Depression Flashcards
what are the brain structures associated with depression?*
- insular cortex
- prefrontal cortex
- anterior cingulate cortex
- nucleus accumbens
- amygdala
- hippocampus
what are the symptoms of depression (nine)?
- depressed mood
- apathy (diminished interest or pleasure in all or almost all activities)
- insomnia/hypersomnia
- change in weight/appetite
- fatigue or loss of energy
- feeling of worthlessness or inappropriate guilt
- psychomotor agitation or retardation
- diminished ability tot think or concentrate or indecisiveness
- suicidal thoughts or attempts
what are the risk factors for the onset of depression?
- temperamental - negative affectivity/feelings or emotions (neuroticism)
- environmental - adverse childhood experience and stressful life events
- genetics - ~40% heritability, 2-4 times higher in family members with depressed individuals
- physiological - substance abuse
- 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
- imipramine
- iproniazid
- 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?
- imipramine
- iproniazid
- reserpine
- imipramine - NA release
- iproniazid - inhibits monoamine oxidase (MAO) + converts A/NA into dihydroxymandelic acid
- reserpine - inhibits vesicular monoamine transporter (VMAT)
what is the function of the following according to the serotonergic hypothesis of depression?
- imipramine
- iproniazid
- reserpine
- imipramine - releases serotonin (into the synaptic cleft by inhibiting its reuptake into the post-synapse)
- iproniazid - inhibits MAO - converts serotonin into 5-hyroxyindoleacetic acid
- 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?
- MAOA inhibitor
- tricyclic antidepressants (TAD)
- selective serotonin reuptake inhibitors (SSRI)
Name TWO of each
- MAOAI
- TAD
- SSRI
- MAOAI - moclobemide, brofaroamine
- TAD - imipramine, desipramine
- 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?
- side effects
- therapeutic effects seen after 2-4 weeks
- 1 in 3 patients achieve remission
- 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?
- environment and mental state
- sensitivity of 5-HT receptors change
- NTs changes - NO, BDNF
- blood flow changes - cerebrovascular changes
- A.A imbalance
- protein synthesis
- melatonin (produced from 5-HT)
what the animal model tests for the depressive symtoms
- fatigue
- psychomotor retardation
- anorexia/hyperphagia
- hypersomnia
- lethargy, reduced social interaction
- cognitive disturbances
- depressed mood
- anhedonia
- fatigue - open field (low locomotion and exploration)
- psychomotor retardation - rotarod performance
- anorexia/hyperphagia - decreased food intake
- hypersomnia - EEG
- lethargy, reduced social interaction - forced swim test, tail suspension test, social interaction tests
- cognitive disturbances - marries water maze, radial labyrinth
- depressed mood
- anhedonia - sucrose preference, intracranial self-stimulation
how is tryptophan converted into serotonin?
- tryptophan + tryptophan hydroxylation (TPH) +B4 cofactor = 5-hydroxytryptophan (5-HTP)
- 5-hydroxytryptophan + 5-HTP decarboxylation = 5-hydroxytryptamine (5-HT)/ serotonin
what are the two forms of tryptophan and where do they exert their effects?
- THP1 - peripheral effects
2. TPH2 central effects
name three ways to confirm gene deletion in a serotonin deficient mice?
- in situ hybridisation
- immunohistochemistry (anti-Tph2 antibodies)
- 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
