Antidepressants Flashcards
what occurs during unipolar disorder?
depression
what are 2 alternate names for unipolar disorder?
- major depression
- major depressive disorder
what are 2 symptoms found in unipolar disorder?
more anxiety and agitation
does unipolar disorder have an older or younger age of onset than bipolar?
older
what is the frequency and length of episodes of unipolar disorder compared to the frequency and length of episodes of bipolar?
fewer and longer for unipolar
what is the ratio of men to women with unipolar disorder?
2:1
what the % chance of having unipolar disorder at some point in your life?
6-17%
what is the definition of MZ concordance?
probability of having disorder if your identical twin also has it
what is the MZ concordance of unipolar disorder?
50%
what is the treatment for unipolar disorder?
antidepressants
what is BPD?
switch btwn mania and depression
what is the women:men ratio of BPD?
1:1
what is the % chance of having BPD at some point in your life?
1%
what is the MZ concordance of BPD?
70%
what is the treatment for BPD
antidepressants and lithium
what type of disorder is major depression?
an affective disorder aka a mood disorder
what are the 4 typical symptoms of major depression?
- misery, apathy
- low self-esteem
- low motivation
- poor sleep and appetite
how do diff ppl with major depression compare in terms of symptoms?
many diff symptoms for each person but usually 2 main symptoms:
1. depressed mood
2. decreased interest/pleasure in activities
what is a main characteristic of major depression?
it recurs
what increases your susceptibility for recurrence of depression?
after successive episodes
after a first episode, what % of ppl will have at least 1 more episode within 5 years?
70%
describe the phases of depression
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
what are the 3 major categories of major depression?
- reactive depression
- endogenous/melancholic depression
- atypical depression
what triggers reactive depression? how does it respond to antidepressants?
- triggered by specific stress
- responds less well to antidepressants
what is the cause of endogenous/melancholic depression?
no clear cause but often runs in families
does the type of major depression affect the drug you take?
no
what did ppl initially think caused depression?
too much black bile (one of the four humours) led to melancholia
what is the monoamine hypothesis of depression?
states that depression is caused by a deficit in monoamine transmission
what was the monoamine hypothesis based on?
drugs that seemed to reduce depression caused increased monoamine transmission
drugs that seemed to increase depression caused decreased monoamine transmission
describe how NA is produced and what happens to NA at the synapse (4)
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
are autoreceptors usually inhibitory or excitatory?
inhibitory
where are autoreceptors located? (2)
at cell bodies and dendrites
what are autoreceptors at cell bodies called?
presynaptic autoreceptors
what are autoreceptors at dendrites called?
somatodendritic autoreceptors
what is the function of autoreceptors?
feedback loop to inhibit cell firing rate if too much monoamine transmitter released
where does reserpine come from?
snake root plant
how does reserpine affect the cardiovascular system?
it is an antihypertensive
is reserpine thought to cause or prevent depression? how?
prevent depression by depleting monoamine transmitters
what is the mechanism of reserpine?
blocks monoamine vesicle so monoamine cannot release from cell –> less monoamine in synapse
NA from from reuptake is broken broken down by MAO
what do MAOI do?
increase NA transmission
what drug was initially used for TB but found to help with depression?
iproniazid
what was the problem with iproniazid?
caused liver damage
what is the mechanism of iproniazid? what does it lead to?
inhibits MAO so monoamine builds up –> leads to increased NA and 5HT
what was the first TCA?
Imipramine
what was imipramine initially used for?
schizophrenia
what is the mechanism of imipramine?
blocks NET (reuptake receptor) so NA builds up in synapse –> leads to increased NA transmission
describe the first Axelrod experiment for the discovery of NET
- normal mouse given NA –> NA accumulates
- mouse with lesioned SNS given NA –> NA does not accumulate
therefore, nerve terminals required for NA to accumulate
describe the second Axelrod experiment for the discovery of NET and what this means
- 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
what are the 3 mechanisms that decrease the results of imipramine blocking NET?
