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Lect 9: Mood disorder drug treatment (SSRI, SNRI, NARI (2nd gen…
Lect 9: Mood disorder drug treatment
Monoamine theory of depression
Depression is due to a deficit in central monoamine (5HT & NA) neurotransmission
Treatments
How to increase 5HT & NA neurotransmission
Tryptophan -> taken into neuron -> converted by 5HTP to TPH -> converted to 5HT by AADC
5HT stored in vesicles protected from cytosolic enzymes & available for release -> AP releases 5HT across synapse -> on variety of receptors -> 5HT2A 5HT1A 5HT2C 5HT1B
Terminate action of 5HT -> taken back up into neuron by Serotonin trpter -> recycled into vesicles or metabolised by monoamine oxidase
5HT biosynthesis
Able to interfere with
Synthesis
Storage
Release
Receptors
Termination -> main drugs of depression
Drugs that target Serotonin transporter-> 5HT able to act for longer on receptors
Decrease 5HT reuptake
TCA (Tricyclic antidepressants)
SSRI
Both effective antidepressants
TCA
E.g. Imipramine
Inhibit 5HT & NA uptake -> therapeutic effect take weeks
But
Block M1 receptors
Dry mouth, blurred vision
Block H1 receptors
Sedation, weight gain
Block alpha 1 receptors
Postural hypotension
Effective but side effects
Clinical use for TCA (dirty drugs -> affinity for trpters & receptors)
Useful:
Severe treatment
Pain
Migraine
Cheap
Not used:
Elderly
Cardiac patients
Suicidal patients
SSRI, SNRI, NARI
2nd gen antidepressants
:
Selective 5HT/NA trpter & x affinity for postsynaptic receptors (fewer side effects)
Efficacy -> SSRI & TCA exhibit = antidepressant efficacy
SSRI -> better adverse side effect profile than TCA
SSRI side effects
Sexual dysfunc
GI
X cause sedation
Other uses:
Treat panic disorder
OCD
Eating disorder
SSRI: selective serotonin reuptake inhibitor
SNRI: serotonin/noradrenaline reuptake inhibitor
NARI: noradrenaline reuptake inhibitor
SSRI vs TCA
Both exhibit equivalent antidepressant efficacy
SSRI better adverse side effect profile than TCA
Impt as lag time before onset of therapeutic efficacy
Delayed onset of action of antidepressants
2-3 weeks before exhibiting antidepressants action
Why?
1) Autoreceptor desensitisation hypothesis
Acute autoreceptor actin inhibits 5HT neuronal activity
Results in decreased 5HT release at terminal & restrains ability of SSRI to increase synaptic 5HT
Emergence of therapeutic efficacy relates to autoreceptor desensitisation
5HT released into synapse -> x enough 5HT to act on post-synaptic receptors -> SSRI block trpter
Trpter on raphe area -> blocked as SSRI goes throughout brain -> increase of 5HT1A autoreceptors -> neuronal firing inhibited -> 5HT decreased slightly -> over time -> desensitised -> releases neurone -> neurone starts firing again
2) Trophism hypothesis
5HT is increased acutely but produces its therapeutic effect by a trophic action-> resulting in synaptic remodelling
SSRI cause trophism & increase trophic factors in experimental animals
Acute autoreceptor actn restrains ability of SSRI to increase synaptic 5HT, emergence of therapeutic efficacy relates to autoreceptor desensitisation
Evidence
SSRI when given to rats -> increases BDNF (brain derived neurotrophic factor) expn
Additionally, seen with ECT (electroconvulsive therapy)
BDNF + other trophic factors->cause synaptic remodelling -> reqd for therapeutic effect
Antidepressants which x inhibit uptake
Monoamine oxidase inhibitors (MAOIs)
5HT released into synapse taken back up into terminal -> x metabolised instead recycled into vesicles -> more released
2 isoforms of MAO
MAOA breaks down 5HT
MAOB breaks down DA
Old MAOI blocked both isoforms irreversibly (e.g. tranylcypromine)
Stimulant effects
Dangerous in overdose
New MAOIs selective for MAOA
Less stimulant
Safer
MAOI interactions
MAOI & SSRI -> together influence serotonin -> Serotonin syndrome
Hyperthermia, confusion hypertensive crisis
MDMA & MAOI -> serotonin syndrome
Atypical antidepressants
Affinity for range of monoamine trpters & receptors
Mirtazepine
Mianserin
Nefazodone
Have a greater affinity for 5HT2A receptor -> contribute to therapeutic effects too
Interacting with synthesis therapeutically
Increase 5HT synthesis
Tryptophan load, improves mood
Releasing agent
MDMA (ecstasy)
Unpractical -> long term neurotoxicity
Drugs used to treat depression
TCA -> 1st gen antidepressants
High incidence of side effects
SSRI, SNRI, NARI -> 2nd gen -> target trpter without hitting receptors
Much better side effect profile
MAOIs
But side effects & interactions
Atypical
Mixed affinity for receptors & trpters
ECT
Causes neurotrophic effects
Summary
Monoamine of depression
HPA theory of depression
Biochem of 5HT,NA
Mechanism of action of TCAs, SSRI, MAOI
Diff bet TCA & SSRI
Mechanism underlying delayed response of antidepressants