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Questions and Answers
Mirtazapine and trazodone are selective serotonin reuptake inhibitors.
False
Tricyclic antidepressants inhibit the reuptake of noradrenaline and 5-HT simultaneously.
True
Phenelzine and tranylcypromine are reversible monoamine oxidase inhibitors.
False
The full antidepressant effects of drug treatment are immediate, occurring within hours of the start of treatment.
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Selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of noradrenaline only.
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All three classes of antidepressant drugs have different efficacy in treating major depression.
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The half-life of most antidepressant drugs is around 12 hours.
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Single doses of antidepressant drugs produce negative biases in emotional processing in healthy volunteers.
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Tricyclic antidepressants are now preferred to SSRIs in the first-line treatment of depression.
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All SSRIs have an appreciable affinity for the noradrenaline uptake site.
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The half-life of fluoxetine is 24-48 hours.
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Desmethylsertraline is 10-50 times more potent than sertraline in inhibiting the reuptake of 5-HT.
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All SSRIs are less effective than tricyclic antidepressants for severely depressed patients.
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SSRIs can cause nausea in up to 50% of patients.
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Cardiovascular side effects are common with SSRIs.
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Long-term use of SSRIs has been associated with a decreased risk of osteoporotic fracture.
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SSRIs have been shown to significantly increase the risk of completed suicide in adults.
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The number needed to harm with SSRIs is lower than the number needed to treat.
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Fluoxetine has a half-life of about 12 hours.
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Escitalopram is marketed as being less effective than citalopram.
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Paroxetine is the least likely of the SSRIs to cause a withdrawal syndrome.
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Both citalopram and escitalopram are associated with a decreased QT interval.
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The half-life of fluoxetine's metabolite is about 24-48 hours.
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All SSRIs have an appreciable affinity for the noradrenaline uptake site.
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The risk of suicidal behaviour decreases significantly in the first 9 days of antidepressant treatment.
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The serotonin syndrome is a rare and benign interaction reported with SSRIs and MAOIs.
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All SSRIs have a similar pharmacokinetic profile and are equally likely to cause a withdrawal syndrome.
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The combination of SSRIs with anticoagulants such as warfarin does not increase the risk of clinically significant bleeding.
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Citalopram, escitalopram, and sertraline are more likely to cause pharmacokinetic interactions than fluvoxamine, fluoxetine, and paroxetine.
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The antidepressant effects of SSRIs are immediate, occurring within hours of the start of treatment.
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A slow withdrawal of SSRIs can be facilitated by switching to fluoxetine.
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Tricyclic antidepressants have a two-ringed structure with an attached side chain.
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Secondary amines have a higher affinity for the 5-HT uptake site than tertiary amines.
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Tricyclic antidepressants inhibit the reuptake of 5-HT only.
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Plasma level monitoring has a clearly established role in the use of tricyclics.
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Lofepramine is an SSRI.
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The recommended starting dose of SSRIs often needs to be increased to produce significant therapeutic benefit.
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Higher doses of SSRIs are always more effective in treating depressive disorder.
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Patients who are starting SSRIs do not need to be warned about the likely side effects.
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Anxiety and agitation during SSRI treatment always mean that the underlying depression is worsening.
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Small doses of trazodone cannot be used to help with sleep during SSRI treatment.
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Patients do not need to be reviewed frequently during the first few weeks of SSRI treatment.
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Lofepramine is a selective inhibitor of serotonin reuptake.
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Clomipramine is useful in treating major depressive disorder only.
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Tricyclic antidepressants have anticholinergic and antihistaminic properties.
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Lofepramine has been shown to be cardiotoxic in overdose.
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Tricyclic antidepressants can be safely combined with α2-adrenoceptor agonists such as clonidine.
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Withdrawal effects from tricyclic antidepressants can be severe and include nausea, anxiety, and insomnia.
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Tricyclic antidepressants can be safely used in conjunction with antiarrhythmic drugs, particularly amiodarone.
