Antidepressants

Question 1

Depression

Answer 1

Low mood
Guilt
Hopelessness
Anhedonia
Suicidality
Disturbed sleep
Altered appetite
Poor concentration

Question 2

Pathology of depression

Answer 2

Unknown
Effective antidepressant drugs suggest dysfunction of 5-HT and/or NA systems.
Low 5-HT

Question 3

Noradrenergic pathways

Answer 3

Locus coeruleus contains NAergic cell bodies.
Projections of hypothalamus and midbrain
Projections of hippocampus and cortex

Question 4

Serotonergic (5-HT) pathways

Answer 4

Dorsal and median raphe nuclei contain serotonergic cell bodies.
Projections to hypothalamus hippocampus and cortex

Question 5

Noradrenaline synthesis

Answer 5

Tyrosin + Tyrosine hydroxylase ->
L-DOPA + DOPA decarboxylase ->
Dopamine + Dopamine β-hydroxylase ->
Noradrenaline

Question 6

5-HT synthesis

Answer 6

Tryptophan + Tryptophan hydroxylase ->
5-HTP + 5-HTP decarboxylase ->
5-HT

Question 7

Monoamine oxidase

Answer 7

Present in DA, NA and 5-HT terminals.
MAO breaks down transmitter in the cytosol.
Vesicles protected from MAO.
NA and 5-HT ,etabolised by both MAOa and MAOb

Question 8

NA metabolism

Answer 8

NA + Monoamine oxidase ->
Aldehyde + Aldehyde dehydrgenase ->
DOPEG + Carechol-o-methyl transferase ->
MHPG

Question 9

5-HT metabolism

Answer 9

5-HT + Monoamine oxidase ->
Aldehyde + Aldehyde dehydrogenase ->
5-HIAA

Question 10

NA receptors

Answer 10

α, β
G-protein coupled receptors (GPCRs)
α1 - Stimulates PI cycle (increase DAG, increase concentration of Ca2+ inside)
α2 - Inhibit adenylate cyclase (decrease cAMP, open K+ channels (GIRK), hyperpolarize)
β1,2,3 - Stimulate adenylate cyclase, increase cAMP

Question 11

5-HT receptors

Answer 11

5-HT 1b/1d/1e/1f/2a/3/4/5/6/7
G-protein coupled
5-HT1(a-f) - Inhibit adenylate cyclase, decrease cAMP
5-HT1a - Opens K+ channels
5-HT2(a-c) - Stimulated PI cycle, increase DAG and increase concentration of Ca2+ inside
Ligand gated (cation) ion channel = 5-HT3

Question 12

Autoreceptors

Answer 12

Both NA and 5-HT terminals have autoreceptors.
These inhibit transmitter release.
NA terminal autoreceptors are α2
5-HT terminal autoreceptors are 5-HT1b
Both NA and 5-HT cell bodies have autoreceptors.
These inhibit firing.
NA cell body autoreceptors are α2.
5-HT cell body autoreceptors are 5-HT1a

Question 13

Monoamine reuptake transporters

Answer 13

Distinct (closely related) transporter proteins.
Preferentially take up NA or 5-HT or DA.
Responsible for termination of neurotransmitter effects.

Question 14

Pharmacotherapy of depression

Answer 14

1950s iproniazid (antiTB) found to elevate mood.
1950s imipramine (analogue of chlorpromazine antipsychotic) found to elevate mood.

Question 15

Pharmacology of antidepressants

Answer 15

Iproniazid found to inhibit MAO
Imipramine found to inhibit NA/5-HT reuptake
‘The monoamine theory of depression’
Relative decrease in NA and/or 5-HT neurotransmission underlies the symptoms of depression. Increase NA/5-HT neurotransmission.

Question 16

MAOIs

Answer 16

Inhibit MAO
Inhibit intracellular metabolism of 5-HT, NA and DA
Increase vesicular 5-HT/NA content
Increase 5-HT/NA release
Effective antidepressants
Increase DA transmission - stimulant
Increase actions of sympathomimetic amines (cheese reaction)
Interaction with reuptake inhibitors (serotonin syndrome)

Question 17

The cheese reaction

Answer 17

Tyramine (cheese, chianti, oxo) and other amines from cold remedies etc.
Normally metabolised by MAO
With MAOIs, amine levels increase
Act as indirect sympathomimetic
Provoke hypertensive crisis

Question 18

Monoamine reuptake inhibitors

Answer 18

Block reuptake of 5-HT and NA

Selective and non-selective

Question 19

Monoamine reuptake

Answer 19

Reuptake inhibitors prevent removal of transmitter from the synaptic cleft.
Levels of transmitter in the cleft increase.
Magnitude and duration of receptor activation is increased.

Question 20

Monoamine reuptake inhibitor antidepressants

Answer 20

Tricyclic antidepressants (TCAs)
-Imipramine
-Amitriptyline
Selective serotonin reuptake inhibitors (SSRIs)
-Fluoxetine (Prozac)
-Paroxetine (Seroxat)
-Sertraline (Zoloft)
-Escitalopram (Cipralex)

Question 21

TCAs

Answer 21

Inhibit reuptake of 5-HT and NA
Related chemical structure
Similar side effects
H1 antagonism - Sedation
mACh antagonism - Dry mouth
α1 antagonism - Postural hypotension

Question 22

SSRIs

Answer 22

EG Paroxetine, fluoxetine
Inhibit reuptake of 5-HT selectively and no receptor interactions.
Fewer side effects than TCAs
Not more effective than TCAs

Question 23

The serotonin syndrome

Answer 23

MAOI plus reuptake inhibitor (TCA or SSRI).
Synergistic increase in synaptic 5-HT provokes malignant hyperthermia.
Most MAOIs are irreversible.
Pharmacological actions outlast plasma elimination.
New enzyme synthesised with t1/2 of 6 weeks.
Some SSRIs have long half life.
There must be a long ‘wash-out’ between different drugs

Question 24

Antidepressants

Answer 24

Don't work acutely
Pharmacological actions evident acutely
Therapeutic actions delayed (4-6 weeks)
Autoreceptor desensitization
Synaptic remodelling

Question 25

Desensitization of autoreceptors (Acutely)

Answer 25

Reuptake blocked at cell body aswell as terminal.
Autoreceptors activated.
Firing inhibited.
Terminal release inhibited.
Synaptic 5-HT levels are not increased.

Question 26

Desensitization of autoreceptors (After several weeks)

Answer 26

Autoreceptors desenitize
Firing is restored
Terminal release is restored
Reuptake still blocked
5-HT levels in synaptic cleft are elevted

Question 27

Antidepressant action

Answer 27

The pharmacology of antidepressants is established.
The true mechanism of antidepressant action is unknown.
Important receptors and brain regions unknown.

Question 28

5-HT promotes synaptic remodelling: Low mood

Answer 28

Depressive symptoms
Low 5-HT
Prevents plasticity in forebrain neurones

Question 29

5-HT promotes synaptic remodelling: Normal mood

Answer 29

Healthy
Increased 5-HT
Supports plasticity in forebrain neurones