Week 3 - Depression, Therapeutics and Antidepressants Flashcards
What are the 2 main nuerotransmitters relating to depression
- Serotonin
- 5HT neurones are located in raphe nuclei (axons project to many parts of brain)
REGULATES:
- sleep, food intake (↑/↓ weight), thermoregulation, pain, motor tone, sexual behaviour
- changes in 5HT is linked to symptoms seen in depression - Noradrenaline / Norepinephrine
- NA neurones are located in locus coerulus (axons project to many parts of brain)
REGULATES:
- alertness, arousal, sensory perception, motor tone
- ↑ NA in synapse = ↑ benefits of above
How is Serotonin (5HT) synthesised, stored, released & reuptaken and its MoA
5HT - 5 hydroxy-triptamine
SYNTHESIS:
1. Start with tryptophan
2. Tryptophan hydroxylase (enzyme) converts it into 5 hydroxy-tryptophan
3. Decarboxylase enzyme converts this into 5 hydroxy-tryptamine (5HT)
STORAGE:
- in vesicles in pre-synaptic terminals
MoA:
- released into synaptic cleft + activates many receptors (14)
- 5HT1 = inhibitory
- 5HT2 = excitatory
- 5HT3 = excitatory
- when activated = influx of Na+ = depolarisation
REUPTAKE:
- have SERT (serotonergic transporters) on pre-synaptic terminal
- removes 5-HT from from synapse
How is Noradrenaline (NA) / Norepinephrine synthesised, stored, released & reuptaken and its MoA
SYNTHESIS:
1. Start with tyrosine
2. Tyrosine converted into L-dopa which is converted into dopamine
3. Dopamine is converted into NA by enzyme (dopamine beta-hydroxylase)
STORAGE:
- in vesicles in pre-synaptic terminal
MoA
- when released into synapse they activate ADRENERGIC receptors on post-synaptic membrane
- inc. β-adrenergic (activated)
- inc. α2-adrenergic receptors (inhibited)
- IF ↑ NA levels in synapse = ↑ in alertness, arousal, motor rone, sensory perception etc.
REUPTAKE:
- NA transporters remove NA from synapse + take it back up into pre-synaptic terminal
- NA is recycled into vesicle
- OR NA is broken down by enzyme
What is depression and the 2 types of depression
When feelings (low, sad etc.) begin INTERFERING with your life AND do not go away OR goes and comes back frequently
- UNIPOLAR
- only experience depression
Includes:- major depressive disorder (MDD)
- postnatal depression (after birth)
- seasonal depression
- dysthmia (like MDD but lasts longer)
ALL above are treated simillarly
- BIPOLAR
- experience alternating periods of depression and mania
Depression misconceptions, epidemiology and other info.
- more women are affected than men
- with treatment, episodes last 3-6 months
- most people recover within 12 months
- risk of reocurrence is high + risk ↑ with every episode
- leading cause of disability
AIM: to treat depression and return mood to baseline + prevent relapse or reocurrence
What are the risk factors / causes for depression
Many causes + these vary between indiviuals, sometimes there may be no obvious reason
Cause an ↑ risk:
1. Life events / trauma
2. Genetic pre-disposition
3. Childhood experience
4. Loss / grief
5. Diet
6. Drugs / alcohol
7. Physical conditions
8. Side effects of medication
9. Chemical changes in brain (i.e. neurotransmission)
- lack of 5-HT - SSRIs - prevent reuptake
- lack of Monoamines (MA) - MAOIs - prevent break down of MA
How does depression present itself
symtoms, frequency etc.