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Tricyclic antidepressants increase the action of warfarin.
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Agranulocytosis is not a contraindication to the use of tricyclic antidepressants.
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Tricyclic antidepressants should be started at a high dose and rapidly increased.
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The dose of amitriptyline to be aimed for is about 50 mg daily or above.
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ECG monitoring is not necessary when increasing the dose of amitriptyline above 225 mg daily.
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Maintenance therapy with amitriptyline for less than 6 months is recommended to reduce the risk of early relapse.
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The risk of recurrence of depression increases with the number of episodes that the patient suffers.
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Monoamine oxidase inhibitors are commonly used as first-line treatment for depression.
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MAOIs can be useful in refractory anxiety states.
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The therapeutic efficacy of MAOIs is well established.
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MAOIs can be used without adhering to strict dietary and drug restrictions.
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MAO- A and MAO- B have the same substrate specificity.
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Tranylcypromine is less likely to give rise to hypertensive crises compared to phenelzine.
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Isocarboxazid has more side effects than phenelzine.
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Phenelzine is the least widely used MAOI.
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Tranylcypromine is an amphetamine-like stimulant.
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MAO- A and MAO- B are encoded by the same gene.
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Tranylcypromine has a higher risk of dependence compared to phenelzine.
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The full MAO activity is restored within 12 hours of stopping moclobemide.
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The maximum dose of phenelzine used in the Medical Research Council study was 90 mg daily.
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Phenelzine, isocarboxazid, and tranylcypromine are reversible inhibitors of MAO-A.
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The incidence of hypertensive reactions is about 5% in patients who are taking MAOIs, even in those who have received dietary counselling.
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Moclobemide has a long half-life, which means its inhibition of MAO-A is longlasting.
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All MAOIs, including moclobemide, bind irreversibly to MAO-A and MAO-B.
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The doses of MAOIs used in the early investigations were likely too high, which led to the poor efficacy of MAOIs in depression.
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About 90% of all reported reactions between foodstuffs and MAOIs have followed the consumption of cheese.
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Phentolamine is used to treat hypertensive reactions caused by MAOIs and food interactions.
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Moclobemide and tyramine reactions are similar to those of non-selective MAOIs.
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The serotonin syndrome is a rare and benign interaction reported with SSRIs and MAOIs.
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The combination of MAOIs with tricyclic antidepressants is always safe and recommended.
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The use of oral nifedipine has been advocated as a treatment for hypertensive reactions caused by MAOIs and food interactions.
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The metabolism of carbamazepine, phenytoin, and other drugs that are broken down in the liver is slowed by MAOIs.
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The combination of tricyclic antidepressants and MAOIs is always contraindicated.
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Trazodone can be used to treat MAOI-induced insomnia at a dose of 200-300 mg.
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The clinical use of MAOIs in depression requires the patient to take a daily dose of 60 mg or more of phenelzine.
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The serotonin syndrome is a rare and benign interaction reported with SSRIs and MAOIs.
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Phenelzine is the only MAOI that can be used in combination with tricyclic antidepressants.
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The combination of MAOIs and tricyclic antidepressants is useful in patients with mild depression.
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Adding tricyclics to MAOIs is less likely to provoke dizziness and postural hypotension.
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The full antidepressant effects of MAOI treatment are immediate, occurring within hours of the start of treatment.
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The patient should be warned about the potential for MAOI-induced insomnia and weight gain when taking tricyclics with MAOIs.
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The response to MAOIs can often be gradual, taking several weeks or even months to feel better.
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Postural hypotension can be effectively managed by increasing the dose of MAOI.
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Withdrawal from MAOIs is not associated with anxiety and dysphoria.
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Insomnia is best managed by increasing the dose of MAOI.
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The use of support stockings is not a suggested measure to manage postural hypotension.
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Patients who respond to MAOIs typically stop therapy after a few weeks.
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Moclobemide is a type of tricyclic antidepressant.
