EXAM 4 Antidepressant Dr. Pond Flashcards
What is major depression disorder (MDD)?
according to DSM-5
5 or more of these symptoms: the first 2 have to be there
-depressed mood !!!
-diminished interest or pleasure in daily activities !!!
-weight loss or gain
-insomnia or hypersomnia
-psychomotor agitation or retardation
-fatigue
-feelings of worthlessness or inappropriate guilt
-loss of ability to concentrate, indecisiveness
-recurrent thoughts of death, suicide
ideation
Which receptors are targeted by many antidepressant drugs?
serotonergic receptors
noradrenegerc receptors
What is the main area of norepinephrine?
REMINDER
Locus coerulus (LC)
How is Norepinephrine made in the body?
Diet -> Tyrosine -> L-DOPA -> Dopamine -> Norepinephrine
Which enzymes are involved in the production of Norepinephrine?
Tyrosine Hydroxylase:
Tyrosine to L-DOPA
DOPA decarboxylase:
L-DOPA to Dopamine
Dopamine beta-hydroxylase:
Dopamine to NE
(NE could be converted into Epinephrine)
Are NE ionotropic or metabotropic?
metabotropic
Where on the receptors do we find the NE receptors?
pre and postsynaptic
How does Norepinephrine get turned off in the presynaptic cleft?
-NET
->it will take NE back into the presynaptic receptor where it gets stored in Monoamine vesicles via (VMAT)
-MAO-A: intracellular degradation!
-COMT: extracellular!
degradation of Monoamines (here Norepinephrine)
Which transporter moves NE into Monoamine vesicles?
VMAT (vesicle monoamine transporter)
Which neurotransmitters are degraded by MAO-A and which ones are by MAO-B?
MAO-A degrades Serotonin and NE
MAO-B degrades Dopamine
Where in the brain do we find Serotonin?
raphe nuclei
nuclei in the brainstem and throughout the brain
How is Serotonin made in the body?
Diet -> Tryptophan -> 5-Hydroxy-Tryptophan ->
5-Hydroxytryptamine (5-HT)
Which enzymes are involved in the production of Serotonin?
Tryptophan Hydroxylase:
Tryptophan to 5-Hydroxy-tryptophan
Aromatic Amino acid (5-HTP) decarboxylase
5-Hydroxy-tryptophan to 5-Hydroxytryptaminee
Where on the receptors do we find 5-HT receptors?
pre and postsynaptic
How is 5-HT turned off in the presynaptic cleft?
-SERT reuptake into the presynaptic neuron -> recycle into the monoamine vesicle via VAMT
-MAO-A: intracellular degradation (if not recycled quick enough)
-no COMT: since Serotonin is not a Catecholamine
What is the MOA for antidepressants and what does it predict?
-block reuptake (NERT or SERT)
-block MAO-A or MAO-B
-alpha-2- antagonism (auto-receptor)
-depending on the target (uptake or MAO) it predicts the efficacy and the side effects
-chronic actions is necessary for antidepressants to be effective (2 weeks) and side effects will resolve in most cases
Role of adrenergic receptors in depression
FYI
ß-1: stimulatory when NE hits
Alpha-1: stimulatory when NE hits
Alpha-2 (auto receptor, negative feedback): inhibitory when NE hits
Why are antidepressants thought to work better after chronic use?
animal studies:
-Enhanced serotonergic transmission
-Reduce stress-reactivity of noradrenergic transmission
-Increases in neurotrophic factors (BDNF, VEGF, others -> increase number of brain cells in the hippocampus)
-Increased neurogenesis (esp. hippocampus, stimulated by BDNF and VEGF))
What is the BBW for antidepressants
increase the risk of suicidal thinking and behavior (suicidality) in children with MDD and psychiatric disorder
Which SSRIs block other receptors in addition to SERT?
Vilazodone
-SERT inhibitor
-5HT1 agonist
Vortioxetine
-SERT inhibitor
-5HT1A agonist, 5HT1B partial agonist
-5HT3 & 5HT7 antagonist
MOA of bupropion
-inhibits DAT and NET
-non-competitive nicotinic receptor antagonist
Side effects of SSRIs
blocking SERT
-anxiety
-insomnia
-asthenia (physical weakness)
-tremor
-sexual dysfunction
-reduced libido, anorgasmia
Side effects of SNRIs
blocking SERT and NET
SERT ADE:
-anxiety
-insomnia
-asthenia (physical weakness)
-tremor
-sexual dysfunction
-reduced libido, anorgasmia
NET: sympathomimetic effects
-nausea
-sweating
-cardiovascular effects
Side effects of Buproprion
-Anorexia
-anxiety
-insomnia
-sweating
-seizures
Which drug is a selective MAO-A inhibitor?
clorgyline
-irreversible
MAO-A degrades: serotonin and NE
Which drug is a selective MAO-B inhibitor?
selegiline
-irreversible
MAO-B degrades: dopamine
Which MAO inhibitors are non-selective?
