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Pharmacology of Depression Questions 1. Sandra is taking warfarin, 3mg once daily. Which of the following antidepressants should be prescribed with caution due to its effect on hepatic enzymes? A. Citalopram B. Venlafaxine C. Fluoxetine D. Sertraline E. Mirtazapine 2. Kara is a 46-year-old woman who presents with anhedonia, sleeping difficulties, appetite changes and low mood. The GP diagnoses moderate depression and is considering prescribing an anti-depressant. Two months ago, Kara saw the GP again for a checkup and was informed she has pre-diabetes. Name a side effect of mirtazapine that might make it less appropriate for this patient. (VSAQ) 3. David has recently been diagnosed with depression and was started on mirtazapine, 15 mg daily. He has been feeling drowsy and sleepy. Action at what receptor is responsible for this side effect? (VSAQ) 4. A patient who is taking sertraline, visits their GP as they have not seen significant improvement in their condition. The GP agrees to switch to mirtazapine. Which of the following is the most appropriate course of action? A. Immediately stop sertraline and take no anti-depressants for at least 3 weeks B. Lower dose of sertraline while introducing a low dose of fluoxetine C. Immediately stop sertraline and start a low introductory dose of fluoxetine D. Gradually decrease the sertraline dose and wait before introducing fluoxetine E. Decrease dose of sertraline and trial a high dose of fluoxetine to compensate 5. Four patients are taking different doses of antidepressant medications. Listed below are the doses and medication for each person. Which patient is most likely to experience sedation as a side effect first? • Luke – mirtazapine, 45mg per day • Maria – venlafaxine, 75mg per day • Georgia – mirtazapine, 15mg per day • Kade – venlafaxine, 150mg per day A. Luke B. Maria C. Georgia D. Kade 6. Name the complication that can occur if a patient is taking both sertraline and fluoxetine at high doses. (VSAQ) 7. A patient presents to hospital after fainting on his way to work. An ECG is performed which shows a prolonged QT interval. Which medication combination is the most likely cause of this finding? A. Sertraline and warfarin B. Citalopram and erythromycin C. Mirtazapine and citalopram D. Venlafaxine and aspirin E. Fluoxetine and apixaban 8. Antonio has recently been diagnosed with depression. He shared with his GP that he has been finding it very difficult to sleep lately. His GP considers prescribing mirtazapine at a low starting dose. Action at which of the following receptors will be most beneficial for Antonio’s sleeping problems? A. 5-HT2 B. H1 C. 5-HT3 D. Alpha-2 E. 5-HT4 9. Which structure/structures is a target for venlafaxine? (VSAQ) D A B C E10. Mike is a 50-year-old man who has recently been diagnosed with Major Depressive Disorder. Mike has agreed to trial some self-help resources but would prefer to also take medication to treat his symptoms. His GP is trying to decide which antidepressant would be most appropriate to prescribe. Mike is currently taking losartan (25mg, once daily) but his blood pressure is not well controlled. Which of the following medications would be suitable for Mike if taken at a high, regular dose? 1. Sertraline 2. Citalopram 3. Fluoxetine 4. Venlafaxine 5. Mirtazapine A. 1, 2 or 4 B. 2, 4, or 5 C. 2, 3, or 5 D. 1 or 3 only E. Any of the 5 SAQ – 10 points Clomipramine is a tricyclic antidepressant that inhibits serotonin and norepinephrine reuptake in presynaptic terminals. Sertraline, along with the other SSRIs, are currently preferentially prescribed over tricyclic antidepressants due to their increased selectivity. Question 1: The following graphs represent the number of dropouts due to adverse effects (y axis) over the dose prescribed (x axis). Assuming the doses have been standardised so that they can be compared, which graph represents sertraline and which one represents clomipramine? (2 points) Graph A Graph BQuestion 2: Name two side effects that can be caused by both drugs. (2 points) Question 3: How does the selectivity of a drug affect the occurrence of side effects? (3 points) Question 4: Venlafaxine is another commonly prescribed antidepressant. Describe the mechanism of action of venlafaxine. (3 points) Answers 1. Correct answer – C Refer to Insendi, Pharmacology > 10.6 – Core Drugs: “Complete inhibition of CYP2D6 and significant inhibition of CYP2C19 (caution with warfarin)”. Extra info for justification: CYP2D6 and CYP2C19 are both part of the hepatic cytochrome P-450 isoenzyme system. These enzymes play a significant role in drug metabolism and some medications can inhibit them, leading to impaired metabolism and excretion of certain medications. Warfarin is metabolised in part by CYP2C19 and fluoxetine can interfere with this isoenzyme leading to inhibition of warfarin metabolism. This can be dangerous for patients and negatively affect the balance between clotting and bleeding. The rest of the antidepressants are less likely to cause significant interactions with warfarin. 