- less NA taken back into terminal –> less NA put into release vesicles
- more NA activates autoreceptors –> NA release is inhibited
- postsynaptic neuron makes more neurons and/or increases signaling pathways downstream of receptor –> supersensitivity
what are things we can indirectly look at to test the monoamine hypothesis and why are these not accurate?
- CSF, blood, urine
- post-mortem brain
- living brain
bad bc we can only measure them indirectly –> a change in something can be interpreted in many ways
what can we directly measure to test the monoamine hypothesis and why are they good to measure?
monoamine metabolites from each monoamine transmitter
good bc easy to measure and build up to higher amounts than the neurotransmitters
why is evidence for the monoamine hypothesis hard to interpret? (3)
- unknown sources of molecules
- confounding factors (is depression caused by the abnormality or the lifestyle, drugs, etc.)
- can’t make direct conclusion
where is 5HT released from?
axon terminals AND dendrites
what are the autoreceptors for 5HT called?
5HT-1A
what happens when there is an increase in 5HT1A autoreceptors?
decreased 5HT release and cell firing
what are the 3 drugs that support the monoamine hypothesis based on their ability to improve mood?
- MAOI –> reduced NA and 5HT breakdown
- TCA –> reduced NA and 5HT reuptake
- SSRI –> reduced NA and 5HT reuptake
what are 3 things that support the monoamine hypothesis based on their ability to worsen mood?
- reserpine –> reduced 5HT and NA release
- Trp-free diet –> reduced 5HT synthesis (only worsens mood for ppl at risk for depression)
- A-methyl-p-tyrosine –> reduced NA synthesis
what was actually shown to be true about reserpine?
it does not cause depression, it is an ANTI-DEPRESSANT
which 2 drugs DO NOT support the monoamine hypothesis?
- L-DOPA –> increases NA synthesis BUT IS NOT AN ANTIDEPRESSANT
- Reserpine, 5HT antagonists, and NA antagonists –> should be depressant BUT ARE ANTIDEPRESSANTS
describe the therapeutic delay of antidepressants
often takes 3-6 weeks before mood plateaus to normal
what is the difference and similarity btwn drugs that target NA vs 5HT?
diff side effects, but same efficacy
why do new drugs target 5HT instead of NA?
fewer adverse effects on sympathetic neurons –> prevents cardiovascular issue
what are the 2 transporters that imipramine blocks?
NET and SERT
how are SSRIs similar to TCAs?
both block NA and 5HT reuptake
how are SSRIs different from TCAs?
TCAs block both NET and SERT
SSRIs blocks SERT more than NET
does reserpine affect different monoamines differently?
no, it just blocks vesicular pump which is not selective for DA/NA/5HT
Where in the brain do antidepressants that act on 5HT cause effect?
they affect the Dorsal raphe area –> the 5HT cell body area
what are synaptosomes used for?
can measure transmitter reuptake blockade in vitro
what are synaptosomes?
nerve terminals that have been broken off
how do you use synaptosomes to test transmitter reuptake?
- 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
how can you determine if a reuptake inhibiting drug is more potent at SERT vs NET using synaptosomes?
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
is an inhibitor that is more potent by 1 log unit helpful? why?
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
what are the 2 limitations of the synaptosome assay?
- synaptosomes do not metabolize drugs
- NA and 5HT pathways interact directly and indirectly thru other neurons –> we cannot see these interactions
why is it a limitation that synaptosomes do not metabolize drugs?
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
what is microdialysis used for?
to indirectly measure reuptake blockade in vivo
how is microdialysis used?
probe inserted into brain to collect fluid and detect extracellular transmitters
what would microdialysis show if an SSRI was being used?
would see increased extracellular 5HT bc drug blocks 5HT reuptake
why does microdialysis only measure extracellular transmitters?
probe is too big to get into synapse
what are 3 results of chronic antidepressant treatment
- decreased beta adrenergic receptors (even though beta blockers are not an obvious antidepressant)
- decreased 5HT autoreceptors –> increased 5HT transmission
- decreased alpha2 adrenergic autoreceptors –> increased NA transmission
what do 5HT autoreceptors do?
inhibit cell firing and release
what are somatodendritic autoreceptors called? and their role?