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The therapeutic efficacy of moclobemide is well established in patients with severe depression and atypical depression.
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Agomelatine is a melatonin receptor antagonist and a 5-HT2C receptor agonist.
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The half-life of agomelatine is around 12 hours.
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Cimetidine increases the metabolism of moclobemide.
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The most common adverse effects of agomelatine are headache and insomnia.
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Agomelatine is often sedating and causes anxiety in patients.
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Mirtazapine is a potent antagonist at several 5-HT receptor subtypes, including 5-HT1 and 5-HT4 receptors.
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Trazodone has a long half-life of around 24 hours.
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Agomelatine should be given with potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin.
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Mirtazapine is a muscarinic cholinergic antagonist and is cardiotoxic.
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The effective dose of mirtazapine is usually between 50-100 mg daily.
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Trazodone is a selective serotonin reuptake inhibitor.
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Venlafaxine is classified as a selective serotonin reuptake inhibitor (SSRI).
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Trazodone has a negligible affinity for other neurotransmitter receptor sites.
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The extended-release formulation of venlafaxine reaches a peak plasma level after about 1.5 hours.
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Trazodone is less cardiotoxic than tricyclic antidepressants, but it has similar cardiotoxic effects in patients with cardiac disease.
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The most serious side effect of trazodone is nausea.
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Venlafaxine is more effective than placebo and of equal efficacy to other available antidepressant drugs, including tricyclic antidepressants and SSRIs.
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The usual starting dose of venlafaxine is 225 mg daily.
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Venlafaxine can cause postural hypotension but does not cause dose-related increases in blood pressure.
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The adverse-effect profile of venlafaxine is significantly different from that of SSRIs.
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Venlafaxine has a narrower dosage range than SSRIs.
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Upward titration of venlafaxine is not necessary in cases where there is insufficient response.
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Venlafaxine is less toxic than SSRIs in acute overdose.
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Sudden discontinuation of venlafaxine is not associated with troublesome symptoms.
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Venlafaxine should not be given concomitantly with CYP3A4 inhibitors.
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Venlafaxine is metabolized partly by CYP2D6.
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Venlafaxine can lower plasma potassium levels.
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Gradual dose reduction is recommended when discontinuing venlafaxine treatment.
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Venlafaxine produces significant effects on hepatic drug-metabolizing enzymes.
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Venlafaxine should be given concomitantly with MAOIs to enhance its effects.
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Duloxetine is about five times more potent in inhibiting the reuptake of noradrenaline than in inhibiting that of 5-HT.
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Vortioxetine produces a similar occupancy of brain 5-HT transporter sites as standard therapeutic doses of SSRIs at a dose of 10 mg.
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Duloxetine can decrease blood pressure.
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Vortioxetine has a half-life of about 12 hours.
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Combination of duloxetine with drugs such as lithium, triptans, and tramadol should be done with caution.
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Duloxetine is extensively metabolized to therapeutically active compounds.
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Vortioxetine is rapidly absorbed, with peak plasma concentrations being reached within 2 hours.
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Duloxetine has a similar adverse-effect profile to SSRIs, but does not cause sexual dysfunction.
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Vortioxetine is known to have a higher incidence of sexual dysfunction compared to other 5-HT reuptake blockers.
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Reboxetine is a selective serotonin reuptake inhibitor (SSRI).
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Reboxetine is metabolized by the liver, where it is a substrate for cytochrome P450 CYP2D6.
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The most common side effects of reboxetine are dry mouth, constipation, sweating, and urinary hesitancy.
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L-Tryptophan is a naturally occurring amino acid that is present in the normal diet, where most of it is used to synthesize 5-HT.
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Tryptophan hydroxylase, the enzyme that catalyses the formation of 5-HT from L-tryptophan, is normally saturated with tryptophan.
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L-Tryptophan is absorbed slowly, with plasma levels peaking about 8 hours after ingestion.
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Increasing tryptophan availability to the brain has no effect on 5-HT synthesis.
