Antidepressants Flashcards
Explain the reason for the “therapeutic lag” associated with antidepressants.
SSRI/SNRI selectively block 5-HT, and these receptors typically sit in the synapse and suck up the unused seratonin. SSRI/SNRI bind to the 5-HT receptor and block it from sucking up seratonin within minutes of drug administration, but clinical efficacy takes several weeks
Describe theories of the etiology of depression that do not involves biogenic amines.
- HPA/stress theory: overactivity of the HPA axis
- Neurogenic theory: stress produces deficiencies in hippocampal neurogenesis
- Immune theory: chronically elevated cytokines lead to “sickness behavior”
More of an observation, not sure whether cause or effect:
HPA/stress theory:
depressed patients have: high cortisol hypertrophied adrenal glands reduced glucocorticoid receptor (GR) function reduced feedback inhibition --can be triggered by early-life stress
GR function can be normalized by treatment with AD meds
predicts treatment outcome
Neurogentic theory:
Neurotrophic factors (e.g., brain-derived neurotrophic factor, BDNF) inhibit apoptosis to enhance cell survival
BDNF levels are decreased by stress, increased by AD medications
BDNF has antidepressant-like effects in animal models
ssri/snri are first line and take ______, for full effect, ____ respond, and _____ decrease in symptoms with _____ for placebo
2-8 weeks for initial full effect, 65% respond, 50% decrease in symptoms with 30% placebo
fluoxetine!
pharmacokinetics of ssri/snri:
97% strongly bound to plasma proteins and this leads to the side effects we see; metabolized in liver, inhibit hepatic enzymes; extremely long half life because the half life of the drug may be 4-6 days but then the metabolite has a half life of 7-15 days (fluoxetine)
TEST: Taking as an example the SNRI duloxetine:
Initially, the depressed individual is hypothesized too have _______, and corresponding _________.
Almost immediately after administration, brain levels of_________. There is an initial period of overstimulation of the pre- and post-synaptic receptors throughout the brain. These signals are translocated by intracellular proteins form the cell membrane to the nucleus and affect the expression of genes that produce ________. Over time neurons move these newly made proteins from the nucleus to distant points of the cell to adapt to the change in stimulation brought about by the drug. Synapses are rearranged, and potentially new neurons are born and grow to innervate new brain areas. It is only after these steps are completed that improvements in mood and motivation can be seen in the patient. It takes________ which is thought to be the reason the the “therapeutic lag” observed with antidepressants.
low firing rates of dopamine, 5-HT and NE neurons, low baseline levels of neurotransmitter in the brain, 5-HT and NE rise. neurotransmitter receptors, transporters, and other proteins, several weeks for these steps to occur,
imipramine
rarely used anymore as monotherapy bc of side effects; these drugs are all equal at their treating of depression, but diff by side effect profile; all have same mechanism of action, blocks uptake of monoamines (NE and seratonin) and have SAME LAG
whats the difference between tca and snri?
tcas interact with lots more nt receptors!anticholinergic effects (antagonism of MUSCARINIC receptor)
dry mouth, sore throat, tachycardia
more common, less severe
Significant CV effects (ORTHOSTATIC HYPOTENSION)
less common, more serious!
sedation, weight gain, seizures, sex dysfunction, delirium
Tranylcypramine (MAO)
one difference in pharmacokinetics of MAO: they are irriversible enzyme inhibitors, so once they grab ahold of the enzyme, the only way to restore functino is to make more enzyme (which takes approx. 2 weeks)
if someone is on a mao inhibitor that wasn’t responding, then you switch to a tricyclic drug:
they don’t have any monoamine oxidase bc they’ve been on an inhibitor, so if you throw the TCA in the mix, you have a huge influx of NE dopamine in the brain and this leads to seizures
MOA of TCA and SSRI/SNRI is_____, while the MOA of MAO is:
blocking reuptake, blocking the degradation of NT
TEST: Reason MAOIs are no longer used:
Hypertensive crisis: Inhibited MAOA unable to metabolize tyramine (from diet); tyramine accumulates, flows into general circulation, promotes a massive release of catecholamines from neurons and adrenal medulla: leads to sudden, severe HT which can be lethal
Diet and OTC meds must also be carefully monitored for tyramine or phenylethylamine.
TEST: The most unique atypical is:
buproprion (DA/NE uptake inhibitor) used in smoking cessation and DOES NOT CAUSE SEXUAL DYSFUNCTION BC IT LACKS THE SERATONERGIC COMPONENT
bupropion:
weak DA/NE uptake inhibitor, also used in cigarette
smoking cessation
unique feature: does not cause sexual dysfunction
trazodone:
weak 5-HT uptake inhibitor; 5-HT1 agonist; 5-HT2A/2C
antagonist; widely used as a hypnotic (sleep aid)
mirtazepine:
blocks 5-HT2, 5-HT3, a2 and histamine
receptors; increases NE and 5-HT release; no uptake inhibition
buspirone:
5-HT1A agonist, also has D2 antagonist effects
Other uses : anxiety; some efficacy in depression
Bupropion & hydroxybupropion can act as
stimulants
agitation, anxiety
appetite-suppressant effect
WOULD GIVE TO A PATIENT THAT IS OBESE!!
Trazodone
sedation
some risk of inducing hypotension (particularly in elderly)
TEST: Mirtazepine
sedation (H1 receptor antagonism)
increased appetite, weight gain (H1 receptor antagonism)
often used in older patients with insomnia & appetite loss!!!
test: OBESE requests antidepressent______ older person that has insomnia and is underweight:
buproprion bc it is an atypical with appetite suppression quality; mirtazepine bc it increases appetite and causes sedation
Lithium
Antimanics, “mood stabilizers*”
doesn’t make bipolar mania worse (like AD does)
first-line treatment (1970)
precise mechanism is unknown
may alter distribution of other ions (Mg++, Ca++, K+, Na+)
decreases synthesis and blocks release of NE and DA
Note: antidepressants can help depression but worsen mania in bipolar
TEST: Key characteristic of Lithium:
95% eliminated through kidney, and must monitor closesly bc it has a very low theraputic index (around 3)’
best drug to prevent suicide and help manic episodes
TEST: Valproate:
blocks voltage-gated Na+ channels, facilitates GABA
pancreatic toxicity) (anticonvulsant turns DOWN activity in the brain cells
TEST? carbamazepine or tegretol
Na+ channel blocker; agonist at some GABA receptors (anticonvulsant turns DOWN activity in the brain cells)
TEST? Lamotrigine:
most recent:
treats depressive symptoms better than other treatments without increasing mania
highly variable pharmacokinetics (so you must monitor closely and more minor side effects in woman for some reason)
