(pharm) pharmacology of depression

Question 1

what five drugs are commonly prescribed to treat depression?

Answer 1

sertraline

citalopram

fluoxetine

venlafaxine

mirtazapine

Question 2

explain the primary mechanism of action of sertraline

Answer 2

inhibition of serotonin transporter prevents serotonin reuptake from synapse

= accumulation of serotonin in synapse

= increased serotonin in CNS regulates mood, personality, and wakefulness

Question 3

what is the drug target for sertraline?

Answer 3

serotonin transporter

Question 4

what are the main side effects of sertraline?

Answer 4

gastrointestinal effects (nausea/diarrhoea)

sexual dysfunction

anxiety

insomnia

Question 5

aside from the serotonin transporter, what does sertraline also mildly inhibit?

Answer 5

dopamine transporter

Question 6

which liver enzyme does sertraline inhibit at high doses (150mg)?

Answer 6

partial inhibition of CYP2D6

enzyme involved in the metabolism of xenobiotics in the body

Question 7

how can sertraline treatment be discontinued?

Answer 7

must be gradually decreased on discontinuation

Question 8

explain the mechanism of action of citalopram

Answer 8

inhibition of serotonin transporter prevents serotonin reuptake from synapse

= accumulation of serotonin in synapse

= increased serotonin in CNS regulates mood, personality, and wakefulness

Question 9

what is the drug target for citalopram?

Answer 9

serotonin transporter

Question 10

what are the side effects of citalopram?

Answer 10

gastrointestinal effects (nausea/vomiting)

sexual dysfunction

anxiety

insomnia

Question 11

what does citalopram act as a mild antagonist for?

Answer 11

muscarinic and histamine (H1) receptors

Question 12

how can citalopram treatment be discontinued?

Answer 12

must be gradually decreased on discontinuation

Question 13

which liver enzyme metabolises citalopram?

Answer 13

CYP2C19

Question 14

explain the mechanism of action of fluoxetine

Answer 14

inhibition of serotonin transporter prevents serotonin reuptake from synapse

= accumulation of serotonin in synapse

= increased serotonin in CNS regulates mood, personality, and wakefulness

Question 15

what is the drug target for fluoxetine?

Answer 15

serotonin transporter

Question 16

what are the side effects of fluoxetine?

Answer 16

gastrointestinal effects (vomiting, nausea)

sexual dysfunction

anxiety

insomnia

Question 17

what does fluoxetine act as a mild antagonist for?

Answer 17

5HT2A and 5HT2C receptors

Question 18

which liver enzymes are inhibited by fluoxetine?

Answer 18

complete inhibition of CYP2D6 and significant inhibition of CYP2C19

Question 19

explain the mechanism of action of venlafaxine

Answer 19

more potent inhibitor of serotonin reuptake than noradrenaline reuptake

increased noradrenaline in the CNS regulates emotions and cognition

Question 20

what are the drug targets for venlafaxine?

Answer 20

serotonin transporter

noradrenaline transporter

Question 21

what are the side effects of venlafaxine?

Answer 21

gastrointestinal effects (nasuea, diarrhoea)

sexual dysfunction

anxiety

insomnia

hypertension (at higher doses)

Question 22

how can venlafaxine treatment be discontinued?

Answer 22

must be gradually decreased on discontinuation

Question 23

explain the mechanism of action of mirtazapine

Answer 23

antagonises central presynaptic alpha-2-adrenergic receptors = increased release of serotonin and noradrenaline

antagonises central 5HT2 receptors = so 5HT1 receptors are unopposed = anti-depressant effects

Question 24

what is the drug target of mirtazapine?

Answer 24

alpha-2 receptors

5HT2 receptors

Question 25

what are the side effects of mirtazapine?

Answer 25

weight gain sedation (low probability of) sexual dysfunction

Question 26

what can taking mirtazapine exacerbate potentially?

Answer 26

can possibly exacerbate REM sleep behaviour disorder

Question 27

what tool is used to screen for depression?

Answer 27

PHQ-9 (patient health questionnaire-9)

Question 28

what is PHQ-9?

Answer 28

patient health questionnaire 9 = tool used to screen for depression in suspected individuals in a primary care setting

Question 29

what does major depressive disorder incorpoate?

Answer 29

minor, moderate and severe depression

Question 30

what are the therapeutic objectives for a patient with a PHQ-9 score of 14?

Answer 30

PHQ-9 of 14 = indicative of moderate depression 1) alleviate symptoms of depression (e.g. disturbed sleep, impaired appetite, low mood) 2) reduce the impact of subsequent functional impairments (i.e. strained relationships, job)

Question 31

what are the three most commonly prescribed SSRIs?

Answer 31

- sertraline - citalopram - fluoxetine

Question 32

why are SSRIs preferentially prescribed compared to other antidepressants?

Answer 32

SSRIs have fewer side effects compared to other anti-depressants = as they are more selective with their target site of action

Question 33

what is the primary mechanism of action of SSRIs?

Answer 33

target = serotonin transporter location = pre-synaptic neurone effect = - inhibit the action of the 5HT transporter so the synaptic concentration of serotonin remains high - increased synaptic serotonin acts more on the 5HT receptors - increase regulation of mood + wakefulness

Question 34

why can citalopram not be prescribed in patients on erythromycin?

