Flashcards in Depression Deck (40):
what are the brain structures associated with depression?*
1. insular cortex
2. prefrontal cortex
3. anterior cingulate cortex
4. nucleus accumbens
what are the symptoms of depression (nine)?
1. depressed mood
2. apathy (diminished interest or pleasure in all or almost all activities)
4. change in weight/appetite
5. fatigue or loss of energy
6. feeling of worthlessness or inappropriate guilt
7. psychomotor agitation or retardation
8. diminished ability tot think or concentrate or indecisiveness
9. suicidal thoughts or attempts
what are the risk factors for the onset of depression?
1. temperamental - negative affectivity/feelings or emotions (neuroticism)
2. environmental - adverse childhood experience and stressful life events
3. genetics - ~40% heritability, 2-4 times higher in family members with depressed individuals
4. physiological - substance abuse
5. course modifiers - other diseases accompanied with depression for e.g. substance abuse and anxiety; chronic debilitating medical conditions like diabetes and CVD
name THREE main antidepressants
where is imipramine and reserpine derived from?
imipramine - histamine
reserpine - it is an alkaloid from plant rauwolfia serpentine
what is the function of the following according to the catecholamine hypothesis of depression?
1. imipramine - NA release
2. iproniazid - inhibits monoamine oxidase (MAO) + converts A/NA into dihydroxymandelic acid
3. reserpine - inhibits vesicular monoamine transporter (VMAT)
what is the function of the following according to the serotonergic hypothesis of depression?
1. imipramine - releases serotonin (into the synaptic cleft by inhibiting its reuptake into the post-synapse)
2. iproniazid - inhibits MAO - converts serotonin into 5-hyroxyindoleacetic acid
3. reserpine - depletes serotonin
what is the impact of serotonin on depression?
the depletion of serotonin will result in depression, therefore you want to increase its uptake
how is serotonin released at the synaptic cleft?
tryptophan (diet) -> 5-HT -> packed into vesicles and transported by VMAT2 -> vesicles released -> 5-HT taken by the 5-HTR at the post synapse
how is serotonin reabsorbed at the synaptic cleft?
- 5-HT is transported back from the synaptic cleft to pre-syanptic neuron
- via SERT (monoamine transporter) and 5-HT autoR on the pre-synaptic cleft
- the auto-receptors are inhibitory (mediate via Gi/Go signalling), therefore excess 5-HT results in reduced release
which components would you target to reduce depression?
- we want to increase the levels of 5-HT everywhere therefore, we
1. inhibit the re-uptake of 5-HT via SERT (TAD,SSRI)
2. inhibit the MAOA (to prevent the unpacked 5-HT conversion; MAOAI)
3. increase tryptophan levels
what are the three main antidepressants?
1. MAOA inhibitor
2. tricyclic antidepressants (TAD)
3. selective serotonin reuptake inhibitors (SSRI)
Name TWO of each
1. MAOAI - moclobemide, brofaroamine
2. TAD - imipramine, desipramine
3. SSRI - Fluoxetine, paroxetine
what are the side effects of anti-depressants?
sex, appetite, vomiting, nausea, anxiety, irritability, insomnia, headaches
what is the role of 5HtaR in serotonin release and re-uptake of serotonin? and what is its role in therapeutic effects being delayed by 2-4 weeks?
- it will bind to this receptor on the pre-synapse, and it signals via Gi/Go, so it will hinder further serotonin release. - So in the first few weeks of anti-depressants you actually get an increase in depressive symptoms because this receptor is further activated (due to high serotonin levels), but this receptor quickly becomes desensitised - you then get a spike in serotonin release, resulting in the anti-depressant effects
what is remission rate of anti-depressants?
only 1 in 3 patients achieve remission
what is the impact of anti-depressants?
reduces the frequency, duration, severity of symptoms and mortality rate (by suicide) instead of curing the disease
what are the limitations of therapeutics used in treating depression?
1. side effects
2. therapeutic effects seen after 2-4 weeks
3. 1 in 3 patients achieve remission
4. reduces the frequency, durations, severity of symptoms and suicide rate instead of curing the disease
what is the impact of reduced tryptophan diet on the brain?
