3.3 Antidepressants Flashcards
Why does the antihypertensive reserpine induce depression?
Because it depletes monoamine vesicles
Why does the antiTB drug iproniazid improve mood in TB patients?
Blocks MAO, involved in the breakdown of monoamines
What causes depression?
‘Depression is due to a deficit in central monoamine (5‑HT and NA) neurotransmission.’
What evidence is there for depression being due to deficit in central monoamine?
• Antidepressant drugs increase monoamines and elevate mood
• Reserpine inhibits monoamine storage and lowers mood
• Inhibition of 5-HT synthesis lowers mood
Changes in monoamine receptors in PET studies in depressed patients
What evidence is there against the current definition of depression?
Cocaine inhibits NA uptake and is not antidepressant
Little evidence of lowered monoamines or metabolites in patients with depression
How is 5-HT synthesised?
Tryptophan
5-HTP
5-HT
How is 5-HT stored?
Compartmentalised into vesicle for protection from cytosolic enzymes and ready for exocytosis
Which receptors are related to 5-HT?
5-HT2A, 5-HT1A, 5-HT2C, 5-HT1P (presynaptic and postsynaptic receptor)
How is 5-HT terminated?
Re-uptake by SERT transporter then recycled by vesicles or degraded by MAO
Which anti-depressants block re-uptake of NA or 5-HT?
Tricyclic antidepressants - TCAs
Selective serotonin re-uptake inhibitors - SSRIs
SNRIs & NARIs
These increase duration and concentration of transmitter
Give example TCAs…
amitriptyline, imipramine, lofepramine
What clinical limitations are there of TCAs…
Delayed onset - 2-3 weeks
Affinity for other post synaptic receptors
• M1 receptor antagonism-dry mouth blurred vision, constipation, urinary retention
• H1 receptor antagonism-sedation, weight gain
• α1-adrenoceptor antagonism-postural hypotension
Side effects immediate, therapeutic effects delayed - feel worse before feel better- poor compliance and poor overall therapeutic efficacy
Cardiotoxic and potentially fatal in overdose
What is the clinical use of TCAs…
Useful for
• Severe, treatment resistant depression and TCA are cheap!
Not used in
• Elderly, young - more sensitive to side effects
• Cardiac patients (increase chance of conduction abnormalities)
• Suicidal patients (overdose)
• Drivers (sedation)
Workers (sedation)
Give examples of SSRI, SNRI and NARI… (2nd generation antidepessants)
• SSRI: selective serotonin reuptake inhibitor (fluoxetine)
• SNRI: serotonin/ noradrenaline reuptake inhibitor (venlafaxine)
NARI noradrenaline reuptake inhibitor (reboxetine)
What are the benefits of the 2nd generation anti-depressants…
Selective for 5-HT or NA transporter and do not have affinity for postsynaptic receptors (fewer side effects)
Which anti-depressants are most effective?
TCAs then SSRIs then SNRIs
however TCAs have extreme amount of side effects
What are the side effects of SSRIs?
• Precipitate anxiety
• Nausea
• Sexual dysfunction (impotence)
• Gastrointestinal (nausea, constipation)
• Weight gain
• Drug interactions with other antidepressant drugs
• Cytochrome P450 inhibition
• CYP1A2, CYP2D6 and CYP3A4
Sedation or anticholinergic side effects limited
What is the function of VMAT 2?
Transports transmitter into vesicles
What is the function of MAO?
MAO will metabolise transmitter outside the vesicles
What do MAO inhibitors do?
Decrease intraneuronal breakdown
Increased vesicle content
Increase release
What are the two isoforms of MAO
MAOa = breaks down 5-HT/NA MAOb = breaks down DA
What did old MAOs used to do?
Older MAOIs blocked both isoforms irreversibly
(e.g. tranylcypramine, phenelzine)
Stimulant effects, - blocking B
Dangerous in overdose - blockin B
What how do new MAOs work?
New MAOIs selective for MAOA, reversable RIMA
(e.g. moclopemide)
Less stimulant
Safer
what is the MAO and cheese effect?
MAO in gut and periphery breaks down dietary amines, if combine MAOI with diet high in amines leads to hypertensive crisis
What is serotonin syndrome?
MAO & SSRIs
Hyperthermia, confusion hypertensive crisis
Particularly important for SSRIs with long elimination half life (e.g. fluoxetine)
MAOI to Fluoxetine 2 weeks break
Fluoxetine to MAOI 5 weeks break
What is the affinity of the atypical antidepressants like?
Have affinity for a range of monoamine transporters and receptors
Give examples of atypical antidepressants?
Mirtazepine
Nefazodone
Mianserin
How can you increase 5-ht synthesis and is it effective?
• Increase precursor availability
• Tryptophan load, in theory should improve mood
• Not clinically effective
• However:
plasma tryptophan levels may be important in therapeutic response of other antidepressants treatments
What increase 5-HT release?
• Releasing agent
• MDMA (ecstasy)
Impractical on account of long term neurotoxicity
Why does a delayed onset of anti-depressants occur?
• 5-HT is increased acutely but produces its therapeutic effect by a trophic action resulting in synaptic remodelling
SSRIs cause trophism and increase trophics factor in experimental animal - strengthening of the synapse - synaptic remodelling
How does increase 5-HT in the DRN cause delayed onset?
SSRIs block 5HT transporter in DRN 5HT levels in the DRN increase 5-HT1a auto receptors are activated Firing is inhibited Terminal release is inhibited - until 2-3 weeks when the receptors becomes desensitised 5-ht1a antagonists could prevent this
What happens to the receptors in the DRN after repeated dosing…
5-HT1A receptors are desensitised
Firing is restored
Terminal release is restored
Synaptic 5-ht levels rise
