Affective disorders - neurobiology & tx Flashcards
NEUROBIOL OF DEPRESSION
i) which neurotransmitter group are most commonly affected in depression? give two exmaples
ii) name three things that can impact on regulation of these NTs
iii) what three things do these also interact with?
i) monoamine NTs such as serotonin and noradrenaline
ii) adverse childhood experience, stress and genetic factors
iii) also interact with the HPA axis, neuroinflammation and neuroplastic changes
what changes are seen in depression in relation to
i) monoamines
ii) GABA and glutamate
iii) HPA axis/glucocorticoids
iv) neuroplasticity and atrophy
v) immune dysfunction
i) disruption of transmission especially in 5HT, NA and DA
ii) decreased GABA and Glu
iii) high serum cortisol levels and lack of response to glucorticoids
iv) reduced hippocampal volume and reduced neuroplasticity
v) increased inflammation
NEURONAL SYSTEMS INVOLVED IN DEPRESSION
i) what do the dorsolateral and ventrolateral PFC regulate? (A)
ii) what do the medial PFC, anterior cingulate cortex and orbitofrontal cortex regulate? (B)
iii) what does the amygdala and ventral striatum regulate? (C)
i) voluntary regulation of emotion
ii) automatic regulation of emotion (instinct)
iii) emotion and reward processing
MONOAMINES AND DEPRESSIVE SYMPTOMS
i) what are the three main monoamine transmitters?
ii) which two regualte fatigue and concentration?
iii) which two regulate anxiety?
iv) which two regulate sexual function, appetite and aggression
v) name three things that all three monoamine transmitters regulate
i) dopamine, serotonin and noradrenaline
ii) noradrenaline and dopamine
iii) NA and 5HT
iv) 5HT and DA
iii) anhedonia, sleep and mood
ROLE OF SEROTONIN IN DEPRESSION
i) which traditional anti-depressant does not act on 5HT?
ii) what effect does manipulating/depeleting tryptophan have in depressed patients? what does this show?
iii) what is seen in post mortem brains of people that had depression
iv) how can the 5HT transporter be measured? what is seen in depressed patients? what does this mean?
i) bupropion
ii) depeleting tryp can make recovered depressed patients go into relapse - shows that decreased 5HT plays a role
iii) reduced 5HT transporters are seen in post mortem brains
iv) use a radiotracer that selectively binds the transporter and visualise using PET
- in depressed patients there is a clear decrease seen (shows serotonin activity is decreased)
what are the three things that demonstrate that serotonin dysfunction plays a role in depression?
1) all traditional anti-depressants affect 5HT/NA systems
2) decreasing 5HT can induce depression
3) reduced 5HT transporter protein in post mortem brains of depressed patients
5HT AND NA PATHWAYS IN THE BRAIN
i) which area of the brain do they both originate from?
ii) which areas does each system originate from specifically?
iii) where do both pathways project to? what does this modulate?
i) both originate from the midbrain
ii) serotonin from the raphe nucleus
noradrenaline from the locus coruleus
iii) both project to the neocortex > PFC & limbic system
- modulation of mood
GENE ENVIRONMENT INTERACTIONS
i) polymorphisims in which gene may contribute to an individual having a mood disorder?
ii) what environmental factor may this be coupled with?
iii) which combination may predispose an individual to a mood disorder?
i) polymoprhisms in the 5HT transporter gene 5-HTT
ii) PM in 5-HTT coupled with maltreatment
iii) SS genotype of 5-HTT gene plus maltreatment in life can put an individual at increased risk of developing a mood disorder
HPA DYSFUNCTION IN MOOD DISORDERS
i) what level is cortisol normally kept at in the blood?
ii) what cortisol levels are often seen in depressed individuals? why is this and what is it mediated by?
iii) what is normally seen when giving a glucocorticoid agonist such as dexamethasone? why?
iv) what is seen in depressed patients when given dexamethasone? what mediates this?
v) which disease associated with abnormal cortisol levels is has an increased prevalence in depressed patients?
i) normally cortisol levels are low in the blood
ii) in depressed individuals high cortisol levels are seen due to lack of negative feedback - mediated by glucocorticoid receptors
iii) normally giving dexamethasone will induce cortisol suppression as it is a GC agonist which feeds back to reduce cortisol levels
iv) in depressed patients there is lack of dexamethasone supression as there are glucocorticoid receptor alterations that affect negative feedback along the HPA axis
v) cushings disease is associated with hypercortisolaemia (due to pituitary overactivation) - increased prevalence in depressed patients
which patients do A and B correspond to? (normal controls or depressed patients?)