1. environment and mental state
2. sensitivity of 5-HT receptors change
3. NTs changes - NO, BDNF
4. blood flow changes - cerebrovascular changes
5. A.A imbalance
6. protein synthesis
7. melatonin (produced from 5-HT)
what the animal model tests for the depressive symtoms
2. psychomotor retardation
5. lethargy, reduced social interaction
6. cognitive disturbances
7. depressed mood
1. fatigue - open field (low locomotion and exploration)
2. psychomotor retardation - rotarod performance
3. anorexia/hyperphagia - decreased food intake
4. hypersomnia - EEG
5. lethargy, reduced social interaction - forced swim test, tail suspension test, social interaction tests
6. cognitive disturbances - marries water maze, radial labyrinth
7. depressed mood
8. anhedonia - sucrose preference, intracranial self-stimulation
how is tryptophan converted into serotonin?
1. tryptophan + tryptophan hydroxylation (TPH) +B4 cofactor = 5-hydroxytryptophan (5-HTP)
2. 5-hydroxytryptophan + 5-HTP decarboxylation = 5-hydroxytryptamine (5-HT)/ serotonin
what are the two forms of tryptophan and where do they exert their effects?
1. THP1 - peripheral effects
2. TPH2 central effects
name three ways to confirm gene deletion in a serotonin deficient mice?
1. in situ hybridisation
2. immunohistochemistry (anti-Tph2 antibodies)
3. mRNA levels by qPCR
what led to the discovery of TPH2?
when TPH was knocked out, it was still found in the hippocampus and frontal cortex along with reduced levels in the periphery, thus indicating the presence of two forms
what does tryptophan2 knock out mice result in?
1. Forced swim test - increased immobility time (increased depression like behaviour)
2. Tail suspension test - decreased immobility time
3. Sucrose preference test - drink more (over eating a sign of depression)
what is the impact of fluoxetine treatment on Tph2 deficient mice?
1. Froced swim test - reduced the immobility time
2. Acid sphingomyelinase (ASM) - reduced ASM activity
3. SERT levels - high miRNA16 + low SERT
4. neurogenesis (but decreases with increase in ageing)
what are the three essential criteria for an ideal rodent model of depression?
1. face validity - almost similar symptoms should be presented in mice as humans
2.etiological validity same factors should cause depression in mice as humans
3. pharmacological validity - reversal of depression symptoms by available anti-depressants and drugs efficient in mice should work in humans and vice versa
what are the three ways of creating a rodent model of mouse?
1. chronic mild stress - mice exposed to mild stress (titling, displacing from home cage etc) for 2-3 weeks will develop CMS
2. psychosocial stress - introduction of a mice with unknown mice or predator (rat) not directly but separated with hole where they smell each other but cannot interact
3. corticosterone injections - injecting glucocorticoids x1 daily for a week will develop depression
what is the evidence for the involvement inflammation in depression?
1. depressed patients have increased inflammatory markers
2. increase in inflammatory mergers precede depression
3. treatment with anti-TNF
name five sources of inflammation
1. inflammatory disease
2. body fat
4. seasonal variation
5. social factors
what are three main impacts of proinflmmatory cytokines on depression?
1. direct effect on NA and 5-HT metabolism
2. decreased availability of Trp and 5-HT
3. disturbance in kynurenine metabolism with an imbalance in the favour of NMDAR agonist (quinolic acid ) production
on which regions of the brain does pro-inflammatory cytokines act on?
2. dorsolateral pons
4. stria terminalis
how do pro-inflammatory cytokines release inflammatory mediators?
via binding to the receptors on endothelial cells and release mediators like prostaglandins
how do pro-inflammatory cytokines enter the brain?
though active transport system
how many depression associated genes and loci have been found through GWAS? out of these loci how many are new?
42 genes identified with 44 loci and 30 of them are now
name some of the genes associated with depression in
1. neuronal Ca2+ signalling
2. dopaminergic stimulation
3. glutamate neurotranmission
4. pre-synaptic vesicle trafficking
1. neuronal Ca2+ signalling - CACNA1E, CACNA2D1
2. dopaminergic stimulation - DRD2
3. glutamate neurotranmission - GRIK5, GRM5
4. pre-synaptic vesicle trafficking - PLCO
where are the depression associated genes usually found?
on or near SNP
what is the evidence for the involvement of glial cells in depression?
1. reduced numbers and density of glial cells in post-mortem samples and animal models of depression (in sg24)
2. increased GFAP mRNA levels post riluzole treatment
3. astrocytes derived ATP modulate depressive like behaviour
in which region of ventral PFC in reduced glial numbers seen?
subgenual part of brodmann's area 24 (sg24)