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PHAR 301 > Antidepressants > Flashcards

Antidepressants Flashcards

1
Q

what occurs during unipolar disorder?

A

depression

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2
Q

what are 2 alternate names for unipolar disorder?

A
  1. major depression
  2. major depressive disorder
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3
Q

what are 2 symptoms found in unipolar disorder?

A

more anxiety and agitation

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4
Q

does unipolar disorder have an older or younger age of onset than bipolar?

A

older

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5
Q

what is the frequency and length of episodes of unipolar disorder compared to the frequency and length of episodes of bipolar?

A

fewer and longer for unipolar

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6
Q

what is the ratio of men to women with unipolar disorder?

A

2:1

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7
Q

what the % chance of having unipolar disorder at some point in your life?

A

6-17%

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8
Q

what is the definition of MZ concordance?

A

probability of having disorder if your identical twin also has it

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9
Q

what is the MZ concordance of unipolar disorder?

A

50%

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10
Q

what is the treatment for unipolar disorder?

A

antidepressants

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11
Q

what is BPD?

A

switch btwn mania and depression

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12
Q

what is the women:men ratio of BPD?

A

1:1

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13
Q

what is the % chance of having BPD at some point in your life?

A

1%

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14
Q

what is the MZ concordance of BPD?

A

70%

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15
Q

what is the treatment for BPD

A

antidepressants and lithium

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16
Q

what type of disorder is major depression?

A

an affective disorder aka a mood disorder

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17
Q

what are the 4 typical symptoms of major depression?

A
  1. misery, apathy
  2. low self-esteem
  3. low motivation
  4. poor sleep and appetite
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18
Q

how do diff ppl with major depression compare in terms of symptoms?

A

many diff symptoms for each person but usually 2 main symptoms:
1. depressed mood
2. decreased interest/pleasure in activities

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19
Q

what is a main characteristic of major depression?

A

it recurs

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20
Q

what increases your susceptibility for recurrence of depression?

A

after successive episodes

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21
Q

after a first episode, what % of ppl will have at least 1 more episode within 5 years?

A

70%

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22
Q

describe the phases of depression

A

A. caused by precipitating episode or no apparent reason
B. don’t take treatment –> stay depressed
C. take treatment –> will reach normal mood
D. stop treatment will relapse

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23
Q

what are the 3 major categories of major depression?

A
  1. reactive depression
  2. endogenous/melancholic depression
  3. atypical depression
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24
Q

what triggers reactive depression? how does it respond to antidepressants?

A
  • triggered by specific stress
  • responds less well to antidepressants
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25
Q

what is the cause of endogenous/melancholic depression?

A

no clear cause but often runs in families

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26
Q

does the type of major depression affect the drug you take?

A

no

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27
Q

what did ppl initially think caused depression?

A

too much black bile (one of the four humours) led to melancholia

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28
Q

what is the monoamine hypothesis of depression?

A

states that depression is caused by a deficit in monoamine transmission

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29
Q

what was the monoamine hypothesis based on?

A

drugs that seemed to reduce depression caused increased monoamine transmission

drugs that seemed to increase depression caused decreased monoamine transmission

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30
Q

describe how NA is produced and what happens to NA at the synapse (4)

A

tyrosine –> L-DOPA –> dopamine –> NA

NA is released into synapse:
1. can activate post-synaptic neuron
2. can diffuse away
3. can undergo reuptake by NET, then broken down by MAO or re-released
4. can bind autoreceptor on original receptor

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31
Q

are autoreceptors usually inhibitory or excitatory?

A

inhibitory

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32
Q

where are autoreceptors located? (2)

A

at cell bodies and dendrites

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33
Q

what are autoreceptors at cell bodies called?

A

presynaptic autoreceptors

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34
Q

what are autoreceptors at dendrites called?

A

somatodendritic autoreceptors

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35
Q

what is the function of autoreceptors?

A

feedback loop to inhibit cell firing rate if too much monoamine transmitter released

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36
Q

where does reserpine come from?

A

snake root plant

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37
Q

how does reserpine affect the cardiovascular system?

A

it is an antihypertensive

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38
Q

is reserpine thought to cause or prevent depression? how?

