Depression Flashcards
True/False? Antidepressants are the best-selling drugs on the market
True
True/False? Major depression is an affective disorder
True
Define Monozygotic concordance
The chance of having the same illness if your identical twin has it (confers genetic linkage)
True/False? Depression is not a chronic relapsing disorder
False
After a first episode, almost 70% will have at least one more episode within 5 years
List the 3 different types of major depressive disorder
Reactive depression
- specific stress - responds well to antidepressants
Endogenous (melancholic) depression
- no obvious external cause - often runs in families
Atypical depression (not covered in course)
Where does the term “melancholy” come from?
Melan + choly
black bile
The notion that moods were based off the 4 humors
According to the monoamine hypothesis of depression, what causes depression?
A deficit in monoamine transmission (at certain sites in the brain
How was the monoamine hypothesis of depression founded?
Based on drugs that appeared to relieve and cause depression
What are the monoamines targeted by the monoamine hypothesis of depression?
Noradrenaline, NA
5-hydroxytryptamine (serotonin)
Describe the NA synapse
- Tyrosine is converted to DOPA, which is converted to Dopamine (DA), which is then converted to Noradrenalin (NA)
- NA is the released from the presynaptic neuron and acts on receptors of the postsynaptic neuron and autoreceptors of the presynaptic neuron (-ve feedback)
- NA is then reuptaken into the presynaptic terminal by NAT where it can either be reused, or metabolised by Monoamine Oxidase (MAO)
What is reserpine and what was it reported to do?
Found in snakeroot:
Antihypertensive
Caused depression
Depletes monoamine transmitters
Blocks vesicular monoamine transporter (sends monoamine out of the presynaptic neuron, different from NAT)
What is Iproniazid and what does it do?
Monoamine Oxidase inhibitor: blocks MAO so that more reuptaken NA can be released per vesicle
What is Imipramine and what does it do?
Tricyclic antidepressant:
blocks plasmalemmal NET/NAT, which causes more NT in synapse, which causes more APs at postsynapse
True/False? Imipramine depletes NA
False
What were Axelrod’s 2 experiments, and what were the results?
1) Give normal mouse and SNS-lesioned mice and give labelled NA - accumulation in sympathetic innervation (must be some sort of NA pump)
2) Take same mice and give NA, measure BP - slight increase in intact rat, large increase in denervated rat (no organs to receive NA, all ends up at brain postsynaptic receptors)
What are 2 consequences of inhibiting NA reuptake?
Decreased Recycled NA - less in release vesicles
Increased autoreceptor-mediated inhibition of NA release
True/False? Iproniazid blocks metabolism of NA and 5-HT
True (some MAOIs are more selective)
Name one brand name of fluoxetine
Prozac
What is fluoxetine and what does it do?
Selective Serotonin Reuptake Inhibitor
Blocks SERT more than NET
What does reserpine actually do?
Blocks vesicular pump (not selective for DA/NA/5-HT
What are three facts that support the monoamine hypothesis?
- Low 5-HIAA (5-HT metabolite) in suicide attempters CSF
- Increased 5-HT1A autoreceptors in suicide victims
- Drugs that improve/worsen mood have mechanisms that follow the hypothesis
What are 3 ways to worsen mood?
- Take reserpine (maybe)
- Tryptophan-free diet (only if you’re at risk for depression)
- alpha-methyl-para-tyrosine
What are the three main problems with the monoamine hypothesis?
- not all drugs “agree” with the hypothesis
- Therapeutic effect is delayed
- Logical issue
True/False? Reserpine causes depression
False
The study had small n, uncontrolled trials
Which 4 drugs do not agree with the monoamine hypothesis?
