depression

Question 1

what are limitations of current treatments for depression

Answer 1

limited efficacy

slow onset of therapeutic action

toxic overdose (SSRIs are relatively safe)

side effects of drugs such as tricyclics

Question 2

what are screens for antidepressant drugs

Answer 2

sucrose preference test: tests for anhedonia

swim test: tests for “behavioural dispair”: floating vs swimming and climbing

resident intruder test: tests for attack behaviour

Question 3

how might you characterise depression in terms of a disorder

Answer 3

a collection of symptoms and signs (endophenotypes): not a single fixed disorder

Question 4

what is the monoamine hypothesis of depression and what evidence is there to support this

Answer 4

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

Question 5

what are biomarkers for depression

Answer 5

there are no consistent biomarkers for depression

Question 6

how does tryptophan/tyrosine depletion influence depression

Answer 6

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

Question 7

what is another state that antidepressive drugs may cause

Answer 7

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

Question 8

what MAO inhibitors are used in treatment of depression?

Answer 8

maclobemide: a reversible MAOa inhibitor
tyramine: non selective competitive inhibitor
phenelzine: non selective irreversible inhibitor

Question 9

what is the cheese reaction

Answer 9

tyramine+ MAO inhibitor causes noradrenaline levels to increase to the equivalent serotonin levels in acute MDMA toxicity

Question 10

how do cyclic antidepressant drugs work?

Answer 10

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

Question 11

what are adverse affects of tricyclics

Answer 11

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

Question 12

what molecule are SSRIs modeld on ?

Answer 12

amphetamine

Question 13

name some SSRIs

Answer 13

citalopram: most selective for SERT
paroxetine: most potent for SERT
vortioxetine: newest SSRI

Question 14

what are adverse effects of SSRIs

Answer 14

rash, tremor, urticaria
GI side effects
loss of libido

but safer in overdose

Question 15

how do non selective MAO inhibitors effect monoamines proportionally

Answer 15

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

Question 16

give 3 facts about dopamine and depression

Answer 16

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

Question 17

what are problems for the monoamine theory of depression

Answer 17

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

Question 18

what is a possible explanation for the therapeutic lag of antidepressives

Answer 18

time is needed for 5HT1a autoreceptor downregulation after inhibition of serotonin transporter

Question 19

how may the hippocampus be involved in depression

Answer 19

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

Question 20

how do neurotrophins effect depression

Answer 20

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

Question 21

how is synaptogenesis effected in depression

Answer 21

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

Question 22

how does ketamine effect depression

Answer 22

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

Question 23

how might inflammation be associated with depression

Answer 23

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

Question 24

how does the microbiome effect MDD

Answer 24

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

Question 25

how might neuroendocrine changes effect MDD

Answer 25

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