Pharmacology of Depression Flashcards
What are the 5 most common, main drug classes prescribed for depression?
- Sertraline
- Citalopram
- Fluoxetine
- Venlafaxine
- Mirtazapine
What is the primary mechanism of action for Sertraline?
SSRI
Inhibition of serotonin reuptake results in an accumulation of serotonin
Serotonin in CNS = role in regulation of mood, personality, and wakefulness
What is the drug target site for Sertraline?
Serotonin transporter
What are the main side effects for Sertraline?
GI effects - nausea, diarrhoea
Sexual dysfunction
Anxiety
Insomnia
What is some extra information about Sertraline?
Mild inhibition of dopamine transporter
Must be gradually decreased on discontinuation.
Partial inhibition of CYP2D6 at high doses (150 mg)
What is the primary mechanism of action for Citalopram?
SSRI
Inhibition of serotonin reuptake results in an accumulation of serotonin
Serotonin in CNS = role in regulation of mood, personality, and wakefulness
What is the drug target site for Citalopram?
Serotonin transporter
What are the main side effects for Citalopram?
GI effects - nausea, diarrhoea
Sexual dysfunction
Anxiety
Insomnia
What is some extra information about Citalopram?
Mild antagonism of muscarinic and histamine (H1) receptors
Must be gradually decreased on discontinuation
Metabolized by CYP2C19.
What is the primary mechanism of action for Fluoxetine?
SSRI
Inhibition of serotonin reuptake results in an accumulation of serotonin
Serotonin in CNS = role in regulation of mood, personality, and wakefulness
What is the drug target site for Fluoxetine?
Serotonin transporter
What are the main side effects for Fluoxetine?
GI effects - nausea, diarrhoea
Sexual dysfunction
Anxiety
Insomnia
What is some extra information about Fluoxetine?
Mild antagonism of 5HT2A and 5HT2C receptors
Complete inhibition of CYP2D6 and significant inhibition of CYP2C19 (caution with warfarin)
What is the primary mechanism of action for Venlafaxine?
SNRIs
Venlafaxine is a more potent inhibitor of serotonin reuptake than norepinephrine reuptake
Noradrenaline in CNS = implicated in regulation of emotions and cognition
What is the drug target site for Venlafaxine?
Serotonin transporter
Noradrenaline transporter
What are the main side effects for Venlafaxine?
GI effects - nausea, diarrhoea Sexual dysfunction Anxiety Insomnia Hypertension - at higher doses
What is some extra information about Venlafaxine?
Must be gradually decreased on discontinuation
What is the primary mechanism of action for Mirtazapine?
Antagonises central presynaptic alpha-2-adrenergic receptors, which causes an increased release of serotonin and norepinephrine
Antagonises central 5HT2 receptors, which leaves 5HT1 receptors unopposed causing anti-depressant effects
What is the drug target site for Mirtazapine?
Alpha-2 receptor
5-HT2 receptor
What are the main side effects for Mirtazapine?
Weight gain
Sedation
What is some extra information about Mirtazapine?
Low probability of sexual dysfunction. May exacerbate REM sleep behaviour disorder
What is the 7-step process to a clinical scenario / consultation?
- Identify the patient’s problem
- Specify the therapeutic objective
- Select a drug on the basis of comparative efficacy, safety, cost and suitability
- Discuss choice of medication with patient (and carer) and make a shared decision about treatment
- Write a correct prescription
- Counsel the patient on appropriate use of the medicine
- Make appropriate arrangements for follow up (Monitor/stop the treatment)
Curtis Nash - 47M = recently diagnosed with hypertension and prescribed losartan (angiotensin 2 receptor blocker (25mg once daily). BP remains high at 147/91mmHg even after a month.
Low mood, anhedonia, low self-esteem. Difficulty getting to sleep, inability to think clearly, describing a ‘fog’ in his head. Symptoms persistent over a month, put a strain relationship with wife and job performance as a teacher.
Patient Health Questionnaire 9 (PHQ-9) = 9 item questionnaire designed to screen for depression in primary care.
Curtis scored 14/27
What is the patient’s problem?
He has MDD
He is moderately depressed according to his PHQ-9 score
So he has moderate MDD
What is the therapeutic objective for this patient?
