Depression Flashcards
what is depression?
recurring or debilitating mental disorder that impairs social and/or occupational functioning (most common mood disorder)
what neuronal system are emotions vs motivations part of?
emotions: limbic system
motivations: mesocorticolimbic system
what is the limbic brain?
cortical border circling the brainstem (oldest part of cortex)
what 4 brain structures are a part of the limbic brain?
amygdala, hippocampus, basal ganglia, and cingulate gyrus (also connects to frontal cortex and hypothalamus)
MDD is associated w/ incr activity in ______ regions and decr activity in the ________
incr in limbic (amygdala)
decr in striatum (motivation)
NTs in what region may be responsible for depression?
limbic
what are 3 monoaminergic NTs?
dopamine, norepinephrine, and serotonin
what do alterations in monoaminergic NTs cause and why?
mood disorders; regulate mood, arousal, and attention
what is the amine hypothesis of depression?
depression results from inadequate monoamine neurotransmission (serotonin and noradrenaline)
what could cause decr monoamine neurotransmission?
less NT release, fewer receptors, impaired signal transduction
what were long-term effects of reserpine?
15% of patients developed depression-like syndrome
how does reserpine cause depressive symptoms?
depletes neurons of dopamine and norepinephrine (inhibits presynaptic NT uptake into vesicles and decr release)
what is ipronazid?
anti-tubercular drug that alleviated depression
how did ipronazid alleviate depression?
inhibited monoamine oxidase/MAO (enzyme that breaks down monoamine NTs) which incr [monoamine NTs]
what are 3 issues w/ monoamine hypothesis for depression?
drugs that restore monoamine levels are moderately effective in 30-50% of patients; inconclusive evidence 5-HT and NA are disrupted in depression; antidepressants take weeks for clinical effects (NT levels change immediately)
what is the glutamatergic hypothesis?
depression is associated w/ decr glutamatergic signaling in cortex
what does decr in glutamatergic signalling impact?
both excitatory and inhibitory function, leading to reduced signal noise
what does loss of glutamatergic signalling also cause? (4)
long-term potentiation, neurotropic production (BDNF), synapse formation, gene transcription
what do MAO inhibitors do?
incr synaptic levels of monoamine NTs (NE and 5-HT) by inhibiting their breakdown by MAO
what is an example of an MAO inhibitor?
ipronazid
what is the “tyramine cheese rxn”?
inhibition of MAO by MAO inhibitors can incr [tyramine] and cause acute hypertension (binds to adrenergic receptors in heart and blood vessels)
what is tyramine?
sympathomimetic monoamine (resembles NA) found in foods such as aged cheese
what is tyramine degraded by?
MAO
what does SSRI stand for?
selective serotonin reuptake inhibitors
what do SSRIs do?
inhibit serotonin (SET) transporters which incr extracellular [5-HT]
what are transporters?
molecules that reuptake NTs from synapse into cell
what does SNRI stand for?
serotonin norepinephrine reuptake inhibitors
what do SNRIs do?
inhibit SETs and NA transporters (NETs)
what is an example of a selective reuptake inhibitor?
fluoxetine
what are 3 limitations of monoamine antidepressants? (MAOIs, SSRIs, SNRIs)
only moderately effective in 30-50% of patients; take several weeks for clinical effect (immediate effects on NT levels); on-target side effects such as nausea, indigestion, dizziness, dry mouth, weight loss, etc.
what is ketamine?
a noncompetitive NMDA/Glu receptor antagonist
what are 3 purposes for ketamine?
anti-depressant (low doses), hallucinogen (medium doses), dissociative anesthetic (high doses) - lethal at higher doses
how does ketamine work to improve symptoms of depression?
blocks activation of NMDA receptors on GABAergic interneurons by Glu which inhibits inhibition (activates) Glu excitatory neurons (incr [Glu])
what are 4 downstream effects of Glu burst from ketamine?
synaptic remodeling, resetting of Glu and GABA systems, BDNF release, gene transcription
what is the effectiveness of SSRIs vs ketamine?
SSRIs: ~15% in 8 weeks
ketamine: ~25% in one day
what are 2 limitations of ketamine?
narrow TI; must be administered intravenously in hospital (due to small TI)
what are future/possible treatments for depression?
drugs that directly target downstream events from synaptic remodeling (inositol, cAMP, CREB) to be more effective and selective
what is rolipram?
phosphodiesterase inhibitor that incr cAMP to treat depression