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Bupropion is structurally and pharmacologically similar to other antidepressants.
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The antidepressant effect of bupropion is inferior to that of SSRIs.
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Bupropion is more likely to cause sexual dysfunction and weight gain compared to SSRIs.
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Bupropion should be used in patients with a history of seizures or eating disorder.
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The risk of seizures with bupropion SR is higher than that seen with SSRIs.
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Bupropion can be safely combined with tricyclic antidepressants and antipsychotic drugs.
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Bupropion is a potent inhibitor of CYP2D6.
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Bupropion has been combined safely with MAOIs in the treatment of depression.
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The amount of L-tryptophan available for brain 5-HT synthesis is only affected by the proportion of L-tryptophan free in plasma.
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L-tryptophan has been shown to have a significant synergistic effect when combined with tricyclic antidepressants in all studies.
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The eosinophilia–myalgia syndrome (EMS) is caused by L-tryptophan itself.
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St John's wort is a well-established treatment for major depression and has a standardized preparation available.
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L-tryptophan has been shown to have a significant antidepressant effect when given alone in most studies.
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The combination of L-tryptophan with SSRIs has been shown to cause severe 5-HT neurotoxicity in all studies.
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St John's wort is known to cause severe cardiovascular side effects in most patients.
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L-tryptophan is contraindicated in patients with a history of severe muscle pain.
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Mirtazapine lacks cardiotoxicity and is relatively safe in overdose.
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Tricyclic antidepressants have no cognitive impairment as a side effect.
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Long-term use of tricyclic antidepressants has been fully evaluated for toxicity.
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Citalopram and escitalopram do not increase the QT interval.
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Venlafaxine is safer than SSRIs in overdose.
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Lofepramine is not relatively safe in overdose.
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Tricyclic antidepressants are not anticholinergic.
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Dyspepsia is a common side effect of SSRIs.
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Extrapyramidal reaction is a rare side effect of SSRIs.
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SSRIs can cause anorgasmia in patients.
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Diarrhea is a rare side effect of SSRIs.
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Sweating is a rare side effect of SSRIs.
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CYP 2C19 is inhibited by Fluoxetine (+++)
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Duloxetine is a strong inhibitor of CYP 1A2
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Fluvoxamine is a moderate inhibitor of CYP 2D6
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Paroxetine is a strong inhibitor of CYP 2C9
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Venlafaxine is a strong inhibitor of CYP 3A/4
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Study Notes
Antidepressant Drugs
- Can be divided into three main classes based on their acute pharmacological properties:
- Monoamine reuptake inhibitors (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), selective noradrenaline and serotonin reuptake inhibitors (SNRIs), and selective noradrenaline reuptake inhibitors (NARIs))
- Monoamine oxidase inhibitors (MAOIs)
- 5-HT2 receptor antagonists (e.g., mirtazapine and trazodone)
Mechanism of Action
- Acute effect of reuptake inhibitors and MAOIs: enhance the functional activity of noradrenaline and/or 5-HT
- Delay in onset of therapeutic activity may be due to:
- Pharmacokinetic factors (e.g., half-life of most antidepressant drugs is around 24 hours)