A

prevent depression by depleting monoamine transmitters

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39
Q

what is the mechanism of reserpine?

A

blocks monoamine vesicle so monoamine cannot release from cell –> less monoamine in synapse

NA from from reuptake is broken broken down by MAO

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40
Q

what do MAOI do?

A

increase NA transmission

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41
Q

what drug was initially used for TB but found to help with depression?

A

iproniazid

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42
Q

what was the problem with iproniazid?

A

caused liver damage

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43
Q

what is the mechanism of iproniazid? what does it lead to?

A

inhibits MAO so monoamine builds up –> leads to increased NA and 5HT

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44
Q

what was the first TCA?

A

Imipramine

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45
Q

what was imipramine initially used for?

A

schizophrenia

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46
Q

what is the mechanism of imipramine?

A

blocks NET (reuptake receptor) so NA builds up in synapse –> leads to increased NA transmission

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47
Q

describe the first Axelrod experiment for the discovery of NET

A
  • normal mouse given NA –> NA accumulates
  • mouse with lesioned SNS given NA –> NA does not accumulate

therefore, nerve terminals required for NA to accumulate

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48
Q

describe the second Axelrod experiment for the discovery of NET and what this means

A
  • normal mouse given NA –> small increase in BP
  • mouse with lesioned SNS given NA –> large increase in BP bc exaggerated response to NA

no nerve terminals that release NA causes SENSITIZATION and receptors are upregulated to cause changes in BP

nerve terminals allows for normal SNS and therefore normal BP

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49
Q

what are the 3 mechanisms that decrease the results of imipramine blocking NET?

A
  1. less NA taken back into terminal –> less NA put into release vesicles
  2. more NA activates autoreceptors –> NA release is inhibited
  3. postsynaptic neuron makes more neurons and/or increases signaling pathways downstream of receptor –> supersensitivity
50
Q

what are things we can indirectly look at to test the monoamine hypothesis and why are these not accurate?

A
  1. CSF, blood, urine
  2. post-mortem brain
  3. living brain

bad bc we can only measure them indirectly –> a change in something can be interpreted in many ways

51
Q

what can we directly measure to test the monoamine hypothesis and why are they good to measure?

A

monoamine metabolites from each monoamine transmitter

good bc easy to measure and build up to higher amounts than the neurotransmitters

52
Q

why is evidence for the monoamine hypothesis hard to interpret? (3)

A
  1. unknown sources of molecules
  2. confounding factors (is depression caused by the abnormality or the lifestyle, drugs, etc.)
  3. can’t make direct conclusion
53
Q

where is 5HT released from?

A

axon terminals AND dendrites

54
Q

what are the autoreceptors for 5HT called?

A

5HT-1A

55
Q

what happens when there is an increase in 5HT1A autoreceptors?

A

decreased 5HT release and cell firing

56
Q

what are the 3 drugs that support the monoamine hypothesis based on their ability to improve mood?

A
  1. MAOI –> reduced NA and 5HT breakdown
  2. TCA –> reduced NA and 5HT reuptake
  3. SSRI –> reduced NA and 5HT reuptake
57
Q

what are 3 things that support the monoamine hypothesis based on their ability to worsen mood?

A
  1. reserpine –> reduced 5HT and NA release
  2. Trp-free diet –> reduced 5HT synthesis (only worsens mood for ppl at risk for depression)
  3. A-methyl-p-tyrosine –> reduced NA synthesis
58
Q

what was actually shown to be true about reserpine?

A

it does not cause depression, it is an ANTI-DEPRESSANT

59
Q

which 2 drugs DO NOT support the monoamine hypothesis?

A
  1. L-DOPA –> increases NA synthesis BUT IS NOT AN ANTIDEPRESSANT
  2. Reserpine, 5HT antagonists, and NA antagonists –> should be depressant BUT ARE ANTIDEPRESSANTS
60
Q

describe the therapeutic delay of antidepressants

A

often takes 3-6 weeks before mood plateaus to normal

61
Q

what is the difference and similarity btwn drugs that target NA vs 5HT?

A

diff side effects, but same efficacy

62
Q

why do new drugs target 5HT instead of NA?