- Alleviate his depressive symptoms - improve mood, anhedonia, sleep difficulties, self-esteem, think clearly
- Reduce likely functional impairment depressive symptoms on his daily life - improve relationship with wife and job performance (usually comes along with alleviating depressive symptoms)
Despite GP informing Curtis of the benefits of counselling, self-help programmes and CBT, Curtis wants a ‘pill’ to treat his depression.
GP informs him of different types of anti-depressants and their side effects. Recommends SSRI = fewer side effects. He is on anti-hypertensive (Losartan) and low dose erythromycin to treat chronic prostatitis.
What is the mechanism of action of SSRIs?
CNS serotonin AKA 5-HT = regulation of mood, personality, wakefulness
5-HT = 5-hydroxytriptamine 5-HTT = 5-hydroxytriptamine transporter
So the SSRIs inhibit the 5-HTT in the pre-synpatic neuron to increase the 5-HT in the synapse
More serotonin acts on the post-synaptic neuron, improving mood, personality and wakefulness
For SSRIs:
What is the target?
What is the location?
What is the effect?
5-HTT
On the pre-synaptic neuron
Increased serotonin availability
The three most commonly prescribed SSRIs are:
Sertraline
Citalopram
Fluoxetine
Considering Curtis’ medical history, which drug would you avoid?
Both, erythromycin and citalopram as they prolong the QT interval
This would not be good for his CV issues
GP prescribes sertraline, 50mg orally once a day. It takes some time to work, may experience side effects before this. Urges him to take it until his next appointment in two weeks.
The data above shows the effect of increasing the SSRI dose on (i) reduction in depression rating and (ii) dropouts due to adverse effects.
The study has established equivalence dosing e.g. 50mg sertraline is equivalent to 20mg fluoxetine.
What are the key take home messages from the data in the two dose response curves above?
First graph (i) = peak at 30 mg of fluoxetine, and then a plateau at higher doses (only a small improvement with the SSRIs alone)
Second graph (ii) = exponential increase in dropouts due to adverse effects
Why might the effectiveness of the SSRIs plateau after the peak dosage?
Receptor-saturation
Due to finite number of receptors, so there will be excessive 5-HT in the synapse as all the receptors are occupied
Curtis does not see an improvement with Sertraline. Why does the GP taper him off the sertraline slowly, and wait a period of time before starting the next drug?
Withdrawal symptoms or relapse if not slowly tapered off
Wash out period - without this may lead to ‘serotonin syndrome’ = too much excitability
Two regularly prescribed anti-depressants are venlafaxine and mirtazapine.
What are the drug targets for these?
Venlafaxine:
Transport proteins - serotonin transporter and noradrenaline transporter
Leads to increased serotonin and noradrenaline
Mirtrazapine:
Receptors - antagonist of the: Alpha-2 receptor, Histamine H1 receptor, 5-HT2 receptor and 5-HT3 receptor
Leads to increased noradrenaline
Affects on H1 receptor can make you drowsy but that may help with the sleep
Revisit Curtis’ presenting history. Which drug – venlafaxine or mirtazapine – should the GP prescribe next and why?
Venlafaxine = noradrenaline transporter inhibitor
Increased noradrenaline may increase BP, and may not help his sleeping difficulties
Mirtazapine = H1 antagonist = sedation
This can help his sleep and will not adversely affect his BP
Although it does suppress his REM sleep slightly
GP prescribes mirtazapine - 15mg, orally once daily. 4 weeks later, Curtis feels improvement.
Explain the data found in this table in terms of selectivity, affinity and efficacy:
Highest affinity H1 receptor = sedation Alpha-2 receptor = anti-depressant effect 5HT2 receptor = antidepressant effect 5HT3 receptor = anti-emetic Lowest affinity
Selectivity = not very selective
Affinity shows that sedative effects come in before anti-depressant and anti-emetic effects
At low doses = sedative effects
At higher doses = noradrenaline effects helps counteract sedative effects
Efficacy = no efficacy as they are antagonist, they block actions of receptors
Why does Curtis need to be monitored regularly?
Compliance - may be affected due to lack of libido, weight gain etc.
May start feeling better and stop taking them