- Neuroadaptive changes in the brain triggered by acute potentiation of monoamine function
- Studies have implicated various mechanisms, including:
- Desensitization of inhibitory autoreceptors on 5-HT and noradrenaline cell bodies
- Increased production of neurotrophins (e.g., brain-derived neurotrophic factor (BDNF))
- Increased synaptogenesis and neurogenesis
Selective Serotonin Reuptake Inhibitors (SSRIs)
- Preferred over tricyclic antidepressants in the first-line treatment of depression due to:
- Better tolerability
- Lower toxicity in overdose
- Six SSRIs available for clinical use in the UK:
- Citalopram
- Escitalopram
- Fluoxetine
- Fluvoxamine
- Paroxetine
- Sertraline
- Pharmacological properties:
- Inhibit reuptake of 5-HT with high potency and selectivity
- Low affinity for other monoamine neurotransmitter receptors
- Pharmacokinetics:
- Absorbed slowly
- Peak plasma levels reached after 4-8 hours
- Half-lives range from 20-72 hours
- Eliminated primarily through hepatic metabolism
Efficacy of SSRIs in Depression
- Superior to placebo in treating major depression
- Generally as effective as tricyclic antidepressants
- May be less effective than tricyclics for more severely depressed patients, particularly inpatients
Unwanted Effects of SSRIs
- Gastrointestinal effects:
- Nausea (20% of patients)
- Dyspepsia
- Bloating
- Flatulence
- Diarrhea
- Neuropsychiatric effects:
- Insomnia
- Daytime somnolence
- Agitation
- Tremor
- Restlessness
- Irritability
- Headache
- Extrapyramidal side effects:
- Parkinsonism
- Akathisia
- Other effects:
- Sexual dysfunction
- Sweating
- Dry mouth
- Cardiovascular side effects (rare)
- Skin rashes
- Elevated liver enzymes
- Increased risk of osteoporotic fracture
SSRIs and Suicidal Behavior
- Risk of suicidal behavior may be greater in adolescents and children
- Increased risk of self-harm, particularly in the first 9 days of treatment
- Importance of close monitoring during early stages of treatment
Interactions with Other Drugs
- Pharmacodynamic interactions:
- Serotonin syndrome when combined with MAOIs, lithium, and tryptophan
- Increased risk of gastrointestinal bleeding with aspirin and non-steroidal anti-inflammatory drugs
- Pharmacokinetic interactions:
- Inhibition of hepatic cytochrome P450 enzymes by fluvoxamine, fluoxetine, and paroxetine
- Potential for clinically significant interactions with tricyclic antidepressants, antipsychotic agents, anticonvulsants, and warfarin
Treating Depressive Disorder with SSRIs
- The recommended starting dose of SSRIs is often sufficient to produce significant therapeutic benefit, and higher doses may not be more effective due to increased side effects.
- Patients should be warned about likely side effects, including nausea and restlessness during sleep, and potential anxiety and agitation early in treatment.
- Short-term treatment with a benzodiazepine may be helpful, particularly if sleep disturbance is a problem.
- Small doses of trazodone (50-150 mg) may also help sleep, but there are occasional reports of serotonin toxicity with this combination.
Clinical Use of SSRIs
- Patients should be reviewed frequently during the first few weeks of treatment, when support and advice are helpful both to maintain morale and to ensure compliance with medication.
- Improvements in rapport and initiative may be detectable early in treatment, and discussing these changes with the patient can be useful.
- Continuing treatment for at least 6 months lowers the rate of relapse, and SSRIs are effective in the prophylaxis of recurrent depressive episodes.
Tricyclic Antidepressants (TCAs)
- TCAs are useful agents due to their efficacy in severely ill depressed patients and those with treatment-refractory illness.
- TCAs are still used widely for the treatment of neuropathic pain syndromes at low doses.
Pharmacology of TCAs
- TCAs have a three-ringed structure with an attached side chain, and can be distinguished between tertiary amines and secondary amines.
- Tertiary amines (e.g., amitriptyline, clomipramine, and imipramine) have a higher affinity for the 5-HT uptake site and are more potent antagonists of α1-adrenoceptors and muscarinic cholinergic receptors.
- TCAs inhibit the reuptake of both 5-HT and noradrenaline, and have antagonist activities at a variety of neurotransmitter receptors.
Unwanted Effects of TCAs
- Anticholinergic effects include dry mouth, disturbance of accommodation, difficulty in micturition, constipation, and postural hypotension.
- Psychiatric effects include tiredness and drowsiness, insomnia, and acute organic syndromes.
- Mania may be provoked in patients with bipolar disorders, and generally, TCAs are not recommended for patients with bipolar illness.
