Major Depressive disorder (mood disorder) Flashcards
global average 12 month prevalence
4.7% (95% CI 4.4 - 5.0)
MDE: heterogenous condition what does it differ in
-symptom
-severity
-duration
-no. of episodes
what are the factors contributing to MDE
-genetic
-social
-resilience factors
-environmental
-developmental vulnerability
Current treatments
-A2 receptor antagonists
-tricyclic antidepressants
-monoamine oxidase inhibitors (MOIs)
-noreadrenaline reuptake inhibitors (NRIs)
-Selective serotonin reuptake inhibitors (SSRIs)
-Serotonin and noradrenaline reuptake inhibitors (SNRIs)
Less used treatments of MDE
-Vortioxetine
-Agomelatine
-Esketamine
Mono amines in normal brain
-Serotonin 5HT2
-Noreadrenaline 5HT3
-Dopamine 5HT4
Monoamines in depressed brain
low levels of monoamine
(monoamine hypothesis of depression)
Monoamine Hypothesis
depression is due to a functional deficits in monoamine NTs
Evidence 4 MA hypothesis
- antidepressant regulate levels of monoamines in the brain
- chronic treatments with drugs that deplete MAs increase susceptibility to depression
Evidence against the mono amine hypothesis
-the biochemical effects of AntiDs are immediate however they are not seen for weeks
-both amphetamine and cocaine enhance MA but do not have anti-depressant activities
-some ADs do not enhance mono amine transmission
Evidence backing up depression hypothesis that it is caused by imbalance of 5ht in the brain
systematic review (Moncrieff et.al) : no consistent evidence
Cipriani et al., 2018
best AD
-552 trials of 21 AD in patients with moderate to severe MDE
-Agomeltine and vortioxetine were most accepted and effective
Pros of Cipriani et al., 2018
- Included 86 unpublished papers… reduced publication bias
Limitations of Cipriani et al., 2018
- not applicable to teens and kids who also suffer
- maitenence therapy unknown (only carried out for 8 weeks)
- MOIs not included
-no large diff in 50% change in HRDS at 8 weeks across all ADs
HDRS measurement
Hamilton Depression Rating Scale (clinical significance =0.5 SMD in cipriani et al., 2018 =0.3 not clinically signf.)
Class and function of Vortioxetine
Serotonin modulator
3 mode of function
-SERT inhibitor
-Action at GPLRs (5HT1A,B,D and 5HT7)
-Inhibit LGIC 5HT3 receptor
MoA Vortioxetine
- By inhibiting SERT= increase in 5HT in synaptic cleft and thus increases receptor activation
Vortioxetine role at receptors
5HT1A: Receptor agonist
5HT1B: Receptor partial agonist
5HT1D: Receptor Antagonist
( All three accelerate AntiD effects. G Alpha i)
5HT3: reduces the antagonist side effects (nausea, vomiting, bowel motility)
5HT7: Receptor Antagonist: increases glutamate in the prefrontal cortex - aids cognition? normalises circadian rhythm’s? (G alpha S)
G alpha I
inhibits adenylate cyclase decreasing conversion in ATP to cAMP (red. cAMP)
G alpha S
stimulates adenylate cyclase increasing conversion in ATP to cAMP (increase cAMP levels)
How receptors 5HT1A,B,D and 5HT7 control amount of 5HT in brain (without vortioxetine)
neg feedback loop
5HT1A decreases 5HT conc. in brain
5HT1B/D act as auto receptors decreases 5HT conc. in brain and raphe nucleus
5HT7: GABA activation and release decreasing 5HT in raphe nuc.
How receptors 5HT1A,B,D and 5HT7 control amount of 5HT in brain (with vortioxetine)
5HT1A receptor = desensitised increase 5HT in brain (due to full agonist activation)
5HT1B/D increase 5HT conc. in brain and raphe nucleus
5HT7: when antagonised, GABA activation and release is inhibited at the GABA interneurone.. increasing 5HT in raphe nuc.
reduces all receptor mediation in neg feedback to increase 5HT in brain.
causes higher 5HT levels in brain than SSRIs (decrease depression
MOA maintain 5HT conc. levels below toxic levels (no excitotoxicity/hyper excitation)
SSRI vs Vortioxetine on 5HT3 LGIC Receptor
SSRI
overactivation of receptor = nausea and vomiting
over activation in GI tract causes GI upset
Vortioxetine
less nausea/vom= no activation of 5HT3 in brain stem
Fewer GI upset
Vortioxetine on cognition
Baune et.al, 2018 meta analysis
one of the DSM5 qualifications of MDE is executive dysfunction
in digit symbol substitution test which measures processing speed saw signf increase in processing compared to SSRI MAOIs and TCA
NICE vortioxetine recommendations
Recommends vortioxetine be taken by MDE suffering adults who don’t respond to 2 ADs within a current episode
Agomelatine MoA
Unknown currently
Associated with
-resynchro of circadian rhythm
-increased dopamine and noradrenaline in PFC
-increased BNDF
via
- agonising melatonin receptors
- antagonising 5HT2C receptor
how does Agomelatine do this
evidence for abnormal circadian rhythms can be found in the literature. there is a signf. difference (p=0.03) in melatonin peak time between depressed and control (SEM) limitation of SEM
2 melatonin receptors
M1
M2
both G alpha Q Decrease cAMP levels
moa on circadian
look at white board
BDNF
depression arrises from low levels of BNDF
BNDF is involved in neurogenesis, cell survival, and synaptogenesis
Evidence for BDNF hypothesis
(Shimizu et al, 2003)
lower levels of BNDF in non-treated depressed patients
Evidence for Agomelatine
(Gupta et al., 2017)
effect of Ago on serum BDNF and HAMD score showed signf. reduction in HAMD score and increase in BNDF
limitations to Gupta et al.,2017
- small sample size n-30
- open label
-no placebo
-serum doesn’t match what is occurring in CNS
MOA how ago increases BDNF
unclear most likely via MT receptors 1 and 2 activation synergising with antagonising the 5HT2c receptor
