Depression 2 Flashcards
What is the problem with the monoamine hypothesis but why do we still use it?
Overly simple, might be a secondary cause with other brain abnormalities
BUT
5ht has an influence on pain sensitivity, emotionality, responses to neg/positive events
Suicide victims and depressed people show lower 5-HT metabolites and precursors in the brain or in CSF/BLOOD which is indicative.
Describe polymorphisms to the SERT gene?
Short allele has reduced SERT function (higher 5ht in the synapse)
- forms of stress induced depression
- higher 5ht reducing firing via somatodendtritic autoreceptors in raphe
What do mice with reduced SERT functioning show? (Heterozygous for SERT)
Lower basal activity of raphe 5ht neurons?
How can you study how many 5ht receptors are expressed in the brain?
Receptor binding. Unmedicated depressed people show MORE postsynaptic 5ht2 receptors (compensatory because of low activity)
STUDY: antidepressants can downregulate these receptors
How can you study how well 5ht receptors are working?
Measure biological response to 5ht antagonists/agonists (like hormones)
STUDY: depressed people have reduced sensitivity to 5ht agonists (release less prolactin)
(with depression, 5ht mediated hormonal response is blunted, so receptors aren’t working as well)
- reversed with chronic antidepressants
What does acute SSRI treatment do? (1st few days)
SERT on terminal and body SO
at first, increases 5ht by blocking reuptake, but then increases somatodendritic autoreceptors too (net reduction of 5ht)
What does chronic SSRI treatment do?
autoreceptors are downregulated (reduce negative feedback) and postsynaptic cells are sensitized in PFC and hippo.
STUDY: after chronic SSRI treatment, artificial drugs are less effective at blocking the receptors
Describe NE’s role in depression.
NE: neuroendocrine, reward, attention, arousal, stress response
- NE metabolite/receptor studies unclear
- Depressed patients show increase in A2 receptors (autoreceptors, reducing NE release)
- Chronic treatment (NE or 5HT) downregulates B receptors (same as therapeutic onset)
Ne in locus and 5ht in raphe can talk to each other
Describe DA’s role in depression?
Anergia: reduced motivation
Triple monoamine uptake blockers being developed to try to block all 3 but don’t wanna be addictive like cocaine
How would you go about treating depression? (basics)
Double blind, placebo.
No drug is any better than the other (specific to the person)
- all need chronic administration
CBT can be just as effective (but its time consuming, costly and requries motivation)
- more effective when used in combination
SSRIs can be associated with increased suicide (causal and a bit more motivation to do it) - moniter patients very closely
Describe MAO inhibitors
First class of drug used.
Increases transmitter available for release.
- Inhibits things that metabolize NTs
- changes within hours but no relief for weeks.
Side effects:
- blood pressure, sleep, overeating
Dangerous: 1) combined with drugs than enhance NE (cold medicines)
2) Tyramine (watch what you eat, “the cheese effect”) cause it can lead to increased blood pressure.
Inhibit other liver enzymes (Cp450) that might interact with other drugs (alcohol, opiods, aspirin)
Describe Trycyclic antidepressants
Block presynaptic transporters to inhibit reuptake.
- have different effects on different patients, try a bunch and then see combos
Side effects:
1) Block histamine: cause sedation and fatigue
2) Anticholingergic: dry mouth, constipation, uriner etention, dizzyness, confusion memory loss, blurry vision.
3) Block A1 receptors (can lead to hypotension, tachycardia, arrhythmias, overdose!)
4) Low therapeutic index, fatalities occur at 10x normal dose. be very careful.
Describe SSRIs and their side effects
2nd generation antidepressants
- better side effects than the others
- increase in 5ht receptors
- but can lead to anxiety, movement disorder, nauesa, headache, insomnia, sexual dysfunction.
Serotonin syndrome
Physical dependence and withdrawal that can last weeks (but not a drug of abuse)
- fatigue, insomnia, vivid dreams, anxiety, agitation, irritability
What is serotnoin syndrome?
Dangerous effects when SSRIs combined with other 5ht agonists, or interfere with 5ht metabolism
- agitation, disorientation, ataxia, spasms, fever, shivering diarrhea, blood pressure and heart rate increase.
How do you treat treatment resistant depresssion?
Ketamine! (non competitive NMDA antagonist)
- work way quicker
- small doses (crutial) induce psychotic effects but then reduce symptoms in 70% of dreatment resistant patients
- lasts 1-3 weeks
- intranasal formula by physican
WHY does it work?
- increased excitation, potentiate AMPA receptor function via glutamate and DA release in PFC
- AMPA antagonists prevents the benefits of ketamine
- induces synaptic plasticity via aactivation of signalling cascades after acute effects have worn off
- ketamine metabolites contribute maybe?