-tranylcypromine
-phenelzine
1st gen MAO-i
inhibit MAO-A and MAO-B
Side effects of MAO inhibitors
-sexual dysfunction
-dry mouth
-dizziness
-ORTHOSTATIC HYPOTENSION
-intensifies the depressant effect of alcohol or antihistamines
Explain the drug interaction that is caused by old cheese.
Tyramine is found in old cheese
reverse transport of NE after tyramine is taken up by NET (anti-transport)
since tyramine is metabolized by MAO, MAO-i will increase the level of tyramine -> reverse transport of NE
->hypertensive crisis
How is tyramine metabolized?
by MAO
How does Transdermal Selegiline reduce the risk of tyramine-induced hypertension?
MAO-A is more involved in tyramine metabolism
-by selectively blocking MAO-B, and letting MAO-A be more active and achieve more tyramine breakdown
-transdermal: bypasses GI and liver: higher active concentration of Selegiline
Side effects of MAO-inhibitors
-SNRI effects
-orthostatic hypotension
-Toxicity due to interactions: cheese effect (hypertension crisis), serotonin syndrome
To which receptors does Mirtazapine bind?
-inhibition α2 autoreceptor on noradrenergic
neurons
-inhibits α2 presynaptic receptor on serotoninergic
neurons
-5-HT2 receptor antagonist (block negative feedback -> more serotonin)
What is the role of heteroreceptors in antidepression treatment?
heteroreceptors are located on a neuron that releases a different NT type than the ones that bind to the heterorecpotr
example:
α2 autoreceptor on serotonin neuron (α2 autoreceptor would inhibit serotonin release)
blocking of α2 autoreceptor with Mirtazapine
Side effects of Mirtazapine
-sedation
-weight gain
How are most antidepressants metabolized?
By CYP 450 in the liver
-eliminated through the kidneys
Which antidepressants have low CYP inhibition risk
-venlafaxine
-desvenlafaxine
-citalopram
-escitalopram
-sertraline (Zoloft)
What is the role of Ketamine in depression therapy?
-blocking NMDA receptors on GABA neurons which are directed to glutamatergic neurons (GABA is inhibitory)
-> so blocking NMDA, blocks the inhibition = ACTIVATION -> SYNAPTIC PLASTICITY
-increasing BDNF translation
(by blocking NMDA and preventing the cascade that would phosphorylate eEF2)
-> NEUROGENESIS
What is the net effect of Ketamine depression therapy?
-increase in synaptic plasticity (learning and memory)
-Neurogenesis
->these 2 help with depression
Side effects of Ketamine
-drug of abuse
-Bladder toxicity (K bladder) – painful, potentially irreversible
-Cognitive effects
-Esketamine adverse effects:
sedation (significant), dissociative disorder, drug
dependence, intoxication, dizziness, n/v
MOA of Auvelity
Dextromethorphan
-NMDA antagonist
-sigma-1 agonist
-NET/SERT inhibitor
Bupropion:
-DAT/NET reuptake inhibitor
-nicotinic receptor antagonist
-> in combo believed to inhibit the conversion of dextromethorphan to dextrorphan (via CYP2D6
inhibition)
What is the effect of Dextromorphan on sigma-1 receptors?
promotes glutamate and monoamine (serotonin) release from the vesicles via Ca2+?
MOA of Brexanolone
-positive allosteric modulator of GABA(A) receptor
->increasing the effect of the GABA(A) receptor
->inhibits the cortisol pathway (less cortisol release from the adrenal gland)
What is the indication for Brexanolone?
postpartum depression (given IV)
ADE:
-dry mouth
-drowsiness, dizziness/vertigo,
-loss of consciousness !!!
Which receptors does the drug Gepirone bind to?
-5-HT1A agonist
-inhibitory
Side effects:
-dizziness
-nausea
-headache
-QT prolongation
Which other antidepression drug is a 5-HT1a agonist?
Buspar
also:
-weak 5-HT2 antagonist (autoreceptorsor)
-weak D2 antagonist???
