest)
- so if a depressed patient is a smoker, stopping smoking can increase the likelihood of their depression recovering both by reducing pro-inflammatory cytokines and by lowering their elevated levels of MAO and so increasing their levels of monoamines
what can predict depression?
chronic stress (but not everyone who is stressed gets depressed)
whether an individual develops depression or not may depend on a relative balance between their ____ and ____ factors
vulnerability and resilience factors
what is vulnerability mediated by?
genetic risk factors, early life adversity, and past pistoles of depression etc, which may impair 5-HT mechanisms of resilience
stress and genetic vulnerability elevate _____ and alter cellular plasticity via downregulation of ________ and _______
- elevate glucocorticoid steroids
- via downregulation of growth factors (eg. BDNF) and glucocorticoid receptor sensitivity
the reduction in growth factors such as ___ impacts negatively on the structural and functional processes of the _____ system, especially the _____
- BDNF
- limbic system
- hippocampus
what does BDNF stand for?
brain derived neurotrophic factor
amygdala overactivity is associated with what?
negative cognitive bias = treatable with cognitive therapy
what does HPA axis dysfunction lead to?
low synaptic levels of serotonin and NA
antidepressants increase synaptic ____, ____and ____ and prevent neurotoxic effect of ______ on ______
- 5-HT, NA and BDNF
- effect of glucocorticoids on hippocampus
what is depression also associated with? what can this affect and increase the risk of?
- increased inflammatory markers
- affect brain function
- increase risk of inflammatory disorders such as coronary artery disease
describe psycho education for patient and carers
how is MILD depression treated?
- do not use antidepressants — but consider them if there is a history of moderate to severe recurrent depression or if the depression has persisted for more than 2-3 months
- offer a low-intensity psychosocial intervention — individual guided self-help based on CBT principles, computerised CBT, a structured group physical activity programme
how is MODERATE/SEVERE depression treated?
provide a COMBINATION of antidepressant medication and a high-intensity psychological intervention such as CBT
what are the steps in antidepressants (6-8 week trials)
- SSRI eg. sertraline
- change to venlafaxine, mirtazapine, escitalopram or vorticose tine
- add an augmenting agent eg. a second generation antipsychotic (quetiapine or aripiprazole) or lithium
- change the antidepressant to a tricyclin - amitriptyline or clomipramine
- change the antidepressant to an MAOI eg. phenelzine
antidepressants should be used for how ling after full recovery from MDE?
9 months
how is resistant depression treated?
what psychotherapies are there for MDD?
what are the benefits and drawbacks to the psychotherapies for MDD?
what are the abnormalities of the HPA axis in patients with depression?
