L17 Antidepressants Flashcards
emotional symptoms
low mood, negative thought; loss of motivation, indecisiveness; low self-esteem
imipramine
block noradrenaline and serotonin uptake → improve mood in depressed schizophrenics
Monoamine theory of depression
a functional deficit of noradrenaline and serotonin in certain brain regions
↑ noradrenaline and ↑ 5-HT are equally effective as antidepressants (individual variation)
Monoamine theory of depression issue/limits
- pharmaco weeks not hours or minutes
BDNF (brain-derived neurotrophic factor)
- CNS development and neuronal plasticity
Neuroplasticity BDNF path to CREB
Prepro-bdnf
↓
Pro-bdnf
↓
Mature BDNF
↓Bind to TrkB (tropomypsin rec kinase B)
CREB (cAMP response element
↓
Gene expression
Neuroplasticity of depression involves decrease
BDNF levels in hippocampus/prefrontal cortex
Activity of CREB
transcriptional activity of CREB
↓
Promotes BDNF expression
↓
Causes neurogenesis in the prefrontal cortex and hippocampus
What happens to CREB activity when there is increased stress an cortisol levels
Suppresses he transcription activity of CREB therefore imparing BDNF expression and neurogenesis
What does cortisol and stress do to the prefrontal cortex and hippocampus
Can cause apoptosis in neurons
selective serotonin reuptake inhibitor (SSRIs)
fluoxetine
tricyclic antidepressants (TCAs)
imipramine
monoamine oxidase inhibitors (MAOIs)
- phenelzine
- moclobemide
Which drug has a fast onset of antidepressant effects
Ketamine
fluoxetine simple
- most prescribed antidepressants; first-line treatment
- binds to serotonin transporter and blocks the reuptake of serotonin,
Blocking 5-HT reuptake by drugs (fluoxetine) causes
Elevated synaptic [5HT] but decreased release
somatodendritic 5-HT1A receptor desensitisation + ↑ synaptic [5-HT] postsynaptic
5-HT1 receptor → antidepressant effects
Why does antidepressants take so long (Inhibit serotonin uptake)
Because desensitisation of receptors (5-HTa1) takes long
What is fluoxetine metabolised by
CYP2D6
What enzyme does fluoxetine inhibit
CYP2D6
What is serotonin syndrome
If fluoxetine is taked with another increaser of serotonin but via a different method it will increase via both methods
Fluoxetine Side effects
- agitation and insomnia (5 HT2 receptor)
- nausea (5-HT3 receptor)
- sexual dysfunction
Better adverse effect profile for Fluoxetine
lack of affinity for muscarinic acetylcholine receptors and histamine H1 receptors
Mirtazapine on receptor
a2-adrenoceptors antagonist
Mirtazapine as an antagonist
- inhibit alpha-2 adrenoceptors (central presynaptic) and enhance NA and 5-HT release
- Antagonist to 5-HT2 and 5-HT3 receptors
Mirtazapine side effects
- Histamine H1 antagonism - sedation
- Increase appetite and weight gain
- headaches
Good alternative if adverse effects of SSRIs are problematic
Mirtazapine
Tricyclic antidepressants function
bind serotonin and noradrenaline transporters and inhibit reuptake of 5-HT and noradrenaline → synaptic [5-HT] and [noradrenaline] ↑
Name 1 Tricyclic antidepressants
imipramine
imipramine half life and antagonism
- long half-life - repeated dosing ↑ risk of adverse effects
- muscarinic acetylcholine receptor antagonist - dry mouth, blurred vision
- histamine H1 receptor antagonist - sedation
- not to be combined with monoamine oxidase inhibitor
imipramine metabolite from CYP2C19
desipramine (active)
both parent and this can be further metabolised by CYP2D6
Monoamine oxidase inhibitor drugs
- Phenelzine
- Moclobemide
Monoamine oxidase inhibitors
inhibit monoamine oxidase type A and/or type B ⟶ cytoplasmic concentrations of monoamines ↑ ⟶ rate of spontaneous leakage of monoamines ↑
irreversible MAO-A and MAO-B inhibitor
non-selective, long acting
phenelzine* -
reversible MAO-A inhibitor
Short acting
moclobemide
Monoamine oxidase inhibitors effects
- atropine-like effects - dry mouth, blurred vision
- other drugs that ↑ serotonin levels
- ‘cheese reaction’ (drug-food interaction)
MAO inhibition + tyramine ingestine
Hypertension and headache by MAO would have metabolised Tyramine so it doesn’t go into circulation but MAO inhibited
Ketamine
a non-competitive NMDA receptor antagonist
Ketamine dose
one single subanaesthetic dose - rapid (within hours) and sustained (~24 hours), including in individuals with treatment-resistant depression
* BDNF release
Ketamine spray
nasal spray of Spravato (esketamine, the S-enantiomer) in conjunction with an oral antidepressant for treatment-resistant depression
Ketamine as a rapid acting antidepressant
–proposed mechanisms
* NMDA receptor inhibition
* on GABAergic interneurons (a)
* extrasynaptic (b)
* synaptic (c)
– BDNF translation or release ↑
