6 - Depression Flashcards
1
Q
what is the correct term for a sustained period of depression?
A
major depressive episode
2
Q
MDEs are seen principally in what 3 psychiatric diagnoses?
A
- major depressive disorder
- bipolar disorder
- schizophrenia
3
Q
what questionnaire can help diagnose MDE?
A
patient health questionnaire (PHQ-9)
4
Q
what are the diagnostic criteria for MDE?
A
5 or more in same 2 week period that represent change from normal:
* anhedonia or depressed mood - MUST
* causes significant distress/impairment of function
* not part of bipolar
* not due to direct physiological effects of substances
* not better acocunted for by bereavement
5
Q
what are somatic delusions?
A
fixed false beleifs about pts body, eg. “my body is rotting/hollow/empty”
6
Q
depression is the leading cause of disability in both males and females. who is the burden of depression higher in?
A
- burden of depression is 50% higher in females than males
- leading cause of burden in females in high-, middle-, and low-income contries
7
Q
what are the two types of monoamines relevant in depression?
A
- Noadrenaline - catecholamine
- serotonin - indoleamines
8
Q
what is the general structure of catecholamines?
A
- benzene ring
- 2 hydroxyl side groups
- amine chain
9
Q
what is the general structure of indoleamines?
A
- bicyclic ring of benzene
- fused with pyrrole
- amine side chain
10
Q
how is noradrenaline synthesised?
A
- tyrosine
- hydolysed by tyrosine hydroxylase (TH) into dopamine
- decarboxylysed by DBH (dopamine beta-hydroxylase) into noradrenaline
methyl group added = adrenaline
11
Q
how is serotonin synthesised?
A
- tryptophan
- hydryolysed by tyrptophan hydroylase into 5-hydroxytryptophan
- converted into 5-HT by L-AADC
12
Q
what is tyrosine?
A
non-essential large neutral amino acid (LNAA)
13
Q
how is tyrosine transported across the blood brain barrier?
A
active transport
14
Q
where is tyrosine converted into NAdr?
A
- neuronal cell bodies in pons
- particularly locus ceruleus
15
Q
what is tryptophan?
A
dietary essential, large neutral amino acid (LNAA)
16
Q
where is tryptophan converted into 5-HT?
A
- neuronal cell bodies in raphe nuclei (chain of brainstem nuclei)
- particularly dorsal and medial raphe
17
Q
how are the signals of 5-HT terminated?
A
- 5-HT reuptake transporter (SERT)
- monoamine oxidase (MAO-A) degrades 5-HT in synapse and also some that has been reuptaken
18
Q
how are NAdr signals terminated?
A
- NAdr reuptake transporter
- MAO-A
- COMT (catechol-O-methyl transferase
18
Q
describe the enzymatic degradation of 5HT?
A
- broken down by monoamine oxidase
- into 5-HIAA (hydroxyindole acetic acid)
19
Q
describe the enzymatic degradation of NAdr?
A
- MAO and COMT degrade it
- into vanillylmandelic acid and 3-methoxy-4-hydroxy-phenylglycol
20
Q
what are the 3 types of adrenergic receptors that NAdr acts on?
A
- alpha1
- M2
- N1-3
21
Q
which noradrenergic receptor is most relevant to depression?
A
M2
22
Q
which 5-HT receptor in the only one that isn’t coupled with a G-protein?
A
5-HT3 - ligand gated ion channel
23
Q
serotonin stimulate nuronal firing at all 5HT receptors, apart from which 2?
A
5HT1 and 5HT5
24
NAdr stimulation at alpha2 auto and heteroreceptors on NAdr and 5HT neurons result in what?
* decreased cell firing
* reducing serotonin release
25
NAdr stimulation at alpha1 adreno-heteroreceptors on 5HT cell bodies result in what?
increased 5HT cell firing
26
how does NAdr regulate serotonin?
* NAdr released from cell body and binds to receptors
* if alpha2 auto or hetero on NAdr/5HT neuron, decreases cell firing and 5HT release
* if alpha 1 adrenoreceptor on 5HT cell body, increased 5HT release
27
28
drugs that deplete monoamines cause what?
depression
29
antidepressants increase what neurotransmitters?
5HT and NAdr
30
what was the first anti-depressant?
* iproniazid (developed for TB)
* monoamine oxidase inhibitor
31
give an example of a VMAT blocker that causes depression as a side effect?
* reserpine
* antihypertensive +antipsychotic in 50s
* depletes MOA by blocking VMAT
32
what does VMAT stand for?
vesicular monoamine transporter
33
what does VMAT do?
transports free cytoplasmic NAdr, 5HT, DA in presynaptic nerve terminal into storage vesicles
34
how does reserpine lead to depression?
* reserpine irreversibly blocks VMAT
* cytoplasmic monoamines cannot re-enter vesicles
* instead degraded by MAO and COMT
* leads to long-lasting depletion
* takes days-weeks to replenish new VMAT
35
how is rapid tryptophan depletion achieved?
drinking mixture of LNAAs devoid of tryptophan
36
iproniazid was developed for TB - what other property does it have?
antidepressant as it is a monoamine oxidase inhibitor
37
what type of MAOIs are used in antidepressive therapies?
MAOA
38
what type of MAOIs are used in parkinson's disease?
MAOB - increases dopamine
39
how do MAOIs work?
* inhibit monoamine oxidase
* neuronal and synaptic levels of monoamines increases
40
list an irreversible MAO-A inhibitor?
phenelzine
41
name a reversible MAOAI?
moclobomide
42
what is important about diet when taking MAOA inhibitors?
can't metabolise other monoamines eg. dietary tyramine (red wine, cheese, marmite) - could result in hypertensive diet
43
what is the levels of monoamine oxidase A activity in depressed pts?
high - leads to chronically low synaptic 5HT and NA
44
how does imipramine work in depression?