A = normal controls (cortisol supression post dex admin)
B = depressed patients (no cortisol supress post dex admin)
NEUROPLASTICITY ALTERATIONS AND BRAIN ATROPHY
i) which neurons are principally affected by stress and depression?
ii) name four things that may be decreased in depressed individuals (dendrites/receptors)
iii) what brain area may atrophy be seen in depressed individuals?
iv) what animal model is this effect also seen in?
v) which brain area is especially plastic and has constant formation of new synapses and neurites?
i) pyramidal neurons
ii) 1) decreased apical dendrites
2) decreased dendritic spine density
3) decreased NMDA/AMPA receptors
4) decreased synaptic proteins
iii) hippocampal atrophy is seen in depression
iv) also seen in animal model for chronic stress
v) hippocampus - mega analysis shows significant reduction in hippocampal volume
GABA AND GLUTAMATE
i) what effect is seen on GABA and Glu signalling in chronic stress and depression?
ii) what can reverse the stress/depression deficits
iii) which drug can mediate balanced control? what receptor does this drug act on?
iv) what is the effect of this drug in vitro?
i) decreased GABA and glu signalling
ii) giving GABA and/or Glu can reverse this
iii) ketamine can mediate balance control and it works by blocking the NMDA receptor
- a single dose of ketamine has rapid anti-depressant effects
iv) stimulates synaptogenesis and reverses glu/GABA deficits by providing a balancing effect
IMMUNE DYSFUNCTION IN MAJOR DEPRESS DISORDER
i) what type of disorders show increased prevalence of depression and anxiety? give two examples
ii) what may be raised in the blood in a severley depressed individual that needs hospitalisation? what may this be used for?
iii) what is TSPO? how is it implicated in depression?
iv) how are functional connections in the. brain affected in depression?
i) chronic inflammatory disorders such as MS and rheumatoid arthritis
ii) raised CRP may be seen in severe depression and may be able to stratify patients for use of anti-inflammatory treatment
iii) TSPO = translocator protein which is a marker of microglial activation (inflammation)
- TSPO is increased in depression as there is increased inflammation in specific brain areas
iv) use MRI to vis func connections and see func connection problems from areas such as hippocampus are implicated in depression
CAUSALITY LINKS BETWEEN IMMUNE DYSFUNC AND DEPRESSION?
i) what effect does a pro-inflammatory challenge such as LPS have on mood?
ii) what are the initial symptoms seen when giving IFN alpha? what effects are seen a few weeks after this?
iii) which pro-inflammatory challenge has acute effects and which has sub chronic effects?
iv) which behavioural response is similar to depressive symptoms? what does this suggest?
i) pro-inflam challenge can cause decreased mood and increased anxiety
ii) initial IFN alpha symptoms are fatigue and anaemia then after a few weeks these subside and some patients get depressive symptoms
iii) acute = LPS, sub chronic = IFN alpha
iv) sickness behvaiour is similar to depressive symptoms which suggess that inflammation may be a model of evoke depression like symptoms
MECHANISMS OF IMMUNE DYSFUNCTION AND DEPRESSION
i) what kind of behaviour can LPS induce?
ii) cytokines can induce IDO - what is this enzyme important for?
iii) what is produced when IDO is activated by inflammation? what recepor does this molecule activate and what does that cause?
iv) which NT can raised LPS/CRP impact on? what does tthis cause?
v) name an environmental factor in early life that is assoc with high levels of blood inflamm later on?
i) LPS can induce sickness and depressive behaviours
ii) IDO is important for the synthesis of 5HT and tryptophan
iii) when activated by inflammation IDO will produce KYN instead of 5HT
- KYN will activate NMDA receptors which can cause Glu neurotoxicity
iv) raised LPS/CRP in the blood can cause changes to DA systems which impairs the reward system
v) maltreatment in the first decade of life
IMMUNE DYSFUNC AND DEPRESSION
what are A & B?
