Antidepressants

Question 1

2 major types of depression

Answer 1

1. Unipolar (swing in same direction): reactive or endogenous
2. Bipolar depression or affective disorder (alternate depression and mania): strongly familial

Question 2

What is monoamine theory?

Answer 2

Deficits in monoamine neurotransmitters (noradrenaline and 5-HT) cause depression

Question 3

What are the 2 major forms of monoamine oxidase?

Answer 3

MAO-A and MAO-B

• 5-HT mainly broken down by MAO-A
• Both act on noradrenaline and dopamine

Question 4

What is the MOA of MAOIs?

Answer 4

Inhibit monoamine oxidase to increase biological availability of monoamines

Question 5

Characteristics of phenelzine?

Answer 5

Non-selective and irreversible MAOI

Question 6

ADRs of MAOIs

Answer 6

Postural hypotension: sympathetic block by dopamine accumulation (inhibitory transmitter) in cervical ganglia
Restlessness and insomnia
Serotoninergic (esp if combined with similar effect drugs): hyperexcitable, increased muscular tone, myoclonus, loss of consciousness

Question 7

What is the cheese reaction with MAOIs?

Answer 7

Drug-food interaction with cheese and concentrated yeast products
Causes acute hypertension which leads to severe headache and even intercranial haemorrhage

Question 8

What type of MAOIs are less likely to cause the cheese reaction?

Answer 8

Reversible, MAO-A selective MAOIs (e.g. moclobemide)

Question 9

How do MAOIs cause the cheese reaction?

Answer 9

1. MAOIs prevent breakdown of (tyr)amines in intestine and liver
2. Tyramine accumulates and is taken up into adrenergic terminals
3. Sympathomimetic effect: compete with NA for vesicles -> release of NA into synapse

Question 10

What are the 4 tricyclic antidepressants and their selectivity?

Answer 10

Non-selective for SERT/NET: imipramine, amitriptyline, nortriptyline
Selective for NET: desipramine
(serotonin/norepinephrine transporter: SERT/NET)

Question 11

Why is nortriptyline preferred as choice of TCA?

Answer 11

2nd gen TCA
Milder side effects than amitriptyline and imipramine
Improved compliance

Question 12

List 4 ADRs for TCAs

Answer 12

Sedation: H1 histamine receptor antagonism, tolerance in 1-2 weeks
Postural hypotension: a-adrenoceptor sympathetic block
Dry mouth, blurred vision, constipation: muscarinic receptor antagonism
DDI: plasma protein bound, mainly hepatic metabolised

Question 13

What are the main differences between SSRIs and TCAs?

Answer 13

SSRIs: fluoxetine and citalopram
50-1000-fold selectivity for 5-HT over NA
Fewer adverse effects: safer in overdose -> better compliance

Question 14

List 3 advantages of SSRIs

Answer 14

1. Lack cardiovascular effects: low affinity for a-adrenoceptor
2. Reduced sedation: lack effect at histamine receptors
3. Minimal anticholinergic effects: low affinity for muscarinic receptors

Question 15

Adverse effects of SSRIs

Answer 15

Nausea, insomnia: withdrawal symptoms when plasma levels drop between doses
Sexual dysfunction: increased stimulation of 5HT2 receptors
Sedation: citalopram (histamine antagonism)

Question 16

What drug can be given to prevent SSRI-induced sexual dysfunction?

Answer 16

5HT2 blocker e.g. Cyproheptadine

Question 17

What is serotonin syndrome?

Answer 17

DDI with concomitant use of multiple serotoninergic drugs

Effects: tremor, hyperthermia, cardiovascular collapse

Question 18

List one noradrenaline reuptake inhibitor (NARI)

Answer 18

Reboxetine or maprotiline

Question 19

What differentiates NARIs from other antidepressants?

Answer 19

Reboxetine: 1000-fold selectivity for NA

Fewer adverse effects than SSRIs and TCAs

Question 20

ADRs of reboxetine

Answer 20

Dry mouth, constipation: anticholinergic
Insomnia: increase NA activity in CNS
Tachycardia: increase NA availability at sympathetic synapses

Question 21

What is the MOA of venlafaxine?

Answer 21

SNRI (dual serotonin and noradrenaline reuptake inhibitor): similar reuptake inhibition profile to TCA

Question 22

Advantages of venlafaxine

Answer 22

Fewer side effects than TCA due to change in structure
Works slightly faster
Better in treatment-resistant patients

Question 23

ADRs of venlafaxine

Answer 23

Similar to SSRIs: nausea, insomnia, sexual dysfunction
DDI: serotonin syndrome
Withdrawal effects more common and stronger than SSRIs or TCAs

Question 24

List 4 other antidepressants and their MOA

Answer 24

1. Mirtazapine: NE and specific serotonin antidepressant (NaSSA)
2. Bupropion: NE-dopamine reuptake inhibitor (NDRI)
3. Agomelatine: agonist melatonin MT1 and MT2, antagonist 5HT2C receptor; less TCA/SSRI effects, also for sleep disorders
4. Ketamine: glutamate NMDA receptor antagonist; rapid-onset antidepressant

Question 25

Why is vortioxetine a multimodal serotonergic antidepressant?

Answer 25

5-HT1a receptor agonist
5-HT1b receptor partial agonist
5-HT1d, 5-HT7, 5-HT3 antagonist
Increase extracellular serotonin, dopamine, NE, ACh, histamine in depression-related brain areas

Question 26

How efficacious and safe is vortioexetine compared to other antidepressants?

Answer 26

Efficacious in treatment-resistant patients
Pro-cognitive effects
ADRs: similar to others but increase suicidal ideation in children and teens -> require close monitoring