Antidepressants and Anxiolytics Flashcards
Describe how NE regulates 5HT transmission
NE can act as a brake on serotonin release when it binds to α2 (auto) receptors at the axon terminal and as an accelerator of serotonin release when it binds to α1 receptors at somatodendric regions.
Describe how 5HT can regulate NE and DA transmission
5HT2c receptors located upon GABA interneurons in the brainstem can inhibit NA and DA neuronal stimulation in the VTA and locus coeruleus -> including dopaminergic projection to the nucleus accumbens
What categorises depression?
- Reduced positive affect: deficiency of DA and NE ->decresed alertness, energy, enthousiasm, self-confidence and concentration, anhedonia
- Increased negative affect deficiency of 5HT (and some NE) -> rumination, guilt, disguist, anxiety, irritability etc
Why is depression not explained by the monoamine theory?
- 30 - 40% of patients are resistant to SSRI treatment
- not a biomarker
- monoamine depletion does not induce depressive symptoms in HC
Describe the HPA-axis
Hippocampus mediates the amygdala, which stimulates hypothalamus -> CRF -> pituitary -> ACTH -> adrenal gland -> cortisol -> negative feedback via glucocorticoid receptors that are present on:
- Hippocampus (thus tissue shrinkage causes less inhibition)
- Hypothalamus
- Pituitary
What are consequences of a GR impairment?
The GR function goes down and impairs negative feedback, CRF, ACTH and cortisol levels rise. Increased cortisol catabolic steroid reduces protein synthesis, including BDNF synthesis leading to hippocampal shrinking.
This causes a negative spiral of the stress response and over activation of the amygdala which results in patient becoming pessimistic and thread orientated.
What are affected brain regions in depression?
- Amygdala and ventromedial cortex are hyperactive.
- dlPFC is impaired.
- affects the BBB -> becomes more permeable
Describe the workings of tricyclic agents and their side effects
Inhibit reuptake of serotonin and norepinepherin (and also dopamine).
Most effective anti-depressabt
Has a lot of side effects because they:
-antagonise H1 (causing drowsiness, sedation and weight gain)
-α1 (drowsiness, orhtostatic hypotension)
M1 (in the brain, drowsiness)
-M3 (in the periferie, blurred vision, constipation and dry mouth)
-voltage gated sodium channel blockers (serious safety concerns in overdose; cardiac arrythmia, seizures and coma).
Describe the working of SSRIs
Antagonise SERT which improves increased negative affects but does not improve decreased positive affect.
Increases serotonin levels that interact with 5HT1a receptor and eventually increases dopamine release in mesolimbic system, as well as target 5HT1a receptors in the amygdala itself, regulating the hyperactivity -> stress relief
What are transient side effects of SSRIs?
- 5HT1abd (most sensitive) hetero receptors remain sensitive after chronic SERT inhibition
- 5HT2ac receotors downregulate after chronic SERT inhibition but initially are overactivated causing anxiety
- 5HT3 (ionotropic) downregulate after chornic SERT inhibition but initially overactivated and causes nausia
Explain the delayed onset of antidepressant action
High level of dendrite level serotonin (SERT inhibition) causes increased 5HT transmission to be attenuated due to dendritic 5HT1a auto-receptor action. However, chronic SERT inhibition cause 5HT1a autoreceptors to desensitise, impairing their function and ‘unmask’ the enhancement of post-synaptic 5HT transmission.
Another hypothesis arose from the observation that ketamine shows immediate effect. Maybe delayed onset of SSRIs is due to delayed desensitisation of NMDA receptors.
Give three examples of SSRIs
Fluoxetine -> long half life, 5HT2c antagonism
Sertraline -> also for anxiety, due to signma binding
Citalopram and escitalopram -> super selective SRI
Give an example of SNRIs and describe its anxiolytic effect
- venlafaxine (30:1) metabolised by CYP2D6 into desvenlafaxine (10:1)
Ratio describes Serotonine vs Norepinepherin uptake inhibition difference
NRIs -> inhibits NET which will first worsen anxiety symptoms due to increased NE but over time desensities α1 and β1 but not α2 which is in turn more favoured. α2 increased downstream effect is lowering BP, reduce anxiety, focused attention.
Describe the effect of MAO inhibitors and precautions.
Monoamine oxidase inhibitors cause build-up of extracellular availability of monoamines by inhibiting their breakdown.
MAO inhibitors also prevent the breakdown of tyramine, a by-product in the DA/NE side-pathway, which can also act upon the NET. If tyramine is consumed in big amounts, it may cause dangerously high blood pressure.
MAO inhibitors should not be combined with transporter inhibitors due to chance of dangerously high extracellular monoamines -> serotonin syndrom
Describe the serotonin syndrome, acute treatment and causes.
Caused by extreme high levels of serotonin and norepinepherine, may be induced by MDMA overdose. Can treat by cooling down patient and benzodiazepines to prevent movement heat generation.
Symptoms include hyperthemia, seizure, coma.
