Katzung 12th ed - Chapter 30 - Antidepressant Agents (1 and 2)

Question 1

Briefly describe the monoamine hypothesis for depression.

Answer 1

The monoamine hypothesis suggests that it is a defect in serotonin, noradrenaline or dopamine pathways that causes depression.

Question 2

Briefly describe the neurotrophic hypothesis for depression.

Answer 2

The neurotrophic hypothesis suggests that it is a defect in trophic factors in the brain (such as BDNF) that result in abnormalities of neural plasticity and resilience. This leads to a depressed state, in which neural connections are lost.

Question 3

What is SERT?

Answer 3

This is the serotonin transporter that allows the re-uptake of serotonin from the synaptic cleft to the pre-synaptic nerve terminal.

Question 4

Name as many SSRIs as you can (up to six).

Answer 4

Sertraline, Fluoxetine, Citalopram, Escitalopram, Fluvoxamine, Paroxetine

Question 5

What is an SNRI? Give three examples of SNRIs.

Answer 5

Selective Serotonin and Noradernaline Reuptake Inhibitor. e.g. Venlafaxine, Desvenlafaxine, Duloxetine.

Question 6

Which receptors do SNRIs bind to?

Answer 6

They all bind to both SERT and NET.

Question 7

Describe the basic chemical structure of TCAs.

Answer 7

There are three rings all in a straight line. The first ring and the third ring are hexacarbon rings. The middle ring has variable structure and variable R groups attached to it.

Question 8

What is Lyrica?

Answer 8

Pregabalin.

Question 9

What is Endep?

Answer 9

Amitriptyline.

Question 10

Name as many TCAs as you can.

Answer 10

Imipramine, Desipramine, Amitriptyline, Doxepin, Protryptyline.

Question 11

What are the basic mechanisms of action of TCAs?

Answer 11

TCAs block SERT and NET to varying degrees (they are serotonin and noradrenaline reuptake inhibitors), but they also block many other receptors, causing multiple side effects.

Question 12

What class of antidepressant is mirtazepine?

Answer 12

It is a tetracyclic antidepressant.

Question 13

Name one of the current MAOIs. What is the basic mechanism of action?

Answer 13

Moclobemide. It blocks Monoamine-Oxidase A, which is an enzyme that metabolizes serotonin and noradrenaline.

Question 14

Name as many features of serotonin syndrome as you can.

Answer 14

This occurs when a person has had an excess of serotonergic drugs (e.g. SSRI + MAOI).

• their BP / RR / HR and Temp can all be raised
• diaphoresis
• have large pupils (mydriasis)
• muscle rigidity, convulsions, rhabdomyolysis
• vomiting and diarrhoea.

Question 15

What is the average half-life of an SSRI?

Answer 15

Roughly 24hrs. Fluoxetine is more like 48-72 hours.

Question 16

What is the half-life of venlafaxine?

Answer 16

11 hours

Question 17

What is the average half-life of the TCAs?

Answer 17

Roughly 24hrs.

Question 18

What is CYP2D6 and what does it do?

Answer 18

CYP2D6 is an enzyme system (one of the cytochrome P450 enzymes) that metabolizes TCAs, most opioids, tramadol, beta-blockers and haloperidol.

Question 19

What does serotonin do at the SERT?

Answer 19

It binds to a receptor site on SERT, which induces a conformational change, allowing the entry of serotonin, Cl- and Na+ into the cell.

Question 20

How do SSRIs inhibit serotonin reuptake?

Answer 20

SSRIs bind allosterically to SERT (at a site different to the binding site for serotonin), and inhibit the opening of SERT.

Question 21

In addition to blocking SERT and NET, the TCAs also block other receptors. Which ones?

Answer 21

TCAs also block alpha-adrenergic receptors, muscarinic cholinergic receptors, sodium channels, and histamine receptors.

Question 22

What are some of the adverse effects of TCAs, and why?

Answer 22

TCAs block muscarinic cholinergic receptors, and therefore exhibit anticholinergic side effects, such as dry mouth and constipation. TCAs can also cause orthostatic hypotension due to their blockade of alpha-adrenergic receptors. TCAs can also cause a broad-complex sinus tachycardia due to the sodium channel blockade.

Question 23

For each of the following monoamines, explain whether they are metabolised by MAO-A or MAO-B:
Serotonin
Noradrenaline
Adrenaline
Dopamine

Answer 23

Serotonin - MAO-A
Noradrenaline - MAO-A
Adrenaline - MAO-A
Dopamine - Both

Question 24

What is the risk of overdose with TCAs? How does this compare to SSRIs?

Answer 24

TCAs can be lethal in overdose. SSRIs are much safer in overdose.

Question 25

Name one condition that can be treated with TCAs apart from depression and other mental health issues.

Answer 25

Pain. In particular, chronic pain and fibromyalgia.

Question 26

What are some of the anticholinergic adverse effects of TCAs?

Answer 26

Dry mouth, dry eyes, urinary retention, constipation, blurred vision, confusion.

Question 27

What are some adverse effects of H1-receptor blockade by TCAs?

Answer 27

Sedation and weight gain.

Question 28

How do TCAs cause death in overdose?

Answer 28

They can cause arrhythmias such as VT and VF. The anticholinergic effects can lead to confusion, reduced GCS and seizures.

Question 29

How much of a TCA is required to produce a lethal effect?

Answer 29

Less than 7 days’ supply of amitriptyline (1500mg) can be lethal.

Question 30

If you are giving fluoxetine, which drugs should you avoid giving concurrently? If you want to give a strong analgesic to a patient on fluoxetine, what is safe to give?

Answer 30

Avoid giving beta-blockers, TCAs, tramadol, opioids (except fentanyl), and haloperidol - because these drugs require CYP2D6 for metabolism, and CYP2D6 is inhibited by fluoxetine. Fentanyl is metabolised by CYP3A4.

Question 31

Which antidepressants inhibit CYP2D6?

Answer 31

CYP2D6 is inhibited by fluoxetine and paroxetine.