A

fewer adverse effects on sympathetic neurons –> prevents cardiovascular issue

63
Q

what are the 2 transporters that imipramine blocks?

A

NET and SERT

64
Q

how are SSRIs similar to TCAs?

A

both block NA and 5HT reuptake

65
Q

how are SSRIs different from TCAs?

A

TCAs block both NET and SERT

SSRIs blocks SERT more than NET

66
Q

does reserpine affect different monoamines differently?

A

no, it just blocks vesicular pump which is not selective for DA/NA/5HT

67
Q

Where in the brain do antidepressants that act on 5HT cause effect?

A

they affect the Dorsal raphe area –> the 5HT cell body area

68
Q

what are synaptosomes used for?

A

can measure transmitter reuptake blockade in vitro

69
Q

what are synaptosomes?

A

nerve terminals that have been broken off

70
Q

how do you use synaptosomes to test transmitter reuptake?

A
  • only some will NETs, some will have SERTs so differentiate using radioactive NA/5HT
  • can measure how well the synaptosomes take up NA/5HT in presence of diff drugs
71
Q

how can you determine if a reuptake inhibiting drug is more potent at SERT vs NET using synaptosomes?

A

look at IC50 –> lower concentration of drug required to reach 50% inhibition of 5HT vs NA

therefore, depression is reduced and there is more 5HT in synapse than NA

72
Q

is an inhibitor that is more potent by 1 log unit helpful? why?

A

no, this means the drug is only 10x more selective for SERT than NET so it is hard to find a dose in a patient to inhibit one vs the other

need at least 2 log units of difference

73
Q

what are the 2 limitations of the synaptosome assay?

A
  1. synaptosomes do not metabolize drugs
  2. NA and 5HT pathways interact directly and indirectly thru other neurons –> we cannot see these interactions
74
Q

why is it a limitation that synaptosomes do not metabolize drugs?

A

in vivo, metabolites can be pharmacologically active with their own mechanism

ex. imipramine is more selective for 5HT but its metabolites are more selective for NA

75
Q

what is microdialysis used for?

A

to indirectly measure reuptake blockade in vivo

76
Q

how is microdialysis used?

A

probe inserted into brain to collect fluid and detect extracellular transmitters

77
Q

what would microdialysis show if an SSRI was being used?

A

would see increased extracellular 5HT bc drug blocks 5HT reuptake

78
Q

why does microdialysis only measure extracellular transmitters?

A

probe is too big to get into synapse

79
Q

what are 3 results of chronic antidepressant treatment

A
  1. decreased beta adrenergic receptors (even though beta blockers are not an obvious antidepressant)
  2. decreased 5HT autoreceptors –> increased 5HT transmission
  3. decreased alpha2 adrenergic autoreceptors –> increased NA transmission
80
Q

what do 5HT autoreceptors do?

A

inhibit cell firing and release

81
Q

what are somatodendritic autoreceptors called? and their role?

A

5HT1A

causes reduced cell firing

82
Q

what are axon terminal autoreceptors called? and their role?

A

5HT1B/1D

causes reduced 5HT release

83
Q

does acute SSRI use boost synaptic 5HT a little bit or a lot?

A

acute SSRIs boost synaptic 5HT a bit

84
Q

what does acute SSRI use cause? why?

A

SSRI blocks SERT so 5HT is released but accumulates at dendrite and terminal

overall small increase in synapse 5HT but lower effect bc 5HT acts on autoreceptors

85
Q

does chronic SSRI use boost synaptic 5HT a little bit or a lot?

A

chronic SSRIs boost synaptic 5HT a lot

86
Q

what does chronic SSRI use cause?

A

autoreceptors are downregulated so firing rate and 5HT both return to normal

but SERT is still blocked so 5HT builds up a lot in synapse

this is why it takes a while for anti-depressants to work

87
Q

what does clinical effectiveness depend on? (2)

A
  1. efficacy –> how much improvement if patient takes drug
  2. compliance
88
Q

why is there a high efficacy of drugs in clinical trials?

A

high compliance

89
Q

what are SNaRIs?

A

drugs that block both SERT and NET

90
Q

are SNaRIs more effective than drugs block SERT and NET individually?

A

unclear

91
Q

what is a big problem with antidepressant efficacy? why?