2. Correct answer – weight gain Weight gain is an important side effect of mirtazapine. In the context of pre diabetes, this is significant as higher weight is a risk factor for developing diabetes. 3. Correct answer – Histamine/H1 receptors Inhibition of H1 receptors by mirtazapine causes sedation as H1 receptors are mostly excitatory. This effect is more pronounced at lower doses of mirtazapine due to its high affinity for H1 receptors compared to Alpha-2, 5-HT2 and 5-HT3 receptors 4. Correct answer – D When switching from one antidepressant to another, it’s important to gradually decrease the dose of the current antidepressant and then take no antidepressants for a certain time period. This is called a ‘washout’ period and it depends on the half-life of the medication. If this process is not followed correctly, there is a risk of serotonin syndrome, withdrawal, relapse and drug interactions if a new medication is introduced too soon. 5. Correct answer – C Sedation is a known side effect of mirtazapine caused by the antagonism of H1 receptors. Mirtazapine has a high affinity for H1 receptors, so at a low dose (15mg), sedation will be the first side effect to occur as mirtazapine will preferentially bind H1 receptors. Option A is incorrect because the patient is taking a higher dose of mirtazapine. At higher doses, the plasma concentration of mirtazapine is high enough to bind alpha-2, 5HT2, and 5HT3 receptors. Therefore, the antihistamine effects of mirtazapine are counteracted by the noradrenergic effects which decrease sedation at the higher dose. Options B and D are incorrect because sedation aren’t the most likely side effects of venlafaxine. Instead, insomnia is more likely to occur due to the increased availability of noradrenaline. 6. Correct answer – Serotonin syndrome Both sertraline and fluoxetine are SSRIs, meaning that they increase the availability of serotonin. Too much serotonin in the CNS can cause this dangerous complication characterised by neuromuscular excitation, autonomic effects, and altered mental status. 7. Correct answer – B Both citalopram and erythromycin can prolong the QT interval. Refer to Insendi, Pharmacology > 10.7 – Tutorial Content 8. Correct answer – B Inhibition of H1 receptors by mirtazapine causes sedation as H1 receptors are mostly excitatory. This effect is more pronounced at lower doses of mirtazapine due to its high affinity for H1 receptors compared to Alpha-2, 5-HT2 and 5-HT3 receptors 9. Correct answer – B and C Venlafaxine is a serotonin and norepinephrine reuptake inhibitor and therefore blocks both serotonin and norepinephrine transporters. 10. Correct answer – C Out of the five drugs in this question, venlafaxine is the most likely one to cause hypertension and therefore interfere with the patient’s currently uncontrolled blood pressure. Options A, B and E are incorrect as they include venlafaxine. Option D is incorrect because citalopram and mirtazapine might also help the patient without significantly affecting their hypertension. SAQ – Question 1 Graph A: Clomipramine Graph B: Sertraline Explanation: The more selective a drug is, the less likely it is that it will bind to receptors other than the desired target and cause side effects. For example, a more selective serotonergic drug, will bind 5HT receptors more than noradrenergic or dopaminergic receptors. As it is less likely to bind to dopamine or noradrenaline receptors, it’s less likely to cause adverse effects related to increased dopamine or noradrenaline. Thinking about the graphs, we can infer that the less selective a drug is, the more side effects it will cause. Therefore, the number of dropouts will increase as the side effectsincrease. Side effects are more likely to occur at higher drug doses as the drug concentration increases and it starts binding other receptors. Looking at the two graphs, we can see that graph A is steeper and has a higher number of dropouts at the lowest dose. Graph B on the other hand, increases more gradually and has a lower number of dropouts at the lowest possible dose. Therefore, graph A is consistent with a less selective drug that would cause more side effects, such as clomipramine. Graph B is more consistent with a more selective drug such as sertraline. SAQ – Question 2 Any 2 from: nausea, diarrhoea, sexual dysfunction, anxiety, insomnia Both clomipramine and sertraline increase the availability of serotonin. This can cause the above side effects. You can refer to the drug tables on insendi and look at the side effects of SSRIs. SAQ – Question 3 The more selective a drug is, the less likely it is that it will bind to receptors other than the desired target (1 point) as the structure of the drug molecule is closer to that of the desired receptor (1 point). Low selectivity means that the drug can bind to other receptors and therefore cause effects other than the desired one (1 point). SAQ – Question 4 Venlafaxine blocks the reuptake of both serotonin and norepinephrine (1 point) by targeting the respective transporters at the pre-synaptic terminal (1 point) thus increasing the availability of serotonin and norepinephrine (1 point).