Term
| biological basis of depression: the monoamine theory |
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Definition
Supportive and nonsupportive evidence for the monoamine hypothesis
SUPPORTIVE:
most evidence in support comes from pharmacology
reserpine inhibits the vesicular monoamine transporter (VMAT) resulting in depletion of NE and 5HT storage and depression symptoms
drugs that enhance monoamine neurotransmission (TCA and SSRI) are effective in treating depression
some studies show a decrease in NE and 5HT metabolites in depressed patients
NONSUPPORTIVE:
time period for clinical improvement after therapy initiation
low 5HT and NE levels in the brain is likely an oversimplification
studies cannot consistently find low monoamines in the postmortem brains of depressed patients (some found increased, others decreased)
low NE and 5HT synaptic concentrations is not complete explanation for biological basis of depression |
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Term
| cortisol hypothesis of depression |
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Definition
IMPORTANT RESEARCH FINDINGS ASSOCIATED WITH DEPRESSION
increased cortisol and ABNORMAL dexamethasone suppression test:
plasma cortisol (secreted from the adrenal cortex) is high in depressed individuals and the high cortisol levels are not suppressed by administration of dexamethason
in a normal individual, dexamethasone inhibits secretion of ACTH from the pituitary which lowers secretion of cortisol
high stress levels can cause elevated plasma cortisol; chronically elevated stress can trigger depressive episodes
neuronal loss/apoptosis (prefrontal cortex, hippocampus, amygdala):
post mortem brain of depressed patients show neuron loss in the hippocampus, prefrontal cortex, and amygdala |
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Term
| integrated hypothesis for biological basis of depression |
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Definition
[image]
stress and genetics play an important role that determine depressive symptoms
this hypothesis attempts to integrate the observation that stress as a factor in depression with neuron network changes in the brain
stress increase the glutaminergic neurotransmission (mediated through NMDA receptors) causing neuron death (apoptosis caused by excitotoxicity) in the hippocampus, prefrontal corex, and amygdala
high cortisol levels resulting from stress activate the HPA axis and turn on the transcription of "detrimental" genes which cause neuron death and inhibit neurogenesis in the hippocampus, prefrontal cortex, and amygdala
beneficial genes favor neurogenesis and inhibit apoptosis
depressive symptoms can be defined in terms of the balance between the neuronal apoptosis and neurogenesis caused by environmental and genetic factors |
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Term
| what is the therapeutic mechanism leading up to clinical improvement of depression? (receptor action is rapid, but clinical improvement requires weeks) |
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Definition
there is a gap in time between immediate action (initiated by drug binding to the receptor and intracellular signal transduction) and clinical improvement (symptom alleviation)
IMMEDIATE ACTION OF ANTIDEPRESSANTS:
NE NEURON:
NE released from the vesicle and binds to presynaptic alpha-2 receptor (autoreceptor)
activation of alpha-2 causes decreased NE release and decreased NE synthesis through down regulation of the tyrosine hydroxylase enzyme
NE can be transported back into the presynaptic terminal through the NE transporter (NET) and then repacked into vesicles or degraded by MAO
SEROTONERGIC NEURON:
5HT is transported into the vesicle and then released where it can bind presynaptic 5HT1D receptors (autoreceptors)
activation of the 5HT1D receptors decreases 5HT release and decreases 5HT synthesis through down regulation of the tryptophan hydroxylase reaction (rate limiting step in 5HT synthesis)
5HT can then be transported back into the presynaptic terminal via the serotonin transporter (SERT) or degraded by MAO
DELAYED ACTION (LONG-TERM TREATMENT) OF ANTIDEPRESSANTS:
[image]
BEFORE TREATMENT:
there is low concentration of 5HT and NE in the synapse and low intracellular signaling in the post synaptic neuron (depressive symptoms)
ACUTE TREATMENT:
antidepressant treatment effect (reuptake inhibitors, MAOIs) of increasing synaptic concentration of 5HT and NE is counteracted by decreased release of synthesis of neurotransmitter because of negative feedback through presynaptic receptor
net effect is no increase in synaptic concentration (equal to before treatment levels, postsynaptic signaling low)
no clinical improvement
LONG TERM TREATMENT:
over time with continued antidepressant drug treatment the amount of presynaptic autoreceptors is decreased (less feedback inhibition) so synaptic concentration of neurotransmitter is increased and intracellular signaling in the postsynaptic neuron is increased, in turn favoring expression of beneficial genes |
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Term
| presynaptic regulation of serotonin neurotransmission |
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Definition
[image]
1) tryptophan is concentrated in cytoplasm by symporter
2)tryptophan converted to 5HT by sequential action of hydroxylase (rate limiting) and decarboxylase
3) 5HT is concentrated in vesicles by VMAT (vesicular monoamine transporter, an antiporter using H+ gradient produced by H/ATPase) and then released after membrane depolarization and Ca influx through HVA channels
4) 5HT binds post synaptic and pre synaptic receptors (5HTD1). ***activation of the presynaptic receptors cause negative feedback through control of hydroxylase gene expression
5-6) 5HT can be recycled and packaged back into vesicles or degraded by action of MAO |
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Term
| presynaptic regulation of NE neurotransmission |
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Definition
[image]
1) tyrosine is transported by symporter
2) tyrosine converted to dopamine by action of hydroxylase (rate limiting) and decarboxylase, dopamine packaged into vesicles by VMAT
3) dopamine converted to NE INSIDE VESICLE by action of dopamine-beta-hydroxylase
4) NE released after neuron depolarization and calcium influx
5) Ne binds postsynaptic receptors and presynaptic receptors (alpha-2); ***the presynaptic receptors mediate negative feedback on tyrosine hydroxylase production (rate limiting step!!)