A

compliance

bc ppl often stop taking their antidepressants but ppl who received counseling with antidepressant were more likely to adhere to treatment

92
Q

why is effectiveness of antidepressants controversial (4)

A
  1. usually doesn’t show to be better than placebo
  2. many trials with negative results not published
  3. statistically significant =/= clinically significant
  4. different opinions
93
Q

can ppl guess if they have had placebo or not?

A

yes, sometimes

94
Q

which 2 types of anti depressants have been used less and less? and which 1 type has been used more?

A

TCAs and SNaRIs used less

SSRIs used more

95
Q

what are the initial adverse effects of TCAs? (3)

A
  1. sedation
  2. confusion
  3. discoordination
96
Q

do the initial adverse effects of TCAs last forever? why?

A

no bc tolerance tends to develop

97
Q

what are the 3 main adverse effects of TCAs?

A
  1. antagonize receptors
  2. drug interaction
  3. overdose
98
Q

describe TCAs antagonizing receptors (2)

A
  1. muscarinic ACh receptors –> dry mouth
  2. brain histamine H1 receptors –> sedation
99
Q

describe the TCA drug interaction with aspirin

A

aspirin competes for the same plasma binding proteins and displaces TCA into bloodstream

100
Q

describe the TCA drug interaction with steroid drugs

A

steroid drugs reduce TCA breakdown

101
Q

describe the TCA drug interaction with ethanol

A

ethanol is potentiated by TCAs

102
Q

what happens with TCA overdose? (2)

A
  1. convulsions, then coma
  2. cardiac arrhythmias bc TCAs block NET
103
Q

what are the 3 adverse effects of MAOIs?

A
  1. postural hypotension
  2. dry mouth
  3. cheese reaction
104
Q

why is the mechanism for postural hypotension unclear?

A

MAOI should increase sympathetic tone, but weird bc hypotension occurs

105
Q

why does dry mouth occur with MAOIs?

A

off-target antagonism of muscarinic ACh receptors to counteract PNS

106
Q

why is the cheese reaction occur with MAOIs?

A

dietary tyramine normally broken down by MAO but with MAOI it reaches bloodstream and causes dangerous increase in BP

107
Q

what is different about SSRIs compared to TCAs and MAOIs in terms of side effects?

A

SSRI side effects are safer

108
Q

why are SSRIs safer (4)?

A
  1. no CV side effects
  2. no ACh side effects
  3. low risk of overdose
  4. no cheese reaction
109
Q

what are the 2 adverse effects of SSRIs?

A
  1. 5HT syndrome
  2. low sex drive
110
Q

when does 5HT syndrome get worse?

A

dangerous when combined with MAOI

111
Q

what are antidepressant recommendations from NICE (UK) for mild depression?

A

don’t use routinely bc bad risk-benefit ratio

112
Q

what are antidepressant recommendations from NICE (UK) for moderate or severe depression?

A

use antidepressants combined with high-intensity psychological intervention

113
Q

what percent of patients who begin therapy will be well 1 year later?

A

<50%

114
Q

what are the effects of ketamine?

A

rapid anti-depressant effects

115
Q

does ketamine work for treatment-resistant patients?

A

yes

116
Q

what is esketamine?

A

1st mechanistically new treatment for depression in >60 years

alleviates symptoms within 4 hours

117
Q

what is the ketamine mechanism

A

unsure but partly bc of its ability to block NMDA-type glutaminergic receptors

118
Q

below what dose does the antidepressant dose of ketamine occur?

A

antidepressants effect of ketamine occurs at sub-anaesthetic doses

119
Q

what percent of depressed patients show full remission?

A

50%

120
Q

what is electroconvulsive therapy? (5 points)

A
  • causes full remission or large improvement in >80%
  • but heavily criticized and evidence is weak
  • obscure mechanism
  • not first choice treatment
  • memory loss can be long term
121
Q

what is st johns wort? (5 points)

A
  • may be as effective as standard antidepressants in mild to moderate depression
  • mixed clinical trial results
  • ineffective in severe depression
  • obscure mechanism
  • minor adverse effects but MAJOR drug interactions

PHAR 301 (11 decks)

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