Depression - Treatment Flashcards
How can depression be treated? What is the main mechanism of action behind antidepressant?
non-pharmacological
- cognitive behavioural therapy
= based on helping depressed individuals to recognise and change their negative cognitive processes
- interpersonal therapy
= assumes that depression is multi-factorial but that interpersonal difficulties play a central role in maintaining depressive symptoms
pharmacological
- monoamine oxidase inhibitors
- tricyclic antidepressant
- selective serotonin reuptake inhibitors
main mechanism of action
- is to increase dopamine, serotonin and noradrenaline levels (monoamines)
What are monoamine oxidase inhibitors?
work by inhibiting monoamine oxidase
- enzyme which breaks down monoamines
mechanism of action
- causes increased cytoplasmic noradrenaline and serotonin which leaks out
- increased levels are now found in the synaptic cleft
Which monoamine oxidase subtype do monoamine oxidase inhibitors act on?
inhibition of MAOa correlates with anti-depressant activity
- MAOa is more selective towards 5-HT meaning that 5-HT increases by a greater amount
5-HT > NA > DA
What are the types of MAOIs?
irreversible and non-selective MAOIs
- phenelzine
- isocarboxazid
can have adverse effects due to interactions with other drugs and foods
reversible MAOIs (RIMA) - moclobemide
are only used in severe depression when no other AD works
How can irreversible and non-selective MAOIs have adverse effects?
- phenelzine and isocarboxazid
consumption of foods with tyramine (dietary amine) such as cheese and wine
- tyramine acts as an indirect sympathomimetic stimulating the release of NA from vesicles by displacement
increased NA cannot be broken down so will cause
- increased heart rate, elevated blood pressure, severe hypertension
MAOIs are not selective
- reduce metabolism of opioids
- reduce metabolism of alcohol
What are the side effects of MAOIs?
postural hypotension which leads to dizziness
- peripheral accumulation of DA displace NA in vesicles
excessive central stimulation
- leds to tremors, excitement & insomnia.
overdose of MAOIs
- lead to convulsions
increased appetite and weight gain
- due to downregulation of 5HT receptor
antimuscarinic effects
- dry mouth, constipation, blurred vision, difficulty in micturition (urinating)
What are tricyclic antidepressants?
works by blocking NA & 5-HT transporter
mechanism of action
- accumulates in the synaptic cleft & activates neighbouring noradrenergic/serotonergic receptors
- causes downregulation of pre and postsynaptic receptors in in the long term
Why are TCAs considered dirty drugs?
they block other receptors and have drug interactions
- muscarinic receptors (anti-cholinergic, anti-muscarinic)
= constipation, blurred vision, dry mouth and drowsiness - histaminic receptors (antihistamine, H1 antagonist)
= weight gain & sedation - alpha adrenergic receptors (⍺ adrenergic antagonist iin medullary vasomotor center)
= lowers blood pressure, postural hypotension, tachycardia, dizziness
What are TCAs drug interactions?
metabolism of TCAs is inhibited by certain drugs
- SSRIs (compete for microsomal MAO), steroids
leads to TCA overdose (cannot be used with suicidal patients)
- heart attacks, convulsions, coma, respiratory depression
TCAs potentiate the effects of alcohol and anaesthetics
- cause respiratory depression
What types of people are TCAs contraindicated in?
TCAs cannot be used in those with dementia or the elderly
- causes confusion
TCAs cannot be used in those with cardiovascular disease
- can cause dysrhythmias as it blocks K+ channels
TCAs have a narrow therapeutic window so require frequent monitoring
What is the mechanism of action of TCAs?
block the NA and 5-HT transporters
- increased NA and 5-HT concentration means receptors are continuously bound
neurons are under stress due to excessive bindin g
- homeostatic mechanisms in an attempt to reduce binding
downregulation of receptors
- occurs pre and post synaptically
causes excess monoamines to flood out/leave the neurone
- takes several weeks to down regulate receptors as there is an initial increase in monoamine concentration
What are selective serotonin reuptake inhibitors? What is their mechanism of action?
blocks 5-HT transporter
- increases 5-HT concentration
increase in 5-HT in the synaptic cleft
bombarding and accumulation of 5-HT at the serotonergic receptors
- more activation pre and post synaptically
counter homeostatic mechanism
- downregulates and desensitises receptors pre and post synaptically
takes a few weeks to downregulate receptors
- therapeutic effect takes a few weeks (4-6)
What are the benefits and side effects of SSRIs?
benefits
- lack of anti-cholinergic effects and no cardiotoxicity
- broader therapeutic profile
side effects
- not as effective as TCAs at treating severe depression
- insomnia and sexual dysfunction
- nausea, GI distress, headache
- highest risk of hyponatraemia
- shorter half life = risk of withdrawal effects
- increased risk of suicidal behaviours if under 18
- increased violence due to 5-HT 3 receptor binding
What is the order of use of ADs?
1st line to last
SSRIs are 1st line
- better tolerated, less sedating and safer in overdose compared to TCAs
TCAs are 2nd line
- cardiotoxic (are dangerous in overdose - heart attack, respiratory depression)
MAOI
- rarely used now because of their adverse effects (postural hypotension, dizziness, anticholinergic effects and liver damage)
What are other antidepressants?
venlafaxine/duloxetine
- specific serotonin and noradrenaline re-uptake inhibitors (SNRI), should be considered for severe depression
- cardiac arrhythmias can be exacerbated with higher doses, which can also exacerbate hypertension
trazadone
- 5-HT2 antagonist and 5-HT reuptake inhibitor
- strong ⍺2 antagonist and H1 antagonist
= few side effects, sedative antidepressant
mirtazapine
- alpha adrenoceptor antagonist
- potent 5-HT2, 5-HT3 and H1 antagonist
= few side effects, sedative antidepressant
bupropion
- inhibits NA, DA uptake (transporters) but not 5HT uptake
- treats nicotine dependence (nAchR antagonist)
