Depression

Question 1

what is depression?

Answer 1

recurring or debilitating mental disorder that impairs social and/or occupational functioning (most common mood disorder)

Question 2

what neuronal system are emotions vs motivations part of?

Answer 2

emotions: limbic system
motivations: mesocorticolimbic system

Question 3

what is the limbic brain?

Answer 3

cortical border circling the brainstem (oldest part of cortex)

Question 4

what 4 brain structures are a part of the limbic brain?

Answer 4

amygdala, hippocampus, basal ganglia, and cingulate gyrus (also connects to frontal cortex and hypothalamus)

Question 5

MDD is associated w/ incr activity in ______ regions and decr activity in the ________

Answer 5

incr in limbic (amygdala)

decr in striatum (motivation)

Question 6

NTs in what region may be responsible for depression?

Answer 6

limbic

Question 7

what are 3 monoaminergic NTs?

Answer 7

dopamine, norepinephrine, and serotonin

Question 8

what do alterations in monoaminergic NTs cause and why?

Answer 8

mood disorders; regulate mood, arousal, and attention

Question 9

what is the amine hypothesis of depression?

Answer 9

depression results from inadequate monoamine neurotransmission (serotonin and noradrenaline)

Question 10

what could cause decr monoamine neurotransmission?

Answer 10

less NT release, fewer receptors, impaired signal transduction

Question 11

what were long-term effects of reserpine?

Answer 11

15% of patients developed depression-like syndrome

Question 12

how does reserpine cause depressive symptoms?

Answer 12

depletes neurons of dopamine and norepinephrine (inhibits presynaptic NT uptake into vesicles and decr release)

Question 13

what is ipronazid?

Answer 13

anti-tubercular drug that alleviated depression

Question 14

how did ipronazid alleviate depression?

Answer 14

inhibited monoamine oxidase/MAO (enzyme that breaks down monoamine NTs) which incr [monoamine NTs]

Question 15

what are 3 issues w/ monoamine hypothesis for depression?

Answer 15

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)

Question 16

what is the glutamatergic hypothesis?

Answer 16

depression is associated w/ decr glutamatergic signaling in cortex

Question 17

what does decr in glutamatergic signalling impact?

Answer 17

both excitatory and inhibitory function, leading to reduced signal noise

Question 18

what does loss of glutamatergic signalling also cause? (4)

Answer 18

long-term potentiation, neurotropic production (BDNF), synapse formation, gene transcription

Question 19

what do MAO inhibitors do?

Answer 19

incr synaptic levels of monoamine NTs (NE and 5-HT) by inhibiting their breakdown by MAO

Question 20

what is an example of an MAO inhibitor?

Answer 20

ipronazid

Question 21

what is the “tyramine cheese rxn”?

Answer 21

inhibition of MAO by MAO inhibitors can incr [tyramine] and cause acute hypertension (binds to adrenergic receptors in heart and blood vessels)

Question 22

what is tyramine?

Answer 22

sympathomimetic monoamine (resembles NA) found in foods such as aged cheese

Question 23

what is tyramine degraded by?

Answer 23

MAO

Question 24

what does SSRI stand for?

Answer 24

selective serotonin reuptake inhibitors

Question 25

what do SSRIs do?

Answer 25

inhibit serotonin (SET) transporters which incr extracellular [5-HT]

Question 26

what are transporters?

Answer 26

molecules that reuptake NTs from synapse into cell

Question 27

what does SNRI stand for?

Answer 27

serotonin norepinephrine reuptake inhibitors

Question 28

what do SNRIs do?

Answer 28

inhibit SETs and NA transporters (NETs)

Question 29

what is an example of a selective reuptake inhibitor?

Answer 29

fluoxetine

Question 30

what are 3 limitations of monoamine antidepressants? (MAOIs, SSRIs, SNRIs)

Answer 30

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.

Question 31

what is ketamine?

Answer 31

a noncompetitive NMDA/Glu receptor antagonist

Question 32

what are 3 purposes for ketamine?

Answer 32

anti-depressant (low doses), hallucinogen (medium doses), dissociative anesthetic (high doses) - lethal at higher doses

Question 33

how does ketamine work to improve symptoms of depression?

Answer 33

blocks activation of NMDA receptors on GABAergic interneurons by Glu which inhibits inhibition (activates) Glu excitatory neurons (incr [Glu])

Question 34

what are 4 downstream effects of Glu burst from ketamine?

Answer 34

synaptic remodeling, resetting of Glu and GABA systems, BDNF release, gene transcription

Question 35

what is the effectiveness of SSRIs vs ketamine?

Answer 35

SSRIs: ~15% in 8 weeks ketamine: ~25% in one day

Question 36

what are 2 limitations of ketamine?

Answer 36

narrow TI; must be administered intravenously in hospital (due to small TI)

Question 37

what are future/possible treatments for depression?

Answer 37

drugs that directly target downstream events from synaptic remodeling (inositol, cAMP, CREB) to be more effective and selective

Question 38

what is rolipram?

Answer 38

phosphodiesterase inhibitor that incr cAMP to treat depression