Antidepressants

Question 1

What is the monoamine theory?

Answer 1

Deficits in monoamine neurotransmitters (NA and serotonin) cause depression.

Question 2

What observation was made about Reserpine?

Answer 2

It inhibits noradrenaline and serotonin storage -> NA and serotonin get into cytoplasm and cannot be released into synapse in coordinated way -> depression

Question 3

What is a later finding for the monoamine theory?

Answer 3

Most likely monoamines are important, but there are complex interactions with other neurotransmitter systems as well.

Question 4

What is monoamine oxidase? What are the different forms of MAO?

Answer 4

Enzyme that oxidizes and breaks down monoamines.

MAO-A mainly breaks down serotonin.
MAO-B breaks down NA and dopamine.

Question 5

What MAO inhibitor is used in Parkinson’s Disease?

Answer 5

There is lack of dopamine in Parkinson’s disease. So preserve dopamine by using MAO-B selective inhibitor.

Question 6

What is the MOA of MAOI?

Answer 6

MAOI inhibit breakdown of monoamines -> increase biological availability of monoamines.

Question 7

What is phenelzine?

Answer 7

It is a MAOI, non selective between MAOA and MAOB. Irreversible MAOI.

Question 8

Adverse effects of MAOIs?

What should MAOIs not be combined with?

Answer 8

• postural hypotension (due to sympathetic block produced by accumulation of dopamine in the cervical neck ganglia -> acts as inhibitory transmitter)
• restlessness and insomnia due to CNS stimulation (MAOI block breakdown of NA -> fight or flight)
• should NOT be combined with other drugs enhancing serotoninergic function, e.g. pethidine (bc too much serotonin -> hyperexcitability, increased muscular tone, jerking movements, etc.)

Question 9

What is the cheese reaction?

Answer 9

• a drug food interaction between cheese and MAOI
• less likely to occur with reversible, MAOA selective inhibitors like moclobemide; more likely to occur with irreversible, non-selective MAOI.
• MAOI can lead to accumulation of tyramine (in cheese) -> compete with NA for vesicular compartment -> increase release of NA into synpase -> sympathomimetic effect -> can cause acute hypertension

Question 10

What is the MOA for Tricyclic Antidepressants (TCA)?

Answer 10

Inhibits serotonin transporter or NA transporter -> neurotransmitter stays longer in in synapse -> increase in monoamine

Question 11

Which TCAs are non selective and which are selective?

Answer 11

Non-selective for SERT/NET:
Imipramine, Amitriptyline, nortriptyline

Selective for NET:
Desipramine

Question 12

What is nortriptyline?

Answer 12

• second generation TCA

- milder side effects than amitriptyline and imipramine -> better compliance

Question 13

What are the adverse effects of TCAs?

Answer 13

• sedation due to H1 histamine receptor antagonism -> tolerance to sedation can develop in 1-2 weeks
• Postural hypotension (due to alpha adrenoceptor sympathetic block)
• dry mouth, blurred vision and constipation due to muscarinic receptor antagonism

TCAs metabolized by the liver

Question 14

What are the three TCAs?

Answer 14

1st gen - imipramine

2nd gen - amitriptyline and nortriptyline

Question 15

What is the most widely prescribed antidepressant today?

Answer 15

Fluoxetine

Question 16

Examples of SSRI (selective serotonin reuptake inhibitors)?

Answer 16

Fluoxetine and citalopram

Question 17

Advantages of SSRI?

Answer 17

It has fewer adverse effects than TCAs.

Low affinity for alpha adrenoceptors -> less postural hypotension, lack of cardiovascular effects and safer in overdose

Lack of effect at histamine receptors -> reduced sedation

Low affinity for muscarinic cholinergic receptors -> minimal anticholinergic effects like dry mouth and constipation

Overall SSRI is safer in overdose and less side effects lead to better compliance. Improved side effect orofile also allows for prescription of more adequate doses.

Question 18

Adverse effects of SSRI?

Answer 18

Nausea, insomina (when plasma level of drug falls betwen doses. usually only when you first start taking the drug)

Sexual dysfunction (cyproheptadine or other 5HT2 blockers can be given ro prevent SSRI induced sexual dysfunction)

Citalopram has some histamine receptor antagonism leading to sedation

Serotonin syndrome can occur if SSRI taken with other drugs increasing serotoninergic activity like MAOI. Effects include tremors, hyperthermia (feel v hot) and cardiovascular collapse)

Question 19

What are NARI?

Answer 19

Noraderenaline Reuptake Inhibitors.

• greater selectivity for NA than serotonin
• example: reboxetine
• fewer adverse effects than TCAs and SSRI.

Question 20

What is maprotiline?

Answer 20

An earlier NARI, has TCA like adverse effects due to alpha adrenoceptor and histamine receptor effects and occasionally caused seizures.

Question 21

Adverse effects of reboxetine (NARI)?

Answer 21

• dry mouth, constipation due to anticholinergic effects
• insomnia due to increased noradrenergic activity in the CNS
• tachycardia due to increased availability of NA at sympathetic fff synapses

Question 22

What are SNRIs?

Answer 22

• serotonin and noradrenaline reuptake inhibitors
• similar dual serotonin and NA reuptake inhibition profiles as non selective TCAs
• examples include Venlafaxine, desvenlafaxine and duloxetine.

Question 23

Advantages of Venlafaxine?

Answer 23

• fewer adverse effects than TCAs

Question 24

Adverse effects or SNRIs?

Answer 24

• serotoninergic adverse effects similar to SSRI like nausea, insomnia and sexual dysfunction
• serotonin syndrome when combined with other serotoninergic drugs and MAOI
• withdrawal effectsmay be more common and stronger than for SSRI and TCA

Question 25

What are the other 5 non-first line antidepressants?

Answer 25

• mirtazapine: NaSSA (Noradrenaline and specific serotonin antidepressant)
• bupropion: NDRI (Noradrenaline Dopamine Reuptake Inhibitor)
• agomelatine
• ketamine: glutamate NMDA receptor antagonist
• vortioxetine: multi modal antidepressant

Question 26

Advantages of vortioxetine?

What is something to note about vortioxetine?

Answer 26

• may be efficacious in patients resistant to other antidepressants
• may have pro cognitive effects
• may raise risk of suicidal thoughts or actions in children and teens -> close monitoring required in initial stages (but beneficial for them in long run)