6) NE can be recycled (NE transporter and packaging back into vesicles)
7) in cytoplasm, NE can be degraded by action of MAO (associated with mitochondria) |
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Term
| secondary, adaptive changes that occur after weeks of antidepressant administration |
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Definition
[image]
long term treatment with antidepressants cause a decrease in the number of presynaptic receptors (less negative feedback) leading to higher concentrations of NTs in the synapse and more intracellular signaling
activation of signal transduction pathways by NE and 5HT (and brain-derived neurotrophic factor, BDNF) "turn off" detrimental gene expression and "turn on" beneficial gene expression which favors neurogenesis thus restoring neuron loss in the hippocampus, prefrontal cortex, and amygdala (alleviation of symptoms)
the production of BDNF is increased with antidepressant drugs; TrkB is a type of receptor kinase found in the brain
action on molecular target -> decreased negative feedback -> restored postsynaptic intracellular signaling -> altered gene expression |
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Term
| selectivity spectrum of reuptake inhibitors |
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Definition
[image]
selectivity is not absolute
selectivity is dependent on difference (ratio) in affinity of drugs for the reuptake transporters (SERT and NET)
since the selectivity is dependent on difference in affinity
selectivity depends on concentration of drug; the plot of number of NET and SERT blocked versus drug concentration illustrates this point
[image]
this drug is more specific for SERT (higher affinity); takes less drug to block the receptors |
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Term
| therapeutic mechanism of TCAs |
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Definition
IMMEDIATE ACTION:
inhibits reuptake of NE and/or 5HT
[image]
energy for NT reuptake (against a concentration gradient) is provided by co-transport of Na+ (Na concentration is higher outside cell)
although the above figure implies channel-like transport, it is thought that the transporter "flips" through the membrane (extracellular face of the transporter "flips" to the intracellular face) thereby moving NT and Na inside the cell; after the NT is released the transporter "flips" back; this model of transport has been proposed for all monoamine transporters
DELAYED ACTION:
decrease presynaptic alpha-2 and 5HT1D receptors
increase neurotrasmitter synaptic concentration
gene transcription and neuron growth |
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Term
| symptom improvement as a function of TCA plasma concentration |
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Definition
[image]
the antidepressant effect, determined from subjective rating scales is optimal at plasma concentrations between 200-400 and declines at higher levels (increase in ADRs)
there is a window of optimal drug concentration
although this graph represents nortriptyline it may be extended to other TCA antidepressants |
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Term
| properties of nonselective TCAs: tertiary amines and secondary amines |
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Definition
TERTIARY AMINES:
mixed or selectivity for 5HT reuptake inhibition
side effects (H1, alpha-1, M, Na+ channel)
high plasma protein binding
N-demethylation
SECONDARY AMINES:
selectivity for NE reuptake inhibition
side effects (H1, alpha-1, M, Na+ channel), TERTIARY > SECONDARY
high plasma protein binding
some tertiary amines are metabolized by N-demethylation to secondary amines
tertiary amines tend to have preference for 5HT reuptake inhibition
secandary amines have selectivity for NE reuptake inhibition
both are antagonists of H1, alpha-1 adrenergic, M receptors and inhibit Na+ channels causing unwanted effects
side effects of tertiary amines are more severe |
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Term
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Definition
dry mought (xerostomia), constipation, urinary retention, blurred vision
these effect usually disappear (tolerance develops)
orthostatic (postural) hypotension due to blockage of alpha-1 receptors is most prominent during initial days of treatment
tolerance develops
sedation from central histamine receptor antagonism
cardiotoxicity especially with overdose (QT interval, QRS complex)
contraindicated in patients with cardiac arrhythmias (TCAs can block Na+ channels in heart causing conduction problems)
ECG may show prolonged QT interval and QRS complex widening
lower seizure threshold
weight gain attributed to H1 and possibly serotonin system effects |
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Term
| TCA drug interaction and other considerations |
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Definition