- Cardiovascular effects include tachycardia, postural hypotension, and electrocardiogram changes, and ventricular arrhythmias and heart block can develop occasionally.
Withdrawal and Toxic Effects of TCAs
- TCAs should be withdrawn slowly if at all possible, and sudden cessation may be followed by nausea, anxiety, sweating, and insomnia.
- In overdosage, TCAs produce a large number of effects, including cardiovascular, sedative, and respiratory effects, and urgent expert treatment is required.
Interactions of TCAs with Other Drugs
- TCAs antagonize the hypotensive effects of α2-adrenoceptor agonists, but can be safely combined with thiazides and ACE inhibitors.
- TCAs can lead to hypertension with systemically administered noradrenaline and adrenaline, and should not be used in conjunction with antiarrhythmic drugs, particularly amiodarone.
- Plasma levels of TCAs can be increased by numerous other drugs, including cimetidine, sodium valproate, calcium-channel blockers, and SSRIs.
Contraindications of TCAs
- Contraindications include agranulocytosis, severe liver damage, glaucoma, prostatic hypertrophy, uncontrolled epilepsy, and significant cardiovascular disease.
- TCAs must be used cautiously in epileptic patients and in the elderly.
Monoamine Oxidase Inhibitors (MAOIs)
- MAOIs are useful antidepressants, often producing clinical benefit in depressed patients who have not responded to other medication or ECT.
- MAOIs can be useful in refractory anxiety states, but their use has been less widespread due to dietary and drug restrictions to avoid reactions with tyramine and other sympathomimetic agents.
Pharmacological Properties of MAOIs
- MAOIs inactivate enzymes that oxidize noradrenaline, 5-HT, dopamine, and tyramine, and other amines that are widely distributed in the body as transmitters, or are taken in food and drink or as drugs.
- There are two forms of MAO: type A and type B, encoded by separate genes.
- MAO-A metabolizes intraneuronal noradrenaline and 5-HT, while both MAO-A and MAO-B metabolize dopamine and tyramine.
Compounds Available
- Phenelzine is the most widely used and widely studied compound.
- Isocarboxazid is reported to have fewer side effects than phenelzine and can be useful for patients who respond to the latter drug but suffer from its side effects.
- Tranylcypromine differs from the other compounds in combining the ability to inhibit MAO with an amphetamine-like stimulating effect.
- Moclobemide differs from the other compounds in selectively binding to MAO-A, which it inhibits in a reversible way.
Pharmacokinetics
- Phenelzine, isocarboxazid, and tranylcypromine are rapidly absorbed and widely distributed.
- They have short half-lives (about 2-4 hours) and are quickly metabolized in the liver by acetylation, oxidation, and deamination.
- People differ in their capacity to acetylate drugs, which may affect the metabolism of MAOIs.
Efficacy of MAOIs in Depression
- MAOIs are superior to placebo and are generally equivalent to tricyclic antidepressants in their therapeutic activity.
- Doses of up to 90 mg daily may be needed to achieve a therapeutic response.
Unwanted Effects
- Common side effects include dry mouth, difficulty in micturition, postural hypotension, confusion, mania, headache, dizziness, tremor, paraesthesia of the hands and feet, constipation, and oedema of the ankles.
- Hydrazine compounds can give rise to hepatocellular jaundice.
Interactions with Foodstuffs
- Some foods contain tyramine, which can cause hypertensive reactions when MAO is inhibited.
- Important early symptoms of hypertensive reactions include a severe and usually throbbing headache.
- The incidence of hypertensive reactions is about 10% in patients who are taking MAOIs, even in those who have received dietary counselling.
Interactions with Drugs
- Patients who are taking MAOIs must not be given drugs whose metabolism depends on enzymes that are affected by the MAOI.
- These drugs include sympathomimetic amines, L-dopa, dopamine, and certain opiates and insulin.
- The ability of MAOIs to cause postural hypotension can increase the hypotensive effects of other agents.