L-DOPA: increases NA synthesis (should be AD but isn’t)
Drugs that should be depressant but aren’t:
- Reserpine
- 5-HT antagonists
- NA antagonists (alpha/beta blockers)
Define the therapeutic delay and its average value
The time difference between plateau of AD levels in blood and rise in mood level, typically 3-6 weeks
Describe a logical issue and give an example
The treatment is known but its origin is not.
eg. asthma, something causes asthma, beta adrenoreceptor agonists happen to fix it (the problem doesn’t have to do with beta-adrenoceptors)
True/False? We can map “where” depression happens in the brain
False
Define a synaptome
A pinched off nerve terminal
How would one use a synaptome to measure reuptake blockage?
Apply labelled NA with(out) test drug, isolate synaptosomes, count NA
True/False? Synaptomes metabolize drugs
False
True/False? NA and 5-HT pathways interact physiologically
True, either directly or indirectly (through other types of neurons)
What is microdialysis and how is it used?
Drilling a hole in the skull and measuring concentrations in CSF
Used to “eavesdrop” on the brain and measure NT concentrations
How do antidepressants work chronically? (3 effects)
- Decreased beta adrenergic receptors (but we don’t know why)
- Decreased 5-HT autoreceptors (increased 5-HT transmission)
- Decreased alpha2 adrenergic autoreceptors (increased NA transmission)
What is a consequence of acute SSRI?
Inhibition of 5-HT reuptake, slight increase in 5-HT release
What is a consequence of chronic SSRI
Downregulation of autoreceptors, fewer negative feedback, huge increase in 5-HT release
True/False? Neuron dendrites release Neurotransmitters
True
Do antidepressants need NA or 5-HT in order to be clinically effective?
Kinda. You need to boost one or the other
Why does a low-tryptophan diet exacerbate depression?
Trp is the precursor to 5-HT
True/False? Tryptophan has antidepressant effects on its own
True (mild tho)
True/False? 5-HT depletion worsens mood in most non-patients (or in patients on selective NAT-blocking drugs)
False
What happens if you take NAT-selective blockers chronically and acutely challenge with a) AMPT, which depletes NA, and b) low TRP, which depletes 5-HT?
a) worsens mood
b) no change
What happens if you take SERT-selective blockers chronically and acutely challenge with a) AMPT, which depletes NA, and b) low TRP, which depletes 5-HT?
a) no change
b) worsens mood
What is the most prescribed antidepressant and why?
SSRIs, cause they tend to work better
True/False? Most TCAs are prescribed for depression
False
What are two things that determine clinical effectiveness?
Efficacy (how much does the patient improve on the drug?)
Compliance (will the patient take the drug reliably?)
True/False? Half of patients who begin therapy will be well one year later
True
True/False? NET and SERT blockers are partially effective
True
What are 6 Adverse effects of antidepressants?
- Postural hypotension (cause uncertain)
- Dry mouth (musc. ACh receptor block)
- The cheese reaction
- Agitation
- Sexual Dysfunction
- Nausea
What is the cheese reaction?
Tyramine (found in cheeses) is broken down in the gut by MAOs. Taking a MAOI will inhibit all MAO, not just the ones in the brain, which leads to an excess of tyramine in the blood, which raises blood pressure
What are 4 adverse effects of TCAs?
- Initial sedation, confusion, incoordination
- Antagonization of certain receptor types
- Sedation (histamine H1)
- Dry mouth etc (musc. ACh)
- Drug interactions
- aspirin (plasma binding proteins)
- steroid drugs reduce TCA breakdown (compete for P450)
- STRONGLY potentiate ethanol’s effect (dangerous)
- Overdose
- Convulsions, then coma
- cardiac arrhythmias
What is/are the adverse effect/s of SSRIs?
5-HT syndrome
List the 3 antidepressant drugs in terms of their adverse effects
(worse) MAOIs > TCAs > SSRIs (best)
What drugs is proposed as a future antidepressant?
Ketamine
Botulinum toxin
Name a treatment for depression that is not drug-related
Electroconvulsive Therapy
What is the main issue with St. John’s Wort
Seriously dangerous drug-drug interactions