pharmacokinetic interactions: interfering with metabolism of the drug/plasma protein binding
pharmacodynamic interactions: receptor interaction
ex) TCA and another drug that both have anticholinergic effects
withdrawal effects:
REBOUND cholinergic activity
cholinergic activity can increase after abrupt withdrawal of TCA (rebound effect)
right after therapy begins side effects from anti-cholinergic activity is most prominent (xerostomia, urine retention, constipation)
tolerance to these effects develop after continued treatment with TCAs
after abrupt withdrawal of the drug cholinergic activity is high producing opposite effects |
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Term
| MOA of venlafaxine and duloxetine |
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Definition
| serotonin-norepinephrine reuptake inhibitors (SNRI) |
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Term
| MOA of serotonin norepinephrine reuptake inhibitors (venlafaxine, duloxetine) |
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Definition
like the TCAs this class inhibits reuptake of both NE and 5HT, but do not have the nonselective receptor interaction profile (much less sedation, hypotension, cardiac conduction effects)
venlafaxine has preference for 5HT reuptake
duloxetine has higher affinity for both transporters compred to venlafaxine, but lower selectivity for 5HT reuptake inhibition
less pharmacodynamic interactions compared to TCAs |
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Term
| selective serotonin reuptake inhibitors (SSRIs) |
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Definition
citalopram
fluoxetine
fluvoxamine
paroxetine
sertraline
vilazodone |
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Term
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Definition
SSRIs have very high affinity for SERT and low affinity for NET, thus they are very selective for inhibiting reuptake of serotonin
have therapeutic use for anxiety disorders, OCD, and PTSD
vilazodone is a new SSRI with additional partial agonist activity on 5HT-1A which makes it unique from other SSRIs
IMMEDIATE ACTION:
inhibits reuptake of 5HT through the blockage of 5HT reuptake transporters
but, presynaptic receptors (5HT-1D) inhibit the release and synthesis of 5HT so there is no net increase in synaptic 5HT concentration
DELAYED ACTION:
the number of presynaptic 5HT-1D receptors decline (release and synthesis of 5HT increases as a result)
higher levels of 5HT in the synapse cause more postsynaptic response and up regulation of beneficial genes (decrease apoptosis and increase neurogenesis) |
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Term
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Definition
overall, fewer than TCAs
SSRIs have higher TI compared to TCAs and are overall better tolerated (no antagonism of other receptors)
nausea most common (5HT3,4 in GI)
serotonin receptors control GI motility
GI effects are attributed to excessive activation of 5HT3 and 5HT4 receptors
drugs to treat IBS bind to 5HT3,4
sexual dysfunction
loss of libido and impaired orgams
symptoms can worsen early in treatment (too much negative feedback all at once) causing concern of suicide |
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Term
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Definition
SEROTONIN SYNDROME
concurrent MAOi use
a drug that potentiates serotonin neurotransmmission (SSRI) concurrently used with MAOIs (or not sufficient time after discontinuation of MAOI) is associated with serotonin syndrome
mechanism: high synaptic 5HT in CNS resulting from the combined effect of reuptake inhibition with less degradation of serotonin
excessive activation of subtypes 1A and 2A are thought to cause symptoms of serotonin syndreom
onset within hours: tremor, hyperthermia, hypertension, coma |
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Term
| drugs that have the potential to cause serotonin syndrome |
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Definition
drugs which increase synthesis of serotonin
increase release of serotonin
decrease degradation of serotonin
reuptake blockers
direct receptor activation
severe or fatal cases are reported with SSRIs and MAOs |
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Term
| drugs that selectively inhibit the reuptake of NE |
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Definition
reboxetine
investigational, relatively low affinity for H1, M, alpha receptors
maprotiline
minor 5HT reuptake inhibitors
LOWERS SEIZURE THRESHOLD
anticholinergic, sedation, hypotension, cardiac conduction effects comparable to TCAs |
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Term
| nonselective MAOIs (A and B) |
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Definition
phenelzine
tranylcypromine
isocarboxazid
non-selective inhibitors are FDA approved and currently marketed in the US for anti-depression