* reversibly blocks SERT and NAT
* increases synaptic 5HT and NA by reducting degradation
45
list 3 tricyclic ADs
desipramine
amitriptyline
clomipramine
46
desipramine, amitryptyline, clomipramine are all what type of antidepressant?
tricyclic
47
list 3 SSRIs
fluoxetine
paroxetine
flucoxamine
sertraline
citalopram
48
fluoxetine, paroxetine, flucoxamine, sertraline, citalopram - what type of antidepressant are these?
SSRIs
49
what are SNRIs?
serotonin and noradrenaline reuptake inhibitors
50
list 2 SNRIs
venlafaxine
duloxetine
51
venlafaxine and duloxetine are examples of what type of antidepressant?
SNRIs
52
what does each antidepressant block?
tricyclics and SNRIs - SERT and NAT
SSRIs block only SERT
53
what is the common outcome of all antidepressants?
increase synaptic 5-HT levels
54
mirtazapine is a new AD that is dual acting by blocking only a single receptor type - what is its mechanism of action?
* adrenergic alpha2 receptor antagonist (blocks)
* blocks negative feedback which tends to reduce NAdr release
* net effect is increased NAdr release
* also blocks negative feedback that reduces 5HT release
* net effect is increased 5HT
55
what is the kindling hypothesis of depression?
* depressive episodes become more easily triggered over time
56
as the number of depressive episodes increases, future episodes are predicted more by what?
the number of prior episodes, rather than by life stress
57
the ventral neural system is important for what?
identification of emotional significance of stimuli and production of affective states
58
what is the dorsal neural system important for?
integration of emotional inputs and the performance of excutive functions
59
how are the dorsal neural system and ventral system abnormal is MDE?
dorsal neural system - underactive
ventral system - overactive
60
in MDE the dorsal neural system is underactive - what symptoms are associated with this?
* DLPFC and dorsal ACC - apathy, deficits in attention and working memory
* **hippocampus - impaired memory consolidation**
61
in MDEs the ventral system is overactive - what symptoms are associated with this?
* ehanced sensitivity to pain
* ventral ACC - depressed mood
* **amygdala - preferential processing of negative stimuli compared to positive**
62
what functional changes happen in the amygdala in MDD?
* overactive when shown sad stimuli
* underactive when shown positive stimuli
63
what is the role of the amygdala?
* modulates visual and attentional processing, particularly facial expression
64
what structural changes occur in the amygdala during depression?
enlargement
65
MDD is associated with what bias?
negative cognitive bias
66
what reverses the negative cognitive bias in depressed pts?
elevated 5HT
67
what is the most efficient treatment for MDD?
combined antidepressants and CBT
68
longer durations in which depressive episodes go untreated is associated with what? what can be the result of this?
* reductions in hippocampal volumes
* associated with treatment resistance
69
what stress hormone is consistently high in pts with MDD?
cortisol
70
consistently high cortisol cannot be supressed by dexamethasone in pts with MDD - what does this suggest?
* their is dysfunction in the HPA axis
* drive is coming from hypothalamus
71
how does chronic stress alter the HPA axis, leading to increased physical illness symptoms and increased risk of inflammatory disorders?
* hypothalamus releases CRH
* pituitary releases excessive ACTH (adrenocorticotrophic)
* adrenal cortex = excessive glucocorticoid release
* increased glucocorticoids dysregulates amygdala function
* increased adrenal activity = increased sympathetic tone = increased release of IL 1 and IL6
* IL1 + IL6 + glucocorticoids = increases MAO = decreases 5HT, NA, DA + neurotrophic factors
* decreased neurotrophic factors = decreased neurogenesis and hippocampal volume
* dysregulation - maintains abnormal levels
* increases physical symptoms and inflammatory risk
72
how does smoking relate to depression management?
ceasing smoking is as effective as starting AD treatment
73
what is BDNF?
growth factor that is downregulated in depression affecting structural and functional processes within the limbic system, especially hippocampus
74
what are the NICE guidelines for treatment of mild depression?
* only consider antidepressants if there is history of depresison
* offer low-intensity psychosocial intervention- CBT, group physical activity programme
75
what are the NICE guidelines for management of moderate or severe depression?
* combination of antidepressant medication and CBT
76
what are the NICE guidelines for antidepressant step-wise appraoch?
* SSRI
* change to venlafaxine, mirtazapine, escitalopram or vortioxetine
* add augmenting agent eg. 2nd gen antipsychotic or lithium
* change antidepressant to tricyclic - amitriptyline or clomipramine
* change to MAOI eg. phenelzine
77
what antidepressants are more effective than others?
agomelatine
amitriptyline
escitalopram
mirtazapine
venlafaxine
paroxetine
78
what are the least effective antidepressants?
fluoxetine
reboxetine
fluvoxamine
trazodone
79
how long should ADs be continued after full recovery from MDE to prevent relapse?
9 months
80
how do CBT and ADs compare for:
* acute efficacy?
* long-lasting protective effect after course ends>
acute efficacy - similar
long-lasting protection - CBT is better
81
what are the guidelines for treatment-resistant depression?
* check diagnosis + alcohol and/or drug misuse
* antidepressant trials, bupropion
* ECT
* neurosurgery - bilateral cingulotomy, deep brain stimulation, vagus nerve stimulation
82
what is the most effective AD treatment? what is a drawback of this?
* electroconvulsive therapy
* relapse risk is very high
83
