Antidepressants (L15) Flashcards
symptoms of depression
- low mood
- guilt
- hopelessness
- anhedonia
- suicidality
- disturbed sleep
- altered appetite
- poor concentration
what is anhedonia?
inability to experience pleasure
facts of depression
- 10% prevalence
- 17% lifetime risk
- long episodes
- recurrent course
- high economic cost
pathology of depression
the pathology of depression is unknown
the pharmacology of effective anti-depressant drugs suggests 5-HT and/or NA dysfunction in the brain
major classical transmitters in the CNS
noradrenaline (NA)
5-hydroxytryptamine (5-HT)
dopamine (DA)
acetylcholine (ACh)
noradrenergic (NA) pathways in the brain
locus coeruleus contains NAergic cell bodies
• projections to the hypothalamus and midbrain
• projections to the hippocampus and cortex
serotonergic (5-HT) pathways in the brain
dorsal and median raphe nuclei contain serotonergic cell bodies
• projections to the hypothalamus, hippocampus and cortex
what are the elements of neurotransmission?
- synthesis
- storage
- release
- interaction with target
- termination
NA/5-HT neurotransmission
neurotransmitter parcelled into vesicles, if not broken down by intracellular MAO
neurotransmitters synthesised from AAs
noradrenaline (NA) synthesis
TYROSINE
• tyrosine hydroxylase
L-DOPA
• DOPA decarboxylase
DOPMAINE
• dopamine-beta-hydroxylase
NORADRENALINErate limiting step in NA synthesis
tyrosine hydroxylase
5-HT synthesis
TRYPTOPHAN
• tryptophan hydroxylase
5-HTP
• 5-HTP decarboxylase
5-HTrate limiting step in 5-HT synthesis
tryptophan hydroxylase
what are the 2 types of MAO and what neurotransmitters do they metabolise?
MAO-A and MAO-B
NA and 5-HT metabolised by both MAO-A and B
DA preferentially metabolised by MAO-B
what does MAO do to the neurotransmitters?
they remove the amine group so it can no longer do its job as a neurotransmitter
NA and 5-HT receptors
interaction with the target
different kind of receptors in different places
receptors can be on the presynaptic and postsynaptic membranes
what are the different kinds of NA receptors?
alpha and beta GPCRs • alpha-1 • alpha-2 • beta-1,2,3
alpha-1 NA receptors
excitatory
• stimulate PI cycle
• increase DAG
• increase [Ca+]
alpha-2 NA receptors
inhibitory
• inhibit adenylate cyclase
• decreases cAMP
• opens K+ channels
beta-1,2,3 NA receptors
excitatory
• stimulate adenylate cyclase
• increases cAMP
what are the different kinds of 5-HT receptors?
5-HT
• 1A, 1B, 1D, 1E, 1F, 2A, 2C, 3, 4, 5, 6, 7
GPCR OR ligand gated ion channels
GPCR 5-HT receptors
5-HT: 1(A-F)
• inhibit adenylate cyclase
• decrease cAMP
5-HT: 2(A-C)
• stimulate PI cycle
• increase DAG
• increase [Ca+]
ligand gated ion channel 5-HT receptors
5-HT 3
what are auto receptors?
they are on the presynaptic membrane and are part of a negative feedback loop
they inhibit transmitter release
NA terminal autoreceptors
alpha-2
5-HT terminal autoreceptors
5-HT 1B
pharmacology of depression
1950s
• iproniazid and imipramine found to elevate mood
iproniazid found to inhibit MAO
imipramine found to inhibit NA/5-HT reuptake
monoamine theory of depression
relative decrease in NA and/or 5-HT neurotransmission underlies the symptoms of depression
pharmacotherapeutic aim of anti-depressants
to increase NA and/or 5-HT neurotransmission
problems with making anti-depressants
nature of dysfunction unknown
brain regions affected unknown
major classes of antidepressants
MAO inhibitors
• reversible, irreversible
• selective, non-selective
MA reuptake inhibitors
• selective, non-selective
MAOIs
inhibit MAO
inhibit intracellular metabolism of 5-HT
increase vascular 5-HT content
increases 5-HT release
examples of MAOI antidepressants
irreversible MAO-A/B inhibitors
• tranylcypromine
irreversible MAO-A inhibitors
• clorgyline
reversible inhibitor of MAO-A (RIMA)
• moclobemide
side effects and interactions of MAOIs
increase DA transmission - stimulant
increase actions of sympathomimetic amines (cheese reaction)
interaction with reuptake inhibitors (‘serotonin syndrome’)
effects in MAO outlast clearance of drug
how do antidepressants affect diet?
they inhibit MAO so have huge dietary restrictions
• cannot breakdown tyramine in food
• cheese, red wine, anchovies
selective and reversible MAOIs
selective
• fewer side effects
• less stimulant
• lower efficacy
reversible
• decrease interaction with other antidepressants
• lower efficacy
monoamine reuptake inhibitor antidepressants
tricyclic antidepressants (TCAs)
selective serotonin reuptake inhibitors (SSRIs)
NA reuptake inhibitors (NARI)
serotonin and NA reuptake inhibitor (SNRI)
what do monoamine reuptake inhibitors do?
precent removal of transmitter from the synaptic cleft
levels of transmitter in the cleft increase
magnitude and duration of receptor activation is increased
what do TCAs do?
inhibit reuptake of 5-HT and NA
related chemical structures similar side effects: • H1 antagonism - sedation • mACh antagonists - dry mouth • alpha-1 antagonism - postural hypotension
what do SSRIs do?
inhibit reuptake of 5-HT selectively
fewer side effects than TCAs
not more effective than TCAs
the serotonin syndrome
MAOI + reuptake inhibitor (TCA or SSRI)
synergistic increase in synaptic 5-HT provokes malignant hyperthermia
most MAOIs are irreversible
many SSRIs have long half-lives
must be a long wash out between different drugs
current theories to explain delayed antidepressant action
postsynaptic receptor adaptation
autoreceptors desensitisation
synaptic remodelling
postsynaptic receptor adaptation: to explain delayed antidepressant action
elevation of synaptic levels of transmitter cause desensitisation of receptors
amount of receptors decrease - decreased effect
this desensitisation is crucial in the therapeutic response
desensitisation of auto receptors: to explain delayed antidepressant action
antidepressants inhibit firing and terminal release via auto receptors
• synaptic 5-HT levels don’t increase
autoreceptors desensitise firing
• terminal release is restored
• synaptic 5-HT levels elevated
synaptic remodelling: to explain delayed antidepressant action
5-HT is a trophic factor - role of development of CNS
antidepressants cause increase in 5-HT
increased 5-HT causes synaptic remodelling which takes time
• spines grow on the postsynaptic neurone on the dendrites
• connectivity and output of neurones increased
