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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
5. amygdala
6. hippocampus


what are the symptoms of depression (nine)?

1. depressed mood
2. apathy (diminished interest or pleasure in all or almost all activities)
3. insomnia/hypersomnia
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

1. imipramine
2. iproniazid
3. reserpine


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
2. iproniazid
3. reserpine

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
2. iproniazid
3. reserpine

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
2. TAD

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
1. fatigue
2. psychomotor retardation
3. anorexia/hyperphagia
4. hypersomnia
5. lethargy, reduced social interaction
6. cognitive disturbances
7. depressed mood
8. anhedonia

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
3. age
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?

1. amygdala
2. dorsolateral pons
3. hypothalamus
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)


what is the impact of anti-depressants on astrocytes?

1. ADS reverse the morphology of depressed astrocytes
2. ADS reverse the gene expression in astrocytes
3. FLX changes multiple gene expression though 5-HTB receptor