CPTP 3.3 Neuropharmacology 1 (Antidepressants) Flashcards
What creates biological vulnerabilities for depression and mood disorders?
- Genetic predisposition
* Early adverse life experiences
Are catecholamines monoamines?
Yes
list the catecholamines
- NA
- Serotonin
- Dopamine
Outline briefly the monoamine hypothesis?
Depression is due to a deficit in central monoamine neurotransmission.
What evidence is there against monoamine theory?
- Cocaine inhibits NA uptake, but isn’s an antidepressant
* Lowered monoamines aren’t seen in patients with depression
Outline the biochemical pathway for the synthesis of 5-HT
Tryptophan –TPH–> 5-HTP
5-HTP –AADC–> 5-HT
TPH = tyrptophan hydroxylase AADC = 5-hydroxytryptophan decarboxylase
What occurs to 5-HT after synthesis?
Either stored into vesicles or broken down by MAO into 5-HIAA and extruded
What are the most important postsynaptic 5-HT receptors?
- 5-HT 1A
- 5-HT 1B
- 5-HT 2A
- 5-HT 2C
What is the 5-HT autoreceptor?
5-HT 1A
How is serotonin terminated?
SERT in the presynaptic membrane pumps 5-HT back into the presynaptic neurone.
It can then either be transported back into vesicles or broken down by MAO
What two pharmacological targets are there for antidepressants?
The termination step:
• MAO
• SERT
Which antidepressants block 5-HT reuptake?
- Tricyclic antidepressants
- SSRIs
- SNRIs (serotonin & noradrenaline)
Which antidepressants block NA reuptake?
- SNRIs (serotonin & noradrenaline)
* NARIs
What effect do reuptake inhibitors have?
They prolong the effects of the neurotransmitter
What are the clinical limitations of TCAs?
- Delayed onset of 2 weeks before effective
- M1 antagonistic effects
- H1 antagonistic effects
- a1-adrenoreceptor antagonistic effects
- Cardiotoxic in overdose
What do TCA M1 antagonistic side effects include?
- dry mouth
- blurred vision
- constipation
- urinary retention
What do TCA H1 antagonistic side effects include?
- Sedation
* Weight gain
What do TCA a1 antagonistic side effects include?
Postural hypotension
What do the clinical limitations of TCAs result in?
Feeling worse before you feel better because the side effects are immediate but the therapeutic effects are delayed
This results in poor compliance
What are the benefits of TCAs
- Can be used for severe or resistant (other drugs aren’t working) depression
- They are cheap
In what groups are TCAs not used?
- Elderly
- Young
- Cardiac patients
- Suicidal patients (overdose)
- Drivers (sedation)
Why are TCAs not used in cardiac patients?
They increase the chance of conduction abnormalities.
What are the ‘second generation’ antidepressant classes? What is special about these?
• SSRIs
• SNRIs
• NARI
Selective for 5-HT or NA transporters and do not have affinity for postsynaptic receptors so there are fewer side-effects
How do SSRI and SNRI efficacies compare to those of TCAs?
The same (but far fewer side-effects) “Clean drugs”, high selectivity
What do the isoforms of MAO do?
- MAO A breaks down 5-HT and NA
* MAO B breaks down Dopamine
What does older MAOIs do? Name the one in the formulary. What are the downsides to these?
Blocks both isoforms of MAO irreversibly.
Phenelzine
- Stimulant effects
- Dangerous in overdose
What do new MAOIs do?
Reversible inhibitors of monoamine oxidase A (RIMA)
- Selective for MAO A
- Reversible
- Dont have the downsides of older MAOIs
What is the main side effect of MAOIs?
The cheese effect:
• MAO in gut and periphery usually breaks down dietary amines
• If MAOIs are used in a diet high in amines, this leads to a increased amine absorption
• Noradrenaline is displaced by these amines causing a hypertensive crisis
What is serotonin syndrome?
Result of drug-drug interaction between MAOIs and SSRIs
• Hyperthermia
• Confusion
• Hypertensive crisis
When does serotonin syndrome most commonly occur?
When switching between MAOIs and SSRIs due to the half lives of some of these drugs being high
Which SSRI has a long half life?
Fluoxetine
How long do you need to wait when making the following drug switches:
1) MAOI –> Fluoxetine
2) Fluoxetine -> MAOI
1) 2 weeks
2) 5 weeks
What are atypical antidepressants?
NEWER antidepressants with an affinity for a range of monoamine transporters and receptors (NaSSA)
Name the atypical antidepressant in the student formulary
Mirtazepine
How can 5-HT synthesis be increased? How clinically effective is this?
Increasing precursor availability by giving a tryptophan load
Not clinically effective on its own but increases therapeutic response of other antidepressant treatments.
How can 5-HT release be increased?
What is the limitation of this?
By using a releasing agent such as MDMA
Causes long-term neurotoxicity
What causes the delayed onset of action of antidepressants?
Neurotrophic hypothesis:
• SSRIs cause acute increase in 5-HT, but the therapeutic effect is a result of the synaptic remodelling caused by 5-HT’s trophism role
• Synaptic remodelling takes time
Autoreceptor hypothesis:
• The acute increase in 5-HT activates autoreceptors, restraining the ability of SSRIs to maintain synaptic 5-HT
• Therapeutic effects arise when these autoreceptors are desensitised
Where do serotonergic and noradernergic neurones begin and end?
Serotonin: • Starts at raphe nuclei Noradrenaline: • Lateral tegmentum • Locus ceruleus
BOTH PROJECT THROUGHOUT THE FOREBRAIN
Where is 5-HTT (5-HT transporter) most densely expressed? What else is densely expressed here and what is the significance of this?
Dorsal raphe nucleus
5-HT 1A receptors
This is where autoreception and thus negative feedback mostly occurs
What protein do SSRIs inhibit?
5-HTT transporters in dorsal raphe nucleus
What are the acute effects of SSRI action?
- 5-HTT transporters blocked
- DRN 5-HT levels rise
- 5-HT 1A autoreceptors stimulated
- Firing is inhibited
- Terminal release is inhibited
This results in acute side effects before the 5-HT 1A receptors are desensitised
What are the side effects of SSRIs?
- Nausea
- Impotence
- Weight gain
