L1 Monoamine hypoth Flashcards
List the three core elements that relate to anxiety disorders
1) Negative cognition - interpret ambiguous stimuli negatively e.g. they’re looking at me so much be laughing at me
2) Physiological - seating, shaking, inc HR, stress, cortisol increase
3) Avoidance - don’t like to go into a room with lots of people - will be embarrassing
List 4 types of anxiety disorder
1) Panic disorder - panic attacks ‘might die’
2) Social anxiety disorder - speech, blush, embarrassment
3) GAD - general worry, tension, threat
4) PTSD - flashback to known event, trigger, 9/11
Benzodiazepines act at the _____ receptor.
They are sedative and anxiolytic and are fast acting (_ weeks)
They are safe but potential for ______.
GABAa
2
Dependence
Buspirone acts at _____ receptors (partial agonist)
Used in GAD
Lacks _____, ____ or abuse seen with benzos
5HT1a (auto receptors and also postsynaptic receptors)
Dependence, sedation
SSRIs have a slow therapeutic onset (4-6 weeks) sertraline suggested as cost effective e.g.used in _ _ _
GAD
Beta blockers e.g. propranolol block peripheral/central _______ activity
Noradrenergic
Atypical antipsychotics e.g rispiradone used as _____ therapy for treatment resistant OCD, PTSD
Adjunct
Talk through the monoamine theory of depression
Deficit in monoamine neurotransmitters e.g. 5HT, NA and DA.
5HT = obsession, anxiety, -ve cognitions DA = combination with NA - appetite, other two - pleasure NA = attention - with DA - appetite, 5HT - mood and sleep
What’re the limitations of existing antidepressants?
Efficacy: <40% achieve remission from symptoms
Tolerability: SE’s deter use - emotional blunting, sexual dysfunction, nausea and vom
Time to onset: 4-6weeks - long time
Discontinuation effects: physical withdrawal - can’t just stop
Suicide risk: controversial in lit but might be due to giving motivation to get out of bed and carry out suicide
5HT1AR - site of action of B_______
Polymorphisms in 5HT1Ar promoter alters expression levels (L___ & G_____, _____)
_____ 5HT1Ar levels in pts with panic disorder (N_______ et al _____)
Buspirone
Lesch & Gutknecht 2004
Neumeister et al 2004
5HT1Ar are GPCRs TRUE or FALSE
TRUE
Buspirone related compounds are gepirone and ipsapirone
- It’s a _____ agonist
- it’s as effective as ______
- As fast acting as BZs (BUT controversial)
- Lacks BZ side effects e.g. _____, ______
- Has no ______ symptoms
- Augment with _____ to activate 5HT1A receptor and desensitise it - so sensitise to SSRI treatment
Partial Diazepam Around 2 weeks Sedation and cog impairment Withdrawal SSRIs
Buspirone partial agonist at 5HT1Ar (GPCR) causes closing of ____ channels presynaptically to decrease NT release and causes opening of __ channels postsynaptically to elicit a slow hyperpolarisation. It also causes inhibition of _____ _____ so less ___ phosphorlyation.
Ca2+
K+
Adenylyl cyclase
PKA
5HT1Ar located in _____ _____.
5HT neurones synapse onto non 5HT neurones in _____ e.g glutamatergic nerve cell.
5HT1A autoreceptors function physiologically as a sort of _______ feedback mechanism to regulate _____ release (sense levels of 5HT and adjust 5HT neurone firing to reduce transmitter release accordingly)
Raphe nuclei
Forebrain
Homeostatic
5HT
5HT1A auto receptors are located on ____ and ____ of 5HT neurones. When they are stimulated they are coupled to gi/go ____ subunits and inhibitory 5HT cell firing through beta/gamma subunits. This reduces NT release.
Soma and dendrites
Alpha
Buspirone is a partial 5HT1Ar agonist and acts at postsynaptic receptors and 5HT1A auto receptors. Activating these receptors results in transiently _____ 5HT activation.
Less
What happens if you infuse buspirone directly into amygdala of rats? What does this mean?
Induces anxiolytic effect so may not have effect at presynaptic receptor at all!
N.b. other 5HT receptors also have an effect on 5HT release not just 5HT1Ar
Buspirone desensitisation:
- On repeated exposure to agonist the GPCR will show reduced response as proportion of receptors, having been stimulated on 1st exposure are NOT capable of signalling on 2nd
- So what happens when give buspirone?
- Pre synaptic receptors exposed to buspirone and repeatedly exposed so causes 5HT neurones to reduce 5HT release
- Eventually 5HT1Ar desensitises and buspirone fails to reduce 5HT firing rate hence the firing rate recovers
- This reason suggests why buspirone takes a couple of weeks to have max, clinical effects
Explain why SSRI’s have a delayed therapeutic effect?
- SSRIs bind 5HT transporter (serotonin reuptake transporter) expressed somatodendritically and at synapses
- In presence of SSRIs the transporters are blocked which leads to an increase in 5HT levels
- Somatodendritically 5HT levels increase which activates 5HT1A autoreceptors and causes a transient decrease in 5HT neurone firing rate
- BUT these 5HT1A auto receptors desensitise on repeated 5HT exposure
- 5HT firing hence begins to recover and 5HT levels increase
- This occurs over a period of weeks, hence why SSRIs MAY take this period of time to have a therapeutic effect
SO ______ in 5HT neurone firing due to _____ auto receptor stimulation thought to contribute to delay in ____ and _____ therapeutic effects.
Decrease
5HT1A
SSRI and Buspirone
How can you utilise desensitisation?
- Aim to ‘speed up’ desensitisation by using a ‘better buspirone’ or don’t allow desensitisation to occur at all and just block receptor instead
better buspirones e.g. gepirone, ipsapirone, flesinoxan
Presynaptic raphe 5HT1A receptors and postsynaptic hippocampal receptors both desensitise TRUE OR FALSE
FALSE
Presynaptic 5HT1Ar in the raphe desensitise BUT postsynaptic hippocampal receptors do not desensitise
Suggest a way of speeding up SSRI effects - name specific drugs…
- Augmentation with SSRI and pindolol (5HT1Ar antagonist with selectivity for presynaptic receptors)
- Pindolol binds 5HT1Ar and prevents desensitisation from occurring and from 5HT neurone firing
- This speeds up the onset of SSRI action as the level of 5HT remains high w/o auto receptor stimulation
REF: Seagrave and Nathan 2005
List 4 new antidepressants and briefly discuss MOA.
Desvenlafaxine
- SNRI
Trazodone extended release
- SSRI and 5HT2a/c antagonist extended relase
Vortioxetine
- SSRI and partial 5HT1Ar partial agonist
- SPARI - serotonin partial agonist reuptake inhibitor
Vilazodone
- Multi-modal antidepressant
- Reuptake inhibitors & 5HT1A, B, 5HT 3&7 agonists
- Speeds up onset and more efficacious than SSRIs
What evidence is there for the role of 5HT1A receptor in anxiety? Human and animal model references
- Polymorphisms in human 5HT1Ar promoter regulating expression levels leads to altered level of 5HT1ar - (Lesch & Gutknecht 2004)
- Decreased 5HT1Ar seen in patients with panic disorder (Neumeister et al 2004)
- 5HT1A receptor is the site of action for anxiolytic buspirone - buspirone acts to decrease symptoms of anxiety in around 2 weeks
- Is as effective as diazepam