Answer 34

both medications prolong the QT interval (cannot take two or more drugs simultaneously that prolong the QT interval) risk factors for prolonged QT interval = increased age, female sex, cardiac disease, metabolic disturbances (e.g. hypokalaemia)

Question 35

what impact does increasing SSRI dose have on the therapeutic effect?

Answer 35

increasing SSRI dose increases therapeutic effect up until 30mg approximately after which it plateaus and at higher doses of serotonin, it causes a decrease in therapeutic effect

Question 36

what impact does increasing SSRI dose have treatment dropouts?

Answer 36

increasing SSRI dose exponentially increases the number of dropouts from treatment = due to the increasing severity of the adverse effects

Question 37

if we assume that the anti-depressant effects of SSRIs are solely due to their action at the serotonin transporter, how do we explain the plateau in the therapeutic effect with increasing dose?

Answer 37

eventually, at some point, all the serotonin produced in the pre-synaptic neurone has been maximally released = no more serotonin is available to be released

Question 38

compare the drug targets for venlafaxine and mirtazapine

Answer 38

venlafaxine = serotonin + noradrenaline transporter mirtazapine = alpha-2 adrenergic autoreceptors + 5HT2/3 receptors + H1 receptors

Question 39

why are patients weaned off SSRIs first before starting new anti-depressants?

Answer 39

when deciding to stop SSRI prescriptions, patients need to slowly decrease dose to nothing = risk of drug interactions, serotonin syndrome, withdrawal symptoms, relapse

Question 40

what does suddenly stopping SSRI prescriptions risk?

Answer 40

increased risk of serotonin syndrome, withdrawal symptoms, relapse and drug interactions

Question 41

how are the risks of stopping SSRIs suddenly avoided?

Answer 41

washout is required before starting a new drug = dose of SSRI is gradually decreased

Question 42

what is a washout period?

Answer 42

the waiting time of a few days or weeks after stopping the old drug before starting the new one = lets your body clear the old drug out of your system

Question 43

why is a washout period important?

Answer 43

lets your body clear the old drug out of your system

Question 44

what happens once the washout period is over?

Answer 44

usually you start with a low dose of the new drug

Question 45

what is the main side effect of venlafaxine?

Answer 45

hypertension | at high doses

Question 46

what are the adernergic effects of venlafaxine and at which doses do they appear?

Answer 46

at 150mg/day = adrenergic effects first appear at 300mg/day = apparent increase in blood pressure and increased heart rate

Question 47

what is the main side effect of mirtazapine?

Answer 47

mirtazapine modestly suppress REM sleep whilst still having a beneficial impact on sleep continuity and duration (due to its anti-histaminergic effects) = can be good for people w depression suffering from sleep disturbance

Question 48

list the possible drug targets for mirtazapine

Answer 48

1) histamine H1 receptor 2) alpha-2 adrenergic receptor 3) 5HT2 receptor 4) 5HT3 receptor

Question 49

describe the binding affinity of mirtazapine to each of its binding sites

Answer 49

from highest to lowest affinity: 1) histamine H1 receptor 2) alpha-2 adrenergic receptor 3) 5HT2 receptor 4) 5HT3 receptor

Question 50

what is the effect of mirtazapine binding to the H1 histamine receptor?

Answer 50

sedation | off-target effects

Question 51

what is the effect of mirtazapine binding to the alpha-2 adrenergic receptor?

Answer 51

anti-depressant effect | on-target effect

Question 52

what is the effect of mirtazapine binding to the 5HT2 receptor?

Answer 52

anti-depressant effect | on-target effect

Question 53

what is the effect of mirtazapine binding to the 5HT3 receptor?

Answer 53

anti-emetic effect | off-target effect

Question 54

what are the off-target effects of mirtazapine and how do they come about?

Answer 54

effects = sedation (H1) and anti-emetic effects (5HT3) highest binding affinity = increased risk of off target effects at low doses when mirtazapine binds to H1 or 5HT3 receptors

Question 55

what dose of mirtazapine is required to induce the sedative effect of mirtazapine?

Answer 55

sedation effect = histamine H1 receptor = highest binding affinity = so lowest dose required for sedative effect (better, undisturbed sleep)

Question 56

what dose of mirtazapine is required to induce the anti-emetic effect of mirtazapine?

Answer 56

anti-emetic effect = 5HT3 receptor = lowest binding affinity = so higher dose required for anti-emetic effect

Question 57

which side effect of mirtazapine would be induced first at a low dose and why?

Answer 57

at low doses, greatest impact on H1 receptors to which they have the highest binding affinity (higher than serotonergic receptors too) = mirtazapine preferentially blocks the histamine receptor over the serotonergic ones at low doses

Question 58

what is the impact/main side effect of mirtazapine at low doses and why?

Answer 58

preferentially blocks the histamine H1 receptor over the alpha-2 adrenergic receptor (next highest binding affinity) so main side effect = sedation = increased duration of sleep + increased sedation at low doses

Question 59

what happens to the sedating effect of mirtazapine at higher doses?

Answer 59

at higher doses, the antihistamine effect of mirtazapine is offset by its increased action in terms of noradrenergic transmission (alpha-2 adrenergic receptor) = reduces sedating effect overall