IRREVERSIBLE inhibitors (form stable covalent bond with MAO enzymes
antidepressant activity is associated with inhibition of type A |
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Term
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Definition
clorgiline
moclobemide
antidepressant activity is associated with inhibition of type A
drugs selectivce for type A are not FDA approved
MOCLOBEMIDE is a REVERSIBLE inhibitor of type A |
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Term
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Definition
selegiline
used for PD treatment |
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Term
| substrate specificity of MAO-A AND MAO-B |
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Definition
MAO-A:
EPI, NE, 5HT
tyramine and dopamine
MAO-B:
tyramine and dopamine
phenylethylamine and benzylamine
MAO-A is the target for drugs useful intreating depression
non selecticve inhibition of both MAO-A and MAO-B blocks the metabolism of tyramine, which is responsible for the food reaction that occurs with these drugs |
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Term
| tissue distribution of MAO |
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Definition
neuron terminals: metabolizes NTs
liver: metabolizes dietary monoamines (tyramine, phenethylamine)
intestine: metabolizes dietary monoamines (tyramine, phenethylamine)
platelets: metabolizes 5HT to regulate platelet aggregation activity |
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Term
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Definition
mitochondria in axon terminal (THERAPEUTIC AND ADRS)
liver and intestines (ADRS)
drugs used in the US are irreversible inhibitors of MAO A and B
the therapeutic site of action of antidepressant MAOIs is in the neuron terminal, but also potential adverse mechanism in the case of serotonin syndrome
inhibition of the eynzymes increases vesicle concentration of NTs and causes direct leakage of NT into the synapses
after down regulation of autoreceptors, MAOIs increase synaptic concentration of NTs
liver and intestine is considered a site of ADRs or drug interaction (metabolism of dietary tyramine is inhibited, metabolic drug-drug interaction) |
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Term
| adverse interaction of MAOIs with tyramine (an indirect sympathomimetic) |
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Definition
NONSELECTIVE (A AND B):
HYPTERTENSIVE CRISIS reaction from amine-containing foods (MAINLY TYRAMINE) from cheese, wine, beer, soy extracts and smoked meats
SELECTIVE:
no tyramine reaction
normally tyramine is metabolized by MAO-A in peripheral tissues before it reaches nerve terminals in the CNS and acts as an indirect sympathomimetic
selective inhibitors of MAO-A have less tyramine related ADRs because type B remains active in the CNS and therefore metabolizes tyramine
the acute effect is tyramine displaces NE from nerve terminals and causes increased synaptic NE
higher concentration of NE in the cytoplasm causes NET to go in reverse direction
elevated NE causes more adrenergic receptor stimulation in heart and blood vessels (basis for the hypertensive "cheese reaction" in patients taking a nonselective MAOI) |
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Term
| drug interactions and other considerations of MAOIs |
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Definition
indirect acting sympathomimetic amines (ephedrine and amphetamine) and triptans potentiated
because of the irreversible nature of MAO inhibition (drug forms covalent bond with enzyme) drug interaction can occur for extended periods of time after discontinuation of the MAOI (the recommended minimum time period is 2 weeks between stopping MAO administration and starting another antidepressant
2 weeks allows sufficient time for synthesis of new enzyme |
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Term
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Definition
uncertain mechanism
weak NE and 5HT reuptake inhibition
active metabolites that inhibit dopamine reuptake
increased SEIZURE RISK
caution with seizure or head trauma history |
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Term
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Definition
serotonin analog
antagonist of 5HT and alpha-2 autoreceptors
sedative activity (H1 blockage)
increases synaptic concentration of 5HT and NE through antagonism of central presynaptic autoreceptors (blocks negative feedback) |
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Term
| MOA of nefazodone and trazodone |
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Definition
may block presynaptic receptors
partial postsynaptic agonist?
HEPATIC FAILURE RISK (NEFAZODONE); priapism; hypotension attributed to alpha-1 antagonism (reflex tachycardia may occur) |
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