5HT1A
causes reduced cell firing
what are axon terminal autoreceptors called? and their role?
5HT1B/1D
causes reduced 5HT release
does acute SSRI use boost synaptic 5HT a little bit or a lot?
acute SSRIs boost synaptic 5HT a bit
what does acute SSRI use cause? why?
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
does chronic SSRI use boost synaptic 5HT a little bit or a lot?
chronic SSRIs boost synaptic 5HT a lot
what does chronic SSRI use cause?
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
what does clinical effectiveness depend on? (2)
- efficacy –> how much improvement if patient takes drug
- compliance
why is there a high efficacy of drugs in clinical trials?
high compliance
what are SNaRIs?
drugs that block both SERT and NET
are SNaRIs more effective than drugs block SERT and NET individually?
unclear
what is a big problem with antidepressant efficacy? why?
compliance
bc ppl often stop taking their antidepressants but ppl who received counseling with antidepressant were more likely to adhere to treatment
why is effectiveness of antidepressants controversial (4)
- usually doesn’t show to be better than placebo
- many trials with negative results not published
- statistically significant =/= clinically significant
- different opinions
can ppl guess if they have had placebo or not?
yes, sometimes
which 2 types of anti depressants have been used less and less? and which 1 type has been used more?
TCAs and SNaRIs used less
SSRIs used more
what are the initial adverse effects of TCAs? (3)
- sedation
- confusion
- discoordination
do the initial adverse effects of TCAs last forever? why?
no bc tolerance tends to develop
what are the 3 main adverse effects of TCAs?
- antagonize receptors
- drug interaction
- overdose
describe TCAs antagonizing receptors (2)
- muscarinic ACh receptors –> dry mouth
- brain histamine H1 receptors –> sedation
describe the TCA drug interaction with aspirin
aspirin competes for the same plasma binding proteins and displaces TCA into bloodstream
describe the TCA drug interaction with steroid drugs
steroid drugs reduce TCA breakdown
describe the TCA drug interaction with ethanol
ethanol is potentiated by TCAs
what happens with TCA overdose? (2)
- convulsions, then coma
- cardiac arrhythmias bc TCAs block NET
what are the 3 adverse effects of MAOIs?
- postural hypotension
- dry mouth
- cheese reaction
why is the mechanism for postural hypotension unclear?
MAOI should increase sympathetic tone, but weird bc hypotension occurs
why does dry mouth occur with MAOIs?
off-target antagonism of muscarinic ACh receptors to counteract PNS
why is the cheese reaction occur with MAOIs?
dietary tyramine normally broken down by MAO but with MAOI it reaches bloodstream and causes dangerous increase in BP
what is different about SSRIs compared to TCAs and MAOIs in terms of side effects?
SSRI side effects are safer
why are SSRIs safer (4)?
- no CV side effects
- no ACh side effects
- low risk of overdose
- no cheese reaction
what are the 2 adverse effects of SSRIs?
- 5HT syndrome
- low sex drive
when does 5HT syndrome get worse?
dangerous when combined with MAOI
what are antidepressant recommendations from NICE (UK) for mild depression?
don’t use routinely bc bad risk-benefit ratio
what are antidepressant recommendations from NICE (UK) for moderate or severe depression?
use antidepressants combined with high-intensity psychological intervention
what percent of patients who begin therapy will be well 1 year later?
<50%
what are the effects of ketamine?
rapid anti-depressant effects
does ketamine work for treatment-resistant patients?
yes
what is esketamine?
1st mechanistically new treatment for depression in >60 years
alleviates symptoms within 4 hours
what is the ketamine mechanism
unsure but partly bc of its ability to block NMDA-type glutaminergic receptors
below what dose does the antidepressant dose of ketamine occur?
antidepressants effect of ketamine occurs at sub-anaesthetic doses
what percent of depressed patients show full remission?
50%
what is electroconvulsive therapy? (5 points)
- 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
what is st johns wort? (5 points)
- 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
