1.1 Pharmacology of antidepressant drugs and mood stabilisers

Question 1

What drug class is iproniazid from?

Answer 1

MAOi

Question 2

What drug class is imipramine from?

Answer 2

TCA

Question 3

What was lithium initially approved for?

Answer 3

Mania

Question 4

What is the mechanism of action of fluoxetine?

Answer 4

Inhibitor of 5HT reuptake.

Question 5

What is the mechanism of action of MAOi?

Answer 5

Slows breakdown of: 
NA
5HT
DA
by inhibiting the mitochondrial enzyme monoamine oxidase.

Question 6

Is depression simply hyposerotoninsm?

Answer 6

No

Question 7

What are the precursor molecules of serotonin?

Answer 7

Tryptophan (from legumes, cheeses, chocolate, red meat)

5-hydroxytryptophan (5HT)

Question 8

Which of the 5HT1/2/3 receptor types are inhibitory or excitatory?

Answer 8

5HT1- inhibitory 
5HT2/3- excitatory 
5HT4- excitatory 
5HT5- inhibitory
5HT6/7- excitatory

Question 9

What are the key receptor types involved in mood + 5HT?

Answer 9

5HT1A, 5HT1B, 5HT2A, 5HT2C, 5HT4, 5HT6, 5HT7

Question 10

Which drug groups target the 5HT1A receptors?

Answer 10

Antidepressants
Anxiolytics- eg. buspirone
Psychosis - Negative symptoms

Question 11

Which drug groups target the 5HT1B and 1D receptors?

Answer 11

Migraine- Tryptans

Question 12

What drug groups target the 5HT- 2A, 2B, and 2C receptor groups?

Answer 12

Antipsychotics (atypical antipsychotics for 5HT2a)

Antidepressants

Question 13

Which drug groups target the 5HT3 receptors?

Answer 13

Anti-emetics

some antidepressants and antipsychotics

Question 14

Which drug groups target the 5HT4 receptors?

Answer 14

GI pro-kinetic drugs, esp in IBS, chronic constipation

Question 15

What is the long term neurobiological effect of SSRIs?

Answer 15

change relative balance of positive to negative emotional processing, providing platform for subsequent cognitive and psychological consolidation
5HT1a receptors are autoreceptors throughout CNS

With antidepressant treatment, the reuptake of 5HT is inhibited, increased 5HT increases 5HT1A autoreceptor stimulation, which results in inhibition of firing (initially)

Chronic stimulation of the 5HT1a causes it to desensitise. Return of normal firing. Leading to more serotonergic transmission due to reuptake blockade. (later = more serotonin)

Question 16

Which SSRIs inhibit the CYP450 enzymes?

Answer 16

fluoxetine

paroxetine

Question 17

What are the most coomon adverse effects related to 5HT- SSRIs?

Answer 17

sexual dysfunction - reversed by traxodone
GI: nausea, dyspepsia, constipation, diarrhoea
short term anxiety

Question 18

What cases may TCAs be preferred for?

Answer 18

Hospitalised or severe depression (maybe)

Question 19

What three receptor types on the post-synaptic membrane do TCAs act on?

Answer 19

adrenergic receptor
histamine receptor
muscarinic acetylcholine receptor

Question 20

What are the main adverse effects of TCAs?

Answer 20

Constipation
Dry Mouth
Blurred vision
Effects on cardiac function- do ECG in overdose
postural hypotension

Question 21

What is the mechanism of action of MAOIs?

Answer 21

irreversible inhibitors (phenelzine, isocarboxazid, tranylcypromine) inhibit monoamine oxidase A and B
MAO-A- metabolises NA, 5HT, tyramine
MAO-B- metabolises DA, tyramine and phenylthylamine
This results in increased storage and availability of 5HT and NA for release.
Sympathomimetic effects - esp tranylcypromine

Question 22

What are the adverse effects of MAOIs?

Answer 22

Hypertensive crisis- tyamine containing foods and drugs cause release of NA.
Foods: cheese, yoghurt, yeast extract, meat, alcohol, broad beans, pickled herring
Drugs: sympathomimetics, OTC cold remedies, pethidine

Symptoms of hypertensive crisis: flushing, headache, increased BP
-rarely, CVA

Treatment: alpha blockade with PENTOLAMINE, CHLORPROMAZINE

Question 23

What are the dopamine related side effects of some antidepressants?

Answer 23

By blocking dopamine, EPS may occur: 
tremor
dystonia
akathisia
tardive dyskinesia 

primarily due to antagonism of DA receptors- D2 esp.

Question 24

What is the action of GABA in adult vs. developing brains?

Answer 24

GABA is the main inhibitory NT in mammalian brains
BUT
GABA Is primarily excitatory in developing brains!

binds and allows Cl- into cell or K+ out of cell
= hyper polarisation

Question 25

Name 4 agonists and 1 antagonist of the GABAa receptor (ligand gated ion channel)

Answer 25

Agonists:

1. Ethanol
2. Benzodiazapines
3. Propofol
4. Anaesthetics

Antagonists:
1. Flumazenil

Question 26

Name 2 agonists of the GABAb receptor - the GPCR that opens ion channels via intermediate G proteins

Answer 26

1. baclofen

2. propofol (both GABA a and b)

Question 27

Name 2 GABA analogues

Answer 27

1. pregabalin

2. gabapentin

Question 28

Which anticonvulsant drugs may be used as a mood stabiliser?

Answer 28

• carbamazepine
• valproate
• semisodium valproate
• lamotrigine

Question 29

Which atypical or second generation antipsychotics may be used as a mood stabiliser?

Answer 29

Olanzapine
risperidone
aripiprazole
quetiapine

Question 30

How does lamotrigine work in mood stabilising?

Answer 30

• blocks Na+ channels- anticonvulsant activity
• reduces excitability - not via GABA
• may inhibit 5HT, NA, and DA uptake

Question 31

What is the mechanism of action of lithium?

Answer 31

Not exactly known
-inhibit 5HT(1a?) autoreceptors
-increase anti-apoptotic factor bcl-2
-inbhibit glycogen synthase kinase-3****
deplete insoditol
-upregulate glutamate re-uptake

Question 32

What is the main mechanism of action in antipsychotics? Where?

Why are there EPS side effects?

Answer 32

D2 - dopamine blocker
-mesolimbic circuits

adverse effects are due to DA blockade in the n igrostiatal and tuberinfundibular pathways

Second generation drugs have 3 main mechanisms of action:

1. increased D2 receptor binding affinity
2. Increased 5HT2c and 5HT2a receptor binding
3. Increased 5HT1a receptor binding

all reduce antipsychotic efficacy