Antidepressants

Question 1

What is the Monoamine Theory

Answer 1

Deficits in monoamine neurotransmitters (NA & 5-HT) causes depression
- MAOI increase bio availability of monoamines

Question 2

2 major forms of MAOI

Answer 2

1) MAO-A
2) MAO-B

• 5-HT broken down mainly by MAO-A
• Both forms acts on NA & dopamine
  (eg. MAO-B selective inhibitors used in Parkinson’s disease)

Question 3

Example of a MAOI

Answer 3

Phenelzine

- Non-selective, irreversible

Question 4

Adverse Effects of MAOIs

Answer 4

Postural hypotension
- Sympathetic block produced by accumulation of dopamine in cervical (neck) ganglia, which acts as inhibitory transmitter

Restlessness & insomnia
- CNS stimulation due to too much NA

Note: Should not be combined with other serotoninergic drugs (eg. pethidine)
–> Hyperexcitability, increased muscular tone, myoclonus, loss of consciousness

Question 5

What is “The Cheese Reaction”

Answer 5

• Tyramines in food are broken down by MAO
• MAOIs lead to accumulation of tyramine & a sympathomimetic effect
• Tyramine is taken up into adrenergic terminals (Competes with NA for the vesicular compartment) -> Increase release of NA into synapses

Effects: Acute hypert/s, severe throbbing headache, occasionally intracranial haemorrhage

Question 6

Non-selective TCAs for SERT/NET

Answer 6

• Imipramine
• Amitriptyline
• Nortriptyline (2nd gen)
• Milder SE, Improved compliance

Question 7

Adverse Effects of TCAs

Answer 7

Sedation
- H1 histamine receptor antagonism

Postural hypotension
- Alpha-adrenoreceptor sympathetic block

Dry mouth, blurred vision, constipation
- Muscarinic receptor antagonism

DDI

• Plasma protein bound
• Hepatic metabolism

Question 8

Examples of SSRI

Answer 8

• Fluoxetine (1st line)
• Citalopram

SSRIs have greater 5-HT reuptake selectivity than TCAs

Question 9

Advantages of SSRI

Answer 9

1) Fewer adverse effects than TCAs
- Low affinity for alpha-adrenoceptors -> Lack of CVS effects, safer in overdose
- Lack of effect at histamine receptors -> Reduced sedation (note: Citaprolam still has some histamine receptor antagonism leading to sedation)
- Low affinity for muscarinic cholinergic receptors -> Minimal anticholinergic SEs

2) Safer in overdose
3) Better compliance (bc of less side effects)
4) Prescription of more adequate doses (bc well tolerated)

TLDR: Efficacy, Safety, Tolerability!
1st line therapy but...
- Only 2/3 get remission
- Adverse effects especially at start
- Discontinuation can be a problem in some

Question 10

Adverse Effects of SSRI

Answer 10

Nausea & Insomnia (usually only at the start, will go away)

Sexual dysfunction

• Due to increased stimulation of 5HT2 receptors
• Management: Cyproheptadine (H-HT2 blocker)

Serotonin syndrome (DDI when used with other drugs that increase serotoninergic activity)
- Tremor, hyperthermia, CVS collapse

Question 11

Example of NARI

Answer 11

Reboxetine

Note: NARIs have greater NA reuptake selectivity than TCAs

Question 12

Advantage of NARIs

Answer 12

Fewer SEs than TCA & SSRIs

Question 13

Adverse Effects of NARI

Answer 13

• Dry mouth, sedation (Anticholinergic effects)
• Insomnia (Increased NA activity in the CNS)
• Tachycardia (Increased NA @ sympathetic “fight/flight” synapses)

Question 14

Examples of SNRIs

Answer 14

MOA: Increase synapse levels of both NA & 5-HT

• Venlafaxine
• Desvenlafaxine (synthetic metabolite of Venlafaxine)
• Duloxetine

Question 15

Advantages of Venlafaxine

Answer 15

• Fewer SE than TCAs
• Claimed to work FASTER than other antidepressants
• Claimed to work better in treatment-resistant patients

Question 16

Adverse Effects of SNRIs

Answer 16

• Nausea
• Insomnia
• Sexual dysfunction
• “Serotonin syndrome” (combined with other serotoninergic drugs)
• Withdrawal effects may be more common & stronger)

Question 17

Other antidepressants

Answer 17

Mirtazapine:
- Norepinephrine & specific serotonin antidepressant

Bupropion:
- Norepinephrine-dopamine reuptake inhibitor

Agomelatine:

• *Helps in sleep disorders
• Agonist of melatonin MT1 & MT2 receptors

Ketamine:
- Glutamate NMDA receptor antagonist used as an anaesthetic currently evaluated for rapid-onset antidepressant effect

Vortioxetine:

• “multimodal serotonergic antidepressant”
• May be efficacious if resistant to other treatments
• May have pro-cognitive effects
• May raise risk of suicidal thoughts/actions in children & teens (Close monitoring required)