Depression (glutamate, 5-HT signalling)

What is the monoamine theory for depression and why do we tend to use it?

• Observation that clinical drugs that increase 5HT improve mood, and those that decrease NA worsen mood

• alpha-methyltyrosine inhibits NA synthesis, reduces mood, MOA inhibitors e.g. phenelzine increase mood

• Biological basis of depression actually poorly understood

What is the enzyme involved in the RDS of seratonin breakdown? Give a drug that inhibts this

• Monoamine oxidase-A (MAO-A)

• Phenelzine

What is the only ionotropic 5-HTR?

• 3

What is interesting about all the different 5-HTR subtypes when it comes to treating depression?

• 5HT1A is Gi, used in anti-anxiety buspirone (Desensitises)

• 5HT1B is Gi, agonist for migrane

• 5H2A is Gq, antagonist binding for anti-psychotics, agonist for LSD

• 5HT3 is ionotopic for anti-emetics

• No specific subtype for depression, targeting different varieties works for different people

What enzyme can be targeted to specifically modulate NA synthesis, not DA synthesis?

• Dopamine beta-hydroxylase (DBH) that converts DA —> NA

What is NA reuptaken by?

• 75% by NET on pre-SN, 25% by EMT on non-neurones

What are some counters to the monoamine theory?

• 2022 review found no evidence that seratonin activity or concentration lowered in depression

• Comparing post-mortem healthyvsdepressed brains for monoamine metabolism or transporters has inconsistent results - but this is hard anyway, how do we know they weren’t depressed?

• Drugs can affect monoamines in minutes, but ant depressive effects take weeks/months - secondary adaptive changes?

• Strong link with glutamate, but not a monoamine

Describe relationship between glutamate and depression

• Stronger link than monoamines

• Decreased glutamate in patients on ad, drugs may be decreasing glutamate

• In rodents, stress increases glutamate, so could correlate

• Excitotoxicity and death due to increased NMDAR agonism

• NMDAR antagonist ketamine licensed for depression - mildly dissociates people from their emotions so they are more responsive to non-pharma intervention

What is potentially the reason for the delayed therapeutic action of SSRIs? Name 2

• Block SERT, initial increase in seratonin in cleft

• This binds to Gi autoinhibitory 5HT1A, so now seratonin release decreased, refractatory anxiety and depression

• Eventually become desensitised, 5HT can be released again

• Fluoxetine, dapoxetine

Discuss the implications of fluoxetine use?

• Most SSRI have some non-sert activity

• Also a 5HT2C antagonist, increased risk of psychosis in those predisposed

• Nausea, insomnia, decreased libido, failure to orgasm (SOSA in dapoxetine)

• 18h half life so useful for chronic uses

• Increased suicidal ideation (sometimes believed that it increases motivation but doesn’t decrease depression in some users / doses / esp. under 18s)

How is dapoxetine an example of SOSA

• Failure to orgasm seen in fluoxetine users

• Dapoxetine half life 1.5h (compared to fluox 18h) so taken before sex to prevent premature ejactulation

What can’t SSRIs be taken with?

• MAO inhibitor e.g. phenelzine

• Decreases reuptake and decreases breakdown of 5HT

• Large increases in 5HT levels

• Seratonin syndrome: tremor, hyperthermia, cardiovascular collapse

What do the tricyclic antidepressents do?

• Block NA and 5HT reuptake by blocking both NET and SERT

• NET block relieves biological symptoms (sleep, libido) and SERT block relieves emotional (low mood)

• More side effects than SSRI

• Good PK - some are metabolized into compounds that are also TCAs e.g. amitriptyline → nortriptyline

Difference between SNRIs and TCAs, give an example

• Molecules are structurally distinct - both tertiary amines but rest of the compound very different

• Both block NET and SERT, TCAs have greater off-site effects e.g. ion channels

• SNRIs supposedly better selectivity and fewer side effects

• Venlafaxine vs amitriptyline

Describe venlafaxine as an antidepressent

• SNRI - both SERT and NET blocking

• Only blocks net when at higher doses

• This improves anti-depressive effect, so NET is clearly important

• Metabolised by CYP2D6 (hard to prescribe with other meds) into desvenlafaxine which gives stronger NET inhibition

What are NASSAs? Give an example

• Noradrenaline and specific serotonin antidepressant

• Antagonizes alpha2 adrR, 5HT2A/C and 5HT3

• Mirtazapine

Describe mirtazepine as an antidepresent

• Presynaptic alpha2 adrR expression reduces NA/5-HT release in negative feedback, so blockage increases NA/5-HT release

• Less side effects than SSRIs as 5HT2A/C and 3 block reduces libido and nausea side effects caused by high 5-HT

• Can be a sedative as also blocks H1R

Describe how monoamine oxidase inhibitors can be anti-depressive, and name two

• Block 5-HT, NA and DA breakdown, more spontaneous leakage from cytoplasm into cleft

• MOA-A preference for 5HT

• MOA-B preference for DA

• Phenelzine (non-selective), moclobemide

Describe phenelzine as an antidepressent

• Non-selective MAO inhibitor

• Decreases 5HT, NA and DA breakdown

• Irreversible

Describe moclobemide as an antidepressent

• MOA-A selective, so more 5HT breakdown than DA

• Reversible

• Shows that MOA-A inhibition alone is sufficient for effective antidepressive action

Discuss the problems of MAOis

• Increase cytoplasmic 5HT/NA inside neurone

• Amount packaged into vesicles remains constant, so no effect on amount released after an AP

• Instead works as more spontaneous leakage from neurone to increase cleft concentration

• Can cause hypotension, tremor, restlessness, cheese effect if non-selective

Discuss the problems of phenelzine as an antidepressent

• Can cause hepatotoxicity

• Non-selective

• MAO expressed in gut inactivates ingested amines e.g. tyramine in cheese

• When blocked, tyramine can enter neurones via NET/VMAT and displace NA, causing severe hypertension

• Not observed with MAO-B selective MAOis e.g. moclobemide

What do SNRIs target?

• NET and SERT

What do TCAs target?

• NET and SERT, but off site effects on Na+ channels, sometimes NMDA receptor