The Serotonin Syndrome
- A number of drugs that potentiate brain 5-HT function can produce a severe neurotoxicity syndrome when combined with MAOIs.
- The main features of this syndrome include myoclonus, nystagmus, headache, tremor, rigidity, seizures, irritability, confusion, agitation, hypomania, and coma.
Contraindications
- These include liver disease, phaeochromocytoma, congestive cardiac failure, and conditions that require the patient to take any of the drugs that react with MAOIs.
Clinical Use of MAOIs in Depression
- Treatment should start with a low dose (15 mg daily) and increase gradually to a maximum dose of 90 mg daily.
- Patients should be given clear written instructions about foods to be avoided and should be warned to take no other medication unless it has been specifically checked with a pharmacist or doctor who knows that the patient is taking MAOIs.
- The response to MAOIs can often be sudden, and patients should be monitored for signs of developing hypomania.
MAOIs
- MAOIs can have a sudden response, with patients feeling better within a day or two
- Dose reduction can help manage side effects, such as insomnia and postural hypotension
- Insomnia can be managed by reducing the dose of MAOI, or adding a benzodiazepine or trazodone (50-150mg at night)
- Postural hypotension can be managed with dose reduction, support stockings, increased salt intake, or mineralocorticoids
- Withdrawal from MAOIs can lead to anxiety and dysphoria, and sudden cessation can lead to more severe symptoms
- Gradual withdrawal is recommended, and patients should wait 2 weeks before stopping irreversible MAOI treatment and easing dietary restrictions
Moclobemide
- Moclobemide is a reversible type A MAOI with advantages over conventional MAOIs, including freedom from tyramine reactions and quick offset of activity
- Moclobemide is better tolerated than tricyclic antidepressants or irreversible MAOIs, but side effects still occur in 20-30% of patients
- Starting dose of moclobemide is 150-300mg daily, increasing to 600mg over several weeks as needed
- Treatment-resistant patients may require higher doses, but above 900mg daily, usual MAOI dietary restrictions apply
- Moclobemide interactions include serotonin syndrome with SSRIs, venlafaxine, or clomipramine, and adverse reactions with opiates, sympathomimetic amines, and L-dopa
Agomelatine
- Agomelatine is a more recently licensed antidepressant with a melatonin receptor agonist and 5-HT2C receptor antagonist mechanism of action
- Agomelatine has a short half-life of 2 hours and low bioavailability, requiring once-daily dosing at 9.00 pm
- Efficacy is comparable to venlafaxine and paroxetine, but long-term efficacy is not well established
- Common side effects include nausea, dizziness, somnolence, insomnia, anxiety, and fatigue
- Serious side effect: increased liver enzymes (ALT and AST), requiring liver function tests before and during treatment
Mirtazapine
- Mirtazapine is a quadricyclic compound with complex pharmacological actions, including 5-HT2 and 5-HT3 receptor antagonism, and histamine H1 receptor antagonism
- Mirtazapine has a sedating profile, but is not anticholinergic and is relatively safe in overdose
- Pharmacokinetics: well-absorbed, peak plasma levels in 1-2 hours, half-life of 16 hours, and daily dosing is possible
- Efficacy: demonstrated in both placebo-controlled and comparator trials, with effective doses between 10mg and 45mg daily
- Common side effects include drowsiness, dry mouth, increased appetite, and body weight gain
- Serious side effect: leucopenia, requiring vigilance for possible signs
Trazodone
- Trazodone is a triazolopyridine derivative with complex actions on 5-HT pathways, including 5-HT2 receptor antagonism and α1-adrenoceptor antagonism
- Pharmacokinetics: short half-life (4-14 hours), metabolized to active metabolite m-CPP
- Efficacy: superior to placebo, with effective doses between 150mg and 600mg daily
