Pharmacology of Depression - Core Drugs & Case Study

Question 1

What are the 5 core drugs for depression treatment

Learned about in Phase 1 medicine

Answer 1

Sertraline

Citalopram

Fluoxetine

Venlafaxine

Mirtazapine

Question 2

In 2020 - sertraline was the 16th most commonly prescribed drug in West London area

What is the primary mechanism of action of sertraline?

Answer 2

Inhibition of sertraline re-uptake transporter

Results in accumulation of serotonin

Serotonin plays role in CNS in the regulation of mood, personality and wakefulness

Question 3

What role does serotonin play in the CNS?

Answer 3

Regulation

• Mood
• Personality
• Wakefulness

Question 4

What is the drug target for Sertraline?

Answer 4

Serotonin transporter

Question 5

What are the main side effects of taking sertraline?

Answer 5

GI side effects

• Nausea
• Diarrhoea

Sexual dysfunction

Anxiety

Insomnia

Question 6

How does sertraline effect the dopamine transporter?

Answer 6

Mild inhibition of dopamine transporter

Question 7

What does sertraline inhibit at high doses?

Answer 7

Partial inhibition of CYP2D6 at high doses (150mg)

Question 8

How should one discontinue use of sertraline?

Answer 8

Must be gradually decreased on discontinuation

Question 9

In 2020 - Citalopram was 27th most commonly prescribed drug in West London area

What is the primary mechanism of action of Citalopram?

Answer 9

Inhibition of serotonin reuptake

Results in an accumulation of serotonin which plays role in CNS in the regulation of mood, personality and wakefulness

Question 10

What is the drug target of Citalopram?

Answer 10

Serotonin transporter

Question 11

What are the main side effects of taking Citalopram?

Answer 11

GI side effects

• Nausea
• Diarrhoea

Sexual dysfunction

Anxiety

Insomnia

Question 12

How might Citalopram affect muscarinic and histamine (H1) receptors?

Answer 12

Mild antagonism of muscarinic and histamine (H1) receptors

Question 13

What metabolises Citalopram?

Answer 13

CYP2C19

• An enzyme protein
• Member of CYP2C subfamily of cytochrome P450

Question 14

What must be done in the discontinuation of Citalopram?

Answer 14

Must be gradually decreased on discontinuation

Question 15

What is CYP2C19?

Answer 15

• An enzyme protein

- Member of CYP2C subfamily of cytochrome P450

Question 16

What is CYP2D6?

Answer 16

• An enzyme

- Part of cytochrome P450 family

Question 17

In 2020 - Fluoxetine was 68th most commonly prescribed drug in West London area

What is the primary mechanism of action of Fluoxetine?

Answer 17

Inhibition of serotonin re-uptake

Results in an accumulation of serotonin which plays role in CNS in the regulation of mood, personality and wakefulness

Question 18

What is the drug target of Fluoxetine?

Answer 18

Serotonin transporter

Question 19

What are the main side effects of taking Fluoxetine?

Answer 19

GI side effects

• Nausea
• Diarrhoea

Sexual dysfunction

Anxiety

Insomnia

Question 20

What effect can Fluoxetine have on 5HT2A and 5HT2C receptors?

Answer 20

Mild antagonism of these receptors

Question 21

What effect can Fluoxetine have on CYP2D6 and CYP2C19?

Answer 21

Complete inhibition of CYP2D6

Significant inhibition of CYP2C19 (caution with warfarin)

Question 22

In 2020 - Venlafaxine was 83rd most commonly prescribed drug in West London area

What was the primary mechanism of action of Venlafaxine?

Answer 22

Inhibition of serotonin re-uptake + norepinephrine re-uptake

Results in an accumulation of neurotransmitter in synapse

Question 23

What are the drug targets of Venlafaxine?

Answer 23

Serotonin transporter

Noradrenaline transporter

Question 24

What are the main side effects of taking Venlafaxine?

Answer 24

GI effects

• Nausea
• Diarrhoea

Sexual dysfunction

Anxiety

Insomnia

Hypertension (at higher doses)

Question 25

What must be done in the discontinuation of Venlafaxine?

Answer 25

Must gradually decrease Venlafaxine on discontinuation

Question 26

In 2020 - Mirtazapine was 30th most commonly prescribed drug in West London area. What is the primary mechanism of action of Mirtazapine?

