depression Flashcards
what are limitations of current treatments for depression
limited efficacy
slow onset of therapeutic action
toxic overdose (SSRIs are relatively safe)
side effects of drugs such as tricyclics
what are screens for antidepressant drugs
sucrose preference test: tests for anhedonia
swim test: tests for “behavioural dispair”: floating vs swimming and climbing
resident intruder test: tests for attack behaviour
how might you characterise depression in terms of a disorder
a collection of symptoms and signs (endophenotypes): not a single fixed disorder
what is the monoamine hypothesis of depression and what evidence is there to support this
depression is caused by a deficit in monoamine transmission
reserpine depletes neuronal stores of monoamines; administration of reserpine caused depression in 15% of patients
iproniazid prevents monoamine metabolism; also causes euphoria
what are biomarkers for depression
there are no consistent biomarkers for depression
how does tryptophan/tyrosine depletion influence depression
depletion of tryptophan or tyrosine through diet or inhibition of enzymes pCPA/ alpha-methyl tyrosine:
no effect on healthy controls unless family history of depression (could indicate trait/ vulnerability)
tryptophan depletion worsens mood in depressives in remission after treatment with SSRIs
depletion worsens mood in MDD patients taking antidepressents
this does not confirm a causal link
what is another state that antidepressive drugs may cause
antidepression; distinct from non depression
e.g:
ketamine acts quickly (switches off depression?)
monoamine drugs act slowly (switch on antidepression)
or the other way round
what MAO inhibitors are used in treatment of depression?
maclobemide: a reversible MAOa inhibitor
tyramine: non selective competitive inhibitor
phenelzine: non selective irreversible inhibitor
what is the cheese reaction
tyramine+ MAO inhibitor causes noradrenaline levels to increase to the equivalent serotonin levels in acute MDMA toxicity
how do cyclic antidepressant drugs work?
they block neuronal uptake of monoamines
most tryclics block noradrenaline reuptake but not 5HT in vivo except clomipramine
tetracylics such as lofepramine may also be used
mianserin, a tetracylic is not an MAO inhibitor, is a weak monoamine reuptake inhibitor, is also an alpha 2 adrenoceptor antagonist, 5HT2A/C and 5HT3 receptor antagonist
what are adverse affects of tricyclics
alpha 1 andrenoceptor antagonism can cause orthostatic hypotension
H1 receptor antagonism may cause sedation
muscarinic receptor antagonism may cause increased heart rate and dry mouth
overdose may be fatal
what molecule are SSRIs modeld on ?
amphetamine
name some SSRIs
citalopram: most selective for SERT
paroxetine: most potent for SERT
vortioxetine: newest SSRI
what are adverse effects of SSRIs
rash, tremor, urticaria
GI side effects
loss of libido
but safer in overdose
how do non selective MAO inhibitors effect monoamines proportionally
dopamine is metabolised by both MAO a and b so is more likely to be effected than either NA or 5HT for a given dose of non selective MAOI
give 3 facts about dopamine and depression
the noradrenaline transporter has a higher affinity for dopamine than NA
strong evidence linking DA increase with relief of anhedonia and general mood
selective inhibition of VTA dopaminergic neurones produces a depression like phenotype
what are problems for the monoamine theory of depression
there is a therapeutic lag; pharmacological effects of drugs act very quickly however therapeutic response may take weeks
cocaine and amphetamine are not considered antidepressants
what is a possible explanation for the therapeutic lag of antidepressives
time is needed for 5HT1a autoreceptor downregulation after inhibition of serotonin transporter
how may the hippocampus be involved in depression
hippocampal neurogenesis; chronic antidepressant treatment increases BrdU in the adult hippocampus
chronic mild stress reduces neurogenesis in ventral zone of hippocampus
ventral hippocampus has denser moa innervation than dorsal, only ventral region projects to prefrontal cortex
behavioural response to antidepressants parallel neurogenesis in ventral zone
how do neurotrophins effect depression
neurotrophins (particularly BDNF):
BDNF increases neurogenesis and protects against neurotoxins
BDNF knockout mice show increased cell death in the hippocampus
behavioural effects of intrahippocampal BDNF resembles antidepressants in rats
increased BDNF infusion produced better scores for both swim and climbing test
how is synaptogenesis effected in depression
forebrain BDNF overexpression prevents chronic stress induced dendritic atrophy in the hippocampus and reduces immobility in the porsolt swim test
ketamine may cause synaptic remodelling through glutamate burst causing LTP like effects, causes GluA1 synthesis as opposed to internalisation found in depression
how does ketamine effect depression
stops the inhibition of NMDA receptor which causes increased synaptic atrophy and apoptosis, also promotes BDNF function
disinhibition of glutamatergic pyramidal output
stimulation of synaptic glutamate receptors, particularly AMPA receptors
activates BDNF, mTOR signalling and synaptic formation
epigenetics?: ketamine increases phosphorylation of histone deacetylase 5
how might inflammation be associated with depression
antidepressants modulate pro/anti inflammatory cytokines
endotoxins increase production of proinflammatory cytokines and impair mood
blocking proinflammatory cytokines; behavioural response resembles antidepressants
interferon alpha therapy commonly causes depression
how does the microbiome effect MDD
L. rhamnosus in the gut blunts hormonal response to stress and immobility in the FST, following treatment of penicillin there is increased chance of depression
how might neuroendocrine changes effect MDD
cortisol is often increased in MDD, patients with cushings disease may develop depression
interaction between NA/5HT and cortisol blocks NA uptake2 (OCTs)
cortisol can reduce neurogenesis
