Lecture 5: Antidepressants Flashcards
Major symptoms of major depressive disorder (MDD)
depressed mood
decrease interest in pleasurable stimuli (anhedonia)
for 2 weeks consecutively
2 problems with chemical antidepressant
- delay of therapeutic response: take at least 2-4 weeks of regular dosing before therapeutic effect
(patient stop before the drugs work) - side effect can limit usage: elderly are equally responsive but susceptible to side effects
2 hypothesis of depression
- Monoamine/biogenic amine hypothesis
- Neurotrophic hypothesis
What is monoamine/biogenic amine hypothesis?
deficiency in level of 5-HT, NE and DA
monoamine are packaged into vesicle by VMAT
act on metabotropic and GPCR
What is neurotrophic hypothesis?
Loss of neurotrophic growth factors (BDNF)
leads to neuronal atrophy and death
BDNF activate TRK-B receptor lead to increase neuronal growth
loss of BDNF leads to no activation of TRK-B
4 antidepressant mechanism of action
- block degradation by MAO
- block reuptake by transports
- block autoreceptor inhibition
- bind to specific postsynaptic receptors (5HT2)
Monoamine oxidase inhibitor (MAOIs)
increase synaptic availability of NE and 5HT by blocking their catabolism via the inhibition of MAO-A or MAO-B (enzymes)
MAO-A: targets tyramine, NE, 5-HT and DA
MAO-B: targets mainly DA
LAST LINE OF TREATMENT
Tranylcypromine
irreversible, non-selective MAO-A and MAO-B inhibitors
worse side effect than other MAOIs
Moclobemide
reversible MAO-A inhibitor
Side effects of MAOI
headache, drowsiness, weight gain, dry mouth, hypertension, sexual dysfunction
HYPERTENSIVE CRISIS due to tyramine (cheese) reaction (too much tyramine)
CANNOT COMBINE WITH SSRI or SNRI
intracranial bleeding, stroke, headache
Tricyclic antidepressants
MDD if SSRIs are not effective
chronic pain conditions
Imipramine
TCA
Strong 5-HT and NE reuptake inhibition
anticholinergic - treat enuresis (bedwetting)
Desipramine
TCA
Stronger NE than 5-HT reuptake inhibition
weaker anticholinergic action
Treats neuropathic pain
Amitriptyline
TCA
Highly anticholinergic
High a1 blocking properties
SEDATIVE effects
5 anticholinergic effects
dry mouth
constipation
blurry vision
urinary retention
confusion
Cardiac toxicity in TCA
lethal cardiac arrhythmias
due to block of Na/Ca channel
Overdose of TCA
convulsions, coma, cardiac arrhythmias (3 C’s)
Fluoxetine
(Paroxetine, Sertraline, Citalopram, Escitalopram, Fluvoxamine)
SSRIs
most commonly prescribed antidepressants
very safe
MOA of SSRIs
selectively inhibit SERT and block reuptake of 5-HT into presynaptic terminal
increase synaptic 5-HT
also downregulate or desensitize presynaptic autoreceptors on serotonergic neurons
Side effects of SSRIs
short term: nausea, GI upset, diarrhea
long term: sexual dysfunction (30-40% of patients)
low risk of overdose
What cause delayed onset of SSRIs?
acute desensitization of 5-HT1A receptors lead to decrease firing from autoreceptors
returns to normal after 3 weeks
MOA of SNRIs
inhibit both serotonin (SERT) and norepinephrine (NET) transporters
blocks reuptake leads to more 5-HT and NE
unlike TCA not much affinity for other receptors (better side effect profile)
Venlafaxine
(SNRIs)
weak inhibition of NET
great affinity for SERT
used for SEVERE depression
Duloxetine
SNRIs
balanced SERT and NET blockade
increased used for chronic pain over TCAs
Altered neuroendocrine stress pathway
decreased hippocampus volume in depression
Esketamine (ketamine)
NMDA receptor antagonist
treatment of resistant MDD in conjunction with an oral antidepressant
Risk: sedation and dissociation, suicidal thoughts and behaviours
only available in a restricted distribution system
Ketamine MOA
NMDA receptor antagonist (block GABA release)
binds inside channel
rapid antidepressant effect (within 2 hours) last for over a week
given IV
increase glutamate (excitation)
Why is esketamine given over nasal spray
goes directly to brain
What cause rapid antidepressant effect of ketamine?
makes more synapses
increase spine density due to activation of mTOR
promote synaptogenesis through increasing BDNF
ketamine can block release of gaba
disinhibit release of glutamate
binds to AMPA to increase BDNF level
makes more synapses
Scopolamine
anticholinergic drug
High affinity at M1
reduce GABA release
disinhibit release of glutamate
Riluzole
block VG Sodium channel
reduce glutamate release
increase glial glutamate uptake
increase BDNF
increase synaptogenesis
however double blind clinical trial overall negative