A = IDO
B = KYN
ANTI-DEPRESSANT TREATMENT
i) give two examples of classes of first generation anti-depressants and their mechanism of action
ii) are first gen anti-deps selective or non selective for monoamine NTs?
iii) what makes second gen anti-deps different from first gen?
iv) give two examples of classes of second gen anti-deps and a drug example for each
v) which second gen anti-dep acts on a) 5HT and NA
b) DA and NA reuptake transporters
i) MAOis - non selectively inhibit enzymes involved in breakdown of monoamine NTs
tricyclics - non selectively inhibit reupake of monoamines by blocking the reuptake transporter
ii) first gen are non selective for monoamine NTs
iii) second gen are more specific for a single system but first gen are not
iv) second gen = SSRIs eg citalopram/fluoxetine
SNRIs - 5HT and NA reuptake inhibs such as duloxetine and venlafaxine
v) second gen that work on 5HT/NA = mirtazapine
b) work on DA and NA reuptake transporters = buproprion
SSRIs
i) how does efficacy compare to tricyclics? what about tolerability?
ii) which disorders are they effective in treating?
iii) why are SSRIs commonly prescribed? (toxicity and overdose)
iv) name three side effects that may initially be seen
v) how long does it usually take to see relief of depressive symptoms?
vi) what approach should be taken for administration? why?
i) same efficacy to tricyclics but more tolerable
ii) have large spec of action - useful in OCD, PTSD, panic, GAD, social anxiety
iii) SSRIs most commonly prescribed because they have low toxicity and safe in overdose
iv) initial side effects can be N&V, headache, irritability, anxiety
v) usually takes a few weeks for relief of depressive symptoms to be seen
vi) gradual suspension to avoid withdrawal symptoms
SIDE EFFECTS OF ANTI-DEPRESSANTS
i) what are the main side effects of tricyclics? what is seen in overdose
ii) what are the main side effects of MAOis? what is the one that needs to be most carefully monitored? explain
iiI) which second gen drug is good to give if patient also has sleeping problems?
i) tricyclics - constipation, orthostatic hypotension, dry mouth
- cardiotoxicity is seen in overdose
ii) MAOis - dry mouth, GI, headache, insomnia, dizzy
- food interactions need to be carefully monitored eg interac with specific cheeses can give hypertension crises as they contain tyramine
iii) give mirazapine as it is also a sedative
ANTI-INFLAMMATORIES AND DEPRESSION
i) what can lack of response to regular treatment be associated with (in the blood)?
ii) what class of drug may be beneficial against depression? give an example
iii) what are the downsides to using a neuromodulatory drug such as anti-TNFa?
iv) what may newer anti-depressants be derived from?
i) lack of response can be associated with raised CRP levels
ii) NSAIDs such as celecoxib
iii) downsides to NM drug = expensive and lots of SEs
iv) newer anti-deps may be derived from neuromodulatory drugs
BIPOLAR DISORDER - CAUSAL FACTORS
i) is there a high or low level of heritability?
ii) what % of first degree relatives are expected to get bipolar?
iii) what is the biochemistry underlying mania and depressive episodes?
iv) name two psychosocial events related to bipolar
v) is there a mendelian pattern of inheritance?
i) high level of heritability
ii) 10% of first degree relatives are expected to get it
iii) mania = excess DA
depressive = lack of 5HT
iv) stressful life events can trigger bipolar as well as trau,a early in life
v) non mendelian inheritance (many genes involved)
NEUROBIOLOGY OF BIPOLAR
i) what class of neurotransmitter does it principally involve?
ii) bipolar involves intracellular signalling alterations - which molecule works as a drug to alter intracellular signalling?
iii) what effect is seen in the HPA axis?
iv) what morphological change may be seen in brain tissue?
i) monoamines such as dopamine and serotonin
ii) lithium can work as a drug to alter intracellular signalling
iii) HPA axis - flattening of the cortisol curve and non response to dexamethasone
iv) neuronal atrphy and reduced hippocampal volume
MITOCHONDRIAL ALTERATIONS IN BIPOLAR
i) which mitochondrial complex has reduced activity in bipolar? where is this found? why is it important?
ii) what is also seen at a genetic level in bipolar patients?
iii) SNPs of which genes is associated with diagnosis of bipolar? (2)
iv) what molecule has altered levels in the blood and CSF in patients? why may this be?
v) is there an increase or decrease of markers of oxidative stress and antioxidant levels in bipolar patients?
i) complex I has reduced activity
- found in the PFC
- important as it is the rate limiting step for oxygen consumption
ii) reduced mRNA for genes encoding ETC components and antioxidants
iii) SNPs of mitochondrial and nuclear genes encoding ETC components in associated with bipolar diagnosis
iv) lactate levels may be altered in the blood and CSF - this may be due to lactate being a byproduct of dysfunctional mitochondria that cant acces enough O2 for function
v) increase in oxidative stress markers
reduced antioxidant levels
NEURONAL FUNCTION AND O2 AVAILBILITY
i) which organelles provide chemical energy through oxidative phosphorylation?
ii) what % of oxygen does the CNS comsume of all oxygen inspired at rest?
iii) which cells critically depend on oxygen for their survival?
i) mitochondria
ii) 20%
iii) neurons
