EXAM 4 Antidepressant Dr. Pond

Question 1

What is major depression disorder (MDD)?

Answer 1

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

Question 2

Which receptors are targeted by many antidepressant drugs?

Answer 2

serotonergic receptors

noradrenegerc receptors

Question 3

What is the main area of norepinephrine?
REMINDER

Answer 3

Locus coerulus (LC)

Question 4

How is Norepinephrine made in the body?

Answer 4

Diet -> Tyrosine -> L-DOPA -> Dopamine -> Norepinephrine

Question 5

Which enzymes are involved in the production of Norepinephrine?

Answer 5

Tyrosine Hydroxylase:
Tyrosine to L-DOPA

DOPA decarboxylase:
L-DOPA to Dopamine

Dopamine beta-hydroxylase:
Dopamine to NE

(NE could be converted into Epinephrine)

Question 6

Are NE ionotropic or metabotropic?

Answer 6

metabotropic

Question 7

Where on the receptors do we find the NE receptors?

Answer 7

pre and postsynaptic

Question 8

How does Norepinephrine get turned off in the presynaptic cleft?

Answer 8

-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)

Question 9

Which transporter moves NE into Monoamine vesicles?

Answer 9

VMAT (vesicle monoamine transporter)

Question 10

Which neurotransmitters are degraded by MAO-A and which ones are by MAO-B?

Answer 10

MAO-A degrades Serotonin and NE

MAO-B degrades Dopamine

Question 11

Where in the brain do we find Serotonin?

Answer 11

raphe nuclei

nuclei in the brainstem and throughout the brain

Question 12

How is Serotonin made in the body?

Answer 12

Diet -> Tryptophan -> 5-Hydroxy-Tryptophan ->
5-Hydroxytryptamine (5-HT)

Question 13

Which enzymes are involved in the production of Serotonin?

Answer 13

Tryptophan Hydroxylase:
Tryptophan to 5-Hydroxy-tryptophan

Aromatic Amino acid (5-HTP) decarboxylase
5-Hydroxy-tryptophan to 5-Hydroxytryptaminee

Question 14

Where on the receptors do we find 5-HT receptors?

Answer 14

pre and postsynaptic

Question 15

How is 5-HT turned off in the presynaptic cleft?

Answer 15

-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

Question 16

What is the MOA for antidepressants and what does it predict?

Answer 16

-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

Question 17

Role of adrenergic receptors in depression
FYI

Answer 17

ß-1: stimulatory when NE hits
Alpha-1: stimulatory when NE hits
Alpha-2 (auto receptor, negative feedback): inhibitory when NE hits

Question 18

Why are antidepressants thought to work better after chronic use?

Answer 18

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))

Question 19

What is the BBW for antidepressants

Answer 19

increase the risk of suicidal thinking and behavior (suicidality) in children with MDD and psychiatric disorder

Question 20

Which SSRIs block other receptors in addition to SERT?

Answer 20

Vilazodone
-SERT inhibitor
-5HT1 agonist

Vortioxetine
-SERT inhibitor
-5HT1A agonist, 5HT1B partial agonist
-5HT3 & 5HT7 antagonist

Question 21

MOA of bupropion

Answer 21

-inhibits DAT and NET
-non-competitive nicotinic receptor antagonist

Question 22

Side effects of SSRIs

Answer 22

blocking SERT

-anxiety
-insomnia
-asthenia (physical weakness)
-tremor
-sexual dysfunction
-reduced libido, anorgasmia

Question 23

Side effects of SNRIs

Answer 23

blocking SERT and NET

SERT ADE:
-anxiety
-insomnia
-asthenia (physical weakness)
-tremor
-sexual dysfunction
-reduced libido, anorgasmia

NET: sympathomimetic effects
-nausea
-sweating
-cardiovascular effects

Question 24

Side effects of Buproprion

Answer 24

-Anorexia
-anxiety
-insomnia
-sweating
-seizures

Question 25

Which drug is a selective MAO-A inhibitor?

Answer 25

clorgyline

-irreversible

MAO-A degrades: serotonin and NE

Question 26

Which drug is a selective MAO-B inhibitor?

Answer 26

selegiline

-irreversible

MAO-B degrades: dopamine

Question 27

Which MAO inhibitors are non-selective?

Answer 27

-tranylcypromine
-phenelzine

1st gen MAO-i
inhibit MAO-A and MAO-B

Question 28

Side effects of MAO inhibitors

Answer 28

-sexual dysfunction
-dry mouth
-dizziness
-ORTHOSTATIC HYPOTENSION
-intensifies the depressant effect of alcohol or antihistamines

Question 29

Explain the drug interaction that is caused by old cheese.

Answer 29

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

Question 30

How is tyramine metabolized?

Answer 30

by MAO

Question 31

How does Transdermal Selegiline reduce the risk of tyramine-induced hypertension?

Answer 31

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

Question 32

Side effects of MAO-inhibitors

Answer 32

-SNRI effects
-orthostatic hypotension
-Toxicity due to interactions: cheese effect (hypertension crisis), serotonin syndrome

Question 33

To which receptors does Mirtazapine bind?

Answer 33

-inhibition α2 autoreceptor on noradrenergic
neurons
-inhibits α2 presynaptic receptor on serotoninergic
neurons
-5-HT2 receptor antagonist (block negative feedback -> more serotonin)

Question 34

What is the role of heteroreceptors in antidepression treatment?

Answer 34

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

Question 35

Side effects of Mirtazapine

Answer 35

-sedation
-weight gain

Question 36

How are most antidepressants metabolized?

Answer 36

By CYP 450 in the liver
-eliminated through the kidneys

Question 37

Which antidepressants have low CYP inhibition risk

Answer 37

-venlafaxine
-desvenlafaxine
-citalopram
-escitalopram
-sertraline (Zoloft)

Question 38

What is the role of Ketamine in depression therapy?

Answer 38

-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

Question 39

What is the net effect of Ketamine depression therapy?

Answer 39

-increase in synaptic plasticity (learning and memory)

-Neurogenesis

->these 2 help with depression

Question 40

Side effects of Ketamine

Answer 40

-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

Question 41

MOA of Auvelity

Answer 41

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)

Question 42

What is the effect of Dextromorphan on sigma-1 receptors?

Answer 42

promotes glutamate and monoamine (serotonin) release from the vesicles via Ca2+?

Question 43

MOA of Brexanolone

Answer 43

-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)

Question 44

What is the indication for Brexanolone?

Answer 44

postpartum depression (given IV)

ADE:
-dry mouth
-drowsiness, dizziness/vertigo,
-loss of consciousness !!!

Question 45

Which receptors does the drug Gepirone bind to?

Answer 45

-5-HT1A agonist
-inhibitory

Side effects:
-dizziness
-nausea
-headache
-QT prolongation

Question 46

Which other antidepression drug is a 5-HT1a agonist?

Answer 46

Buspar

also:
-weak 5-HT2 antagonist (autoreceptorsor)
-weak D2 antagonist???