Answer 26

Antagonises presynaptic alpha-2-adrenergic receptors This causes an increased release of serotonin and norepinephrine Antagonises central 5HT2 receptors, which leaves 5HT1receptors unopposed —> antidepressant effects

Question 27

In 2020 - Mirtazapine was 30th most commonly prescribed drug in West London area. What is the primary mechanism of action of Mirtazapine?

Answer 27

Antagonises presynaptic alpha-2-adrenergic receptors - This causes an increased release of serotonin and norepinephrine Antagonises central 5HT2 receptors, which leaves 5HT1 receptors unopposed causing anti-depressant effects

Question 28

What are the drug targets of Mirtazapine?

Answer 28

Alpha-2 receptor 5-HT2 receptor

Question 29

What are the main side effects of taking Mirtazapine?

Answer 29

Weight gain Sedation Low probability of sexual dysfunction May exacerbate REM sleep behaviour disorder

Question 30

What sleep behaviour disorder may be exacerbated by taking Mirtazapine?

Answer 30

May exacerbate REM sleep behaviour disorder

Question 31

What is the PHQ-9?

Answer 31

A 9 item questionnaire designed to screen for depression in primary care

Question 32

What are the 3 most commonly prescribed SSRIs?

Answer 32

Setraline Citalopram Fluoxetine

Question 33

For SSRIs: What is the general 1. Target? 2. Location? 3. Effect?

Answer 33

1. 5-HTT 2. Pre-synaptic neuron 3. Increased serotonin availability = anti-depressant effect

Question 34

For SSRIs: What is the general 1. Target? 2. Location? 3. Effect?

Answer 34

1. 5-HTT 2. Pre-synaptic neuron (in brain, e.g. in hippocampus) 3. Increased serotonin availability = anti-depressant effect

Question 35

A patient who is currently on sertraline is being switched to a new anti-depressant. Why do you think the GP slowly weaned the patient off sertraline first before starting the new anti-depressant?

Answer 35

Caution is required when switching from one anti-depressant to another Due to risk of drug interactions, serotonin syndrome, withdrawal symptoms, or relapse Washout required before starting new drug

Question 36

Below is the binding affinity for some of the key drug targets for mirtazapine. The key effect of each receptor subtype is also given. Mirtazapine drug targets & key effect Affinity (highest ---> lowest): 1. Histamine (H1) receptor -- sedation 2. Alpha-2 receptor -- Anti-depressant effect 3. 5HT2 receptor -- Anti-depressant effect 4. 5HT3 receptor -- Anti-emetic effect Explain this information. Consider selectivity, affinity and efficacy

Answer 36

H1-R: - Highest affinity for this receptor so will preferentially block H1-R at low doses - Most selective for this receptor - First thing patients will experience will be Mirtazapine's sedating effects - Will experience sedation at lower doses than needed for anti-depressant and anti-emetic effect A2-R & 5HT2-R - As you increase the dose, start experiencing anti-depressant effects - This reduces the sedative effect somewhat 5HT3-R -

Question 37

Below is the binding affinity for some of the key drug targets for mirtazapine. The key effect of each receptor subtype is also given. Mirtazapine drug targets & key effect Affinity (highest ---> lowest): 1. Histamine (H1) receptor -- sedation 2. Alpha-2 receptor -- Anti-depressant effect 3. 5HT2 receptor -- Anti-depressant effect 4. 5HT3 receptor -- Anti-emetic effect 1. Explain how the effect felt by a patient on Mirtazapine would change with increasing dose, considering affinity and selectivity for each of these targets. 2. Describe the efficacy of Mirtazapine at each of these targets

Answer 37

1. H1-R: - Highest affinity for this receptor so will preferentially block H1-R at low doses - Most selective for this receptor - First thing patients will experience will be Mirtazapine's sedating effects - Will experience sedation at lower doses than needed for anti-depressant and anti-emetic effect A2-R & 5HT2-R - As you increase the dose, start experiencing anti-depressant effects - This reduces the sedative effect somewhat as antihistamine activity is offset by increased noradrenergic transmission 5HT3-R - Lowest affinity for this receptor - This will help with nausea + vomiting - This response will only be seen with very high doses 2. EFFICACY - zero at each of these targets because Mirtazapine is an ANTAGONIST ----> (it has no effects/doesn't produce a response, it blocks one instead)