- Core symptoms (at least 1)
- low mood / sadness
- anhedonia (loss of pleasure in things once enjoyed)
- Additional symptoms
- ↑ or ↓ sleep
- ↑ or ↓ appetite
- fatigue, loss of energy
- suicidal thoughts / acts
- agitation
- poor concentration, memory
- indecisiveness
- feeling guilt, worthless, hopeless
- Frequency
- most of the day
- for most days (of the week)
- for at least 2 weeks
How is depression diagnosed
Patient has to have:
- at least 1 core symptom
- AND 1 or more additional symptoms
- AT the stated frequency
- and its beginning to interfere with life
Diagnsoed using DSM-5
- questionnaire to gather info about symptoms, feelings, thoughts etc,
How is depression categorised
2 categories or 4 sub-groups
- “Less Severe”
a. Subthreshold- have 2-5 symptoms
b. Mild - have 5 symptoms + minor functional impairment
- have 2-5 symptoms
- “More Severe”
a. Moderate
- between mild + severe
b. Severe
- have most symptoms + marked functional impairment + with/without psychotic symptoms
NOTE: severity assess using PHQ-9
- as treatment progresses score patient again
NOTE: for all groups symptoms HAVE to inc. ONE CORE symptom to be diagnosed as depression
What are the basic princples when using antidepressants
- Rate of improvement is highest in first 2 weeks (in symptoms / mood) + lowest during weeks 4-6
- if NO benefits / intolerable SE after 3-4 weeks review treatment
- can take some weeks to start working, trial for 4 weeks (6 weeks for elderly)
- if beneficial will continue with it
- continue for min. 6 months after recovery to PREVENT relapse
- continue for min. of 2 years if had multiple episodes of depression
- REVIEW EVERY 6 months
- AFTER starting review WITHIN 2 weeks (1 week fo 18-25) for suicide risk
NOTE:
- Need to take it daily
- SE may get worse (at start) e.g. anxiety, agitation before it gets better (be aware)
- should NOT be stopped abruptly, need to taper dose down slowly
- can cause withdrawal symptoms, relapses, discontinuation syndrome
-
Explain sucide risk
AFTER starting antidepressants mist review WITHIN 2 weeks (1 week for 18-25) for suicide risk
- check for symptoms, ask patient
- if someone already has risk need to manage their treatment plan, monitoring
Advise patient:
- may have small ↑ risk at start of treatment and when treatment is stopped
- how to seek help
What are the current treatments for depression
3 groups
- Pharmacological - antidepressants
- SSRIs, SNRIs, MAOIs, Trycyclics
- Ketamine (NMDA receptor antagonist) ~ limited data
- Psychotherapy
- CBT, talking therapy, Counselling
- works well alongside pharmacological
- Physical Intervention
- ECT, deep brain stimulation, vagal stimulation
- AIM: reset neronal mechanism to improve symptoms
- have long waiting lists
List the 6 different classes of antidepressants
- SSRIs - selective serotonin reuptake inhibitors
- 1st line due to being more tolerated - SNRIs - selective noradrenaline reuptake inhibitor (2nd line)
- Trycylics
- MAOI - monoamine oxidase inhibitors
- Mirtazapine
- Vortioxetine
How does SSRIs work, side effects and drug examples
MoA: inhibit the reuptake of serotonin
- normally 5-HT is reuptaken into pre-synaptic terminal via SERTs
- BUT SSRIs inhibit SERTs = ↑ conc. of 5-HT in synapse = ↑ activation of 5-HT receptors on post-synaptic neurone
- this occurs immediately BUT effects arent seen for 2-4 weeks
SE:
- hyponatremia
- sexual dysfunction
- need to know if theyve had any dysfunction before beginning treatment
- GI issues
- ↑ risk of bleeding
- platelet function affected
- CONTRAINDICATION if patient is taking anticoagulants
- doesnt cause weight gain
- makes you alert (no drowsiness / sleepy) = take in morning
Examples:
- Citalopram (causes QT prolongation)
- Sertraline
- Fluoxetine
- Paroxetine
How does SNRIs work, side effects and drug examples
MoA: Inhibit reuptake of serotnin
SE:
- same as SSRIs (due to same MoA)
- CONTRAINDICATED in people with uncontrolled hypertension (makes BP worse)
Examples:
- Venlafaxine
- may get withdrawal symptoms
- ↑ risk of overdose due to short half life = avoid in patients with suicide risk
- Duloxetine
How does Tryclics work, side effects and drug examples
MoA: Inhibit reuptake of serotonin
SE:
- increases risk of falls (in elderly = avoid)
- blurred vision
- drowsiness
- effects on BP
Examples:
- Amtriptyline
- Nortriptyline
NOTE: ↑ risk of overdose, can have fatal cardiac effects e.g. QT interval prologation, arrythmia
How does MAOIs work, side effects and drug examples
MoA: inhibit MAO (enzyme) = prevents breakdown of serotonin, noradrenaline and tyramine
- MAOIs correct the lack of MA in synapse
- MAOIs prevent the breakdown of MA by MAO = ↑ MA activating reecptors on post-synaptic neurone
- this occurs immediately BUT effects arent seen for 2-4 weeks
SE:
- Hypertensive crisis
- caused if tyramine accumulates (can displace n.adrenaline)
Examples:
- Phenelzine
- Tranylcypromine
NOTE:
- not commonly used due to dietary restrictions
- advise patients to watch foods like cheese, marmite, alcohol intake (tyramine in these)
- requires specialist advice
How does Mirtazapine work and side effects
MoA: enhances NA and 5-HT neurotransmission
- inihibts reuptake of NA and 5-HT
- antagonises alpha-2 (and 1) adrenergic receptors
- antagonises H1 receptors = sedative effects
SE:
- sedation (wears off as dose increases)
- weight gain
NOTE:
- given to patients with trouble sleeping or gaining weight / decreased apetite
- monitor weigth, BMI, lipid profiles
- take with food to avoid GI disturbances
How does Vortioxetine work and side effects
Newer drug
Given if tried 2 other treatments + they failed
MoA: affects serotonin + other n.transmitters
SE:
- not known as its new
What is hyponatraemia (side effect)
Have lower (than normal) levels of sodium (Na) in blood
- check Na levels at baseline, 2 weeks, 4 weeks then every 3 months
- SSRIs and SNRIs have ↑ risk BUT its a risk for ALL antidepressants
- ↑ risk in first 2-4 weeks of treatment, reduces over time
- normal within 3-6 months
Risk increases if:
- elderly
- female
- have history of it
- on other medication causing it
- low body weight
- co-morbidities
What is serotonin syndrome (side effect)
Can occur within minutes to hours of starting antidedpressant
CAUSE: antidepressant blocks reuptake of serotonin = increase serotonin in synapse
If occurs:
1. Seek medical attention (medical emergency)
2. STOP antidepressant IMMEDIATELY
2. Allow antidepressant to be cleared from system before starting alternative treatment
Symptoms:
- agitation, anxiety, confusion, insomnia
- muscle rigidity, tremors
- hypertension, tachycardia
- nausea, diarrhoea
- dilated pupils
Why do anti-depressants take long for patients to see effects
NORMALLY:
- Raphe nuclei (in brainstem projects to frontal cortex) releases 5-HT into synapse
- 5-HT activates receptors on post-synaptic neurone
- 5-HT is removed from synapse via SERT
- Somatodendritic release of 5-HT from brainstem (NOT driven by AP)
- 5-HT released activates 5-HT1A autoreceptors on pre-synaptic cell body
- 5-HT1A regulates 5-HT release
- when autoreceptor are activated = reduced cell firing = DELAY in effects
AT START OF TREATMENT:
immediate MoA
- SSRIs block SERT = ↑ 5-HT in synapse = ↑ activation of 5-HT1A autoreceptor = ↓ cell firing = ↓ release of 5-HT into synapse
LATER IN TREATMENT:
long-term MoA
- get down-regulation of autoreceptor as patient uses anti-depressant longer (5-HT around cell body longer = overstimulation)
- ↓ in autoregulation = ↑ cell firing = ↑ 5-HT released into synapse = EVEN MORE 5-HT receptor activation (due to presence of SSRI preventing re-uptake)
NICE GUIDELINES for treating “less severe” depression
- Consider SSRIs (1st line)
- start with low dose
- review after 3-4 weeks, if improvement continue
- if no improvement can increase dose or change drug (in same class or in diff. class)
- Review every 6 months
- check adherance
NICE GUIDELINES for treating “more severe” depression
- Use SSRIs (1st line) alongside CBT
- start with low dose
- review after 3-4 weeks, if improvement continue
- if no improvement can increase dose or change drug (in same class or in diff. class) - Review every 6 months
How do you stop antidepressants and what do you need to be aware of
Antidepressants can NOT be stopped abruptly
- Review and discuss with patient
- Gradually reduce dose
- by 25-50% every 2-4 weeks - Inform patient about potential withdrawal symptoms
- more likely to occur with longer periods of treatment, higher doses, abrupt stopping
- severity can vary (mild to severe)
- if expereince symtpoms within days of stopping would re-introduce antidepressant again
What Monitoring is required for all antidepressants + Counselling
MONITORING:
- Mood, energy levels, sleep, behaviour changes
- If condition worsens or imporves
- Suicide risk
- DDIs and ADRs
- Risk of bleeding
- Weight, BMI, metabolic results e.g. blood glucose
- BP, heart rate etc.
- GI effects
- Sexual function
COUNSELLING:
- Risk of withdrawal when stopping
- To not stop treatment abruptly without medical attention
- Importance of adherance
- May take a couple weeks before see effects of treatment
- Drink fluids / stay hyrdated to prevent dry mouth
- Avoid alcohol can worsen SE