- Common side effects include excessive sedation, nausea, dizziness, and postural hypotension
- Serious side effect: priapism, a rare but serious reaction, requiring urgent medical attention
Venlafaxine
- Venlafaxine is a phenylethylamine derivative, a selective serotonin and noradrenaline reuptake inhibitor (SNRI)
- Pharmacokinetics: well-absorbed, peak plasma levels in 1.5-2 hours, half-life of 3-7 hours, with extended-release formulation reaching peak levels in 6 hours
- Efficacy: more effective than placebo and comparable to other antidepressant drugs, with effective doses between 75mg and 375mg daily
- Common side effects include nausea, headache, somnolence, dry mouth, dizziness, and insomnia
- Serious side effects include postural hypotension, blood pressure increases, and potential interactions with other medications
Venlafaxine
- Associated with cardiac arrhythmias, so avoid using in patients with significant cardiac disease
- Can lower plasma sodium levels like SSRIs
- May be less well tolerated than SSRIs
- More toxic than SSRIs in acute overdose
- Suddenly stopping venlafaxine can cause troublesome symptoms like fatigue, nausea, and dizziness
- Recommended to gradually reduce dose over at least 1 week before stopping
Duloxetine
- Classified as an SNRI
- More potent in inhibiting 5-HT reuptake than noradrenaline reuptake
- Little effect on other neurotransmitter receptors
- Pharmacokinetics: well absorbed, peak blood levels at 6 hours, half-life of 12 hours
- Efficacy: superior to placebo, equivalent to SSRIs
- Unwanted effects: nausea, dry mouth, dizziness, insomnia, somnolence, and sexual dysfunction
- Suddenly stopping duloxetine can cause troublesome symptoms
- Drug interactions: inhibits CYP2D6, increasing blood levels of other drugs
Vortioxetine
- Blocks 5-HT reuptake and antagonizes 5-HT receptors
- Produces complex effects on 5-HT neurotransmission
- Pharmacokinetics: slowly absorbed, peak plasma concentrations at 7-11 hours, half-life of 65 hours
- Efficacy: superior to placebo at doses of 10-20 mg
- Unwanted effects: nausea, vomiting, diarrhea, constipation, dizziness, and pruritis
- Drug interactions: similar precautions to SSRIs, avoid concomitant treatment with MAOIs
Reboxetine
- Selective noradrenaline reuptake inhibitor (NARI)
- Pharmacokinetics: peak plasma levels at 2 hours, half-life of 13 hours
- Efficacy: reportedly shows efficacy in placebo-controlled trials and against active comparators
- Unwanted effects: dry mouth, constipation, sweating, and insomnia
- Drug interactions: limited information available, avoid concomitant treatment with MAOIs and ergot derivatives
L-Tryptophan
- Natural amino acid present in diet
- Increases brain 5-HT synthesis
- Pharmacokinetics: rapidly absorbed, peak plasma levels at 1-2 hours
- Efficacy: weak evidence for antidepressant activity, may be superior to placebo in moderately depressed outpatients
- Unwanted effects: nausea, drowsiness, and eosinophilia–myalgia syndrome (EMS)
- Drug interactions: similar to MAOIs, increases brain 5-HT function
St John's Wort
- Extract from the plant Hypericum perforatum
- Active principles: hypericins and hyperforins
- Pharmacology: potentiates monoamine neurotransmission
- Efficacy: more effective than placebo, equal in efficacy to other antidepressants
- Unwanted effects: gastrointestinal disturbance, dizziness, and tiredness
- Drug interactions: induces hepatic enzymes, lowering levels of other drugs
Bupropion
- Structurally and pharmacologically distinct from other antidepressants
- Enhances dopamine and noradrenaline function in the brain
- Efficacy: superior to placebo, equivalent to SSRIs
- Unwanted effects: insomnia, agitation, tremor, and nausea
- Drug interactions: inhibits CYP2D6, increasing blood levels of other drugs
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Description
Classify antidepressant drugs into three main classes based on their acute pharmacological properties. Learn about monoamine reuptake inhibitors, monoamine oxidase inhibitors, and more.
