Antidepressants Flashcards
Depression
Low mood Guilt Hopelessness Anhedonia Suicidality Disturbed sleep Altered appetite Poor concentration
Pathology of depression
Unknown
Effective antidepressant drugs suggest dysfunction of 5-HT and/or NA systems.
Low 5-HT
Noradrenergic pathways
Locus coeruleus contains NAergic cell bodies.
Projections of hypothalamus and midbrain
Projections of hippocampus and cortex
Serotonergic (5-HT) pathways
Dorsal and median raphe nuclei contain serotonergic cell bodies.
Projections to hypothalamus hippocampus and cortex
Noradrenaline synthesis
Tyrosin + Tyrosine hydroxylase ->
L-DOPA + DOPA decarboxylase ->
Dopamine + Dopamine β-hydroxylase ->
Noradrenaline
5-HT synthesis
Tryptophan + Tryptophan hydroxylase ->
5-HTP + 5-HTP decarboxylase ->
5-HT
Monoamine oxidase
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
NA metabolism
NA + Monoamine oxidase ->
Aldehyde + Aldehyde dehydrgenase ->
DOPEG + Carechol-o-methyl transferase ->
MHPG
5-HT metabolism
5-HT + Monoamine oxidase ->
Aldehyde + Aldehyde dehydrogenase ->
5-HIAA
NA receptors
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
5-HT receptors
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
Autoreceptors
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
Monoamine reuptake transporters
Distinct (closely related) transporter proteins.
Preferentially take up NA or 5-HT or DA.
Responsible for termination of neurotransmitter effects.
Pharmacotherapy of depression
1950s iproniazid (antiTB) found to elevate mood. 1950s imipramine (analogue of chlorpromazine antipsychotic) found to elevate mood.
Pharmacology of antidepressants
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.
MAOIs
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)
The cheese reaction
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
Monoamine reuptake inhibitors
Block reuptake of 5-HT and NA
Selective and non-selective
Monoamine reuptake
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.
Monoamine reuptake inhibitor antidepressants
Tricyclic antidepressants (TCAs) -Imipramine -Amitriptyline Selective serotonin reuptake inhibitors (SSRIs) -Fluoxetine (Prozac) -Paroxetine (Seroxat) -Sertraline (Zoloft) -Escitalopram (Cipralex)
TCAs
Inhibit reuptake of 5-HT and NA Related chemical structure Similar side effects H1 antagonism - Sedation mACh antagonism - Dry mouth α1 antagonism - Postural hypotension
SSRIs
EG Paroxetine, fluoxetine
Inhibit reuptake of 5-HT selectively and no receptor interactions.
Fewer side effects than TCAs
Not more effective than TCAs
The serotonin syndrome
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
Antidepressants
Don't work acutely Pharmacological actions evident acutely Therapeutic actions delayed (4-6 weeks) Autoreceptor desensitization Synaptic remodelling
Desensitization of autoreceptors (Acutely)
Reuptake blocked at cell body aswell as terminal. Autoreceptors activated. Firing inhibited. Terminal release inhibited. Synaptic 5-HT levels are not increased.
Desensitization of autoreceptors (After several weeks)
Autoreceptors desenitize Firing is restored Terminal release is restored Reuptake still blocked 5-HT levels in synaptic cleft are elevted
Antidepressant action
The pharmacology of antidepressants is established.
The true mechanism of antidepressant action is unknown.
Important receptors and brain regions unknown.
5-HT promotes synaptic remodelling: Low mood
Depressive symptoms
Low 5-HT
Prevents plasticity in forebrain neurones
5-HT promotes synaptic remodelling: Normal mood
Healthy
Increased 5-HT
Supports plasticity in